Ethical Considerations in Newer Reproductive
Technologies
Frank A. Chervenak*, Laurence B. McCullough†, and Zev Rosenwaks*
Ethics is an essential dimension of newer reproductive technologies. In this rapidly evolving field,
there is a need for an ethical framework to guide both clinical practice and research. In this article,
we provide such a framework that incorporates ethical principles, professional virtues, and the
concept of the fetus as a patient. We then apply this framework to an important current clinical issue:
the number of embryos to be transferred during in vitro fertilization; in addition to an emerging
research issue: gene transfer research on in vitro embryos.
© 2003 Elsevier Inc. All rights reserved.
thics, as it has been practiced for centuries
in all global cultures, is the disciplined study
of morality. Medical ethics has also existed for
centuries. The central question of medical ethics
is, What are the doctor’s moral responsibilities
to the patient, to health care organizations, and
to society?1 Throughout its history, medical ethics has successfully addressed many clinical controversies. It has accomplished this by using the
secular philosophical tools of ethical principles
and professional virtues to create clinically applicable ethical frameworks.2,3 The ethical
framework that we use in this article derives
from the history of medical ethics.
E
Ethical Principles
The ethical principle of beneficence has played
a central role in the history of Western medical
ethics since the time of Hippocrates. Beneficence identifies the physician’s responsibilities
to protect and to promote the health-related
interests of the patient, as these are understood
from a rigorous clinical perspective. The principle of beneficence includes the principle of nonmaleficence, sometimes known as primum non
nocere. The principle of respect for autonomy
entered the history of medical ethics in the 19th
and 20th centuries. This ethical principle identifies the physician’s responsibility to protect and
to promote the patient’s interest, as these are
understood from the patient’s perspective. The
principle of justice, developed since the 18th
century, identifies the physician’s responsibilities to protect and to promote the interests of
health care organizations and society, particu-
larly their economic interests in the allocation of
scarce resources.1,2
Professional Virtues
The professional virtues became prominent in
the 18th century in the English-language literature of medical ethics by 2 physician-philosophers, Dr. John Gregory and Thomas Percival.4-6
Their goal in writing and teaching medical ethics was to reform the market-driven, entrepreneurial, self-interested practice of medicine that
was the dominant practice model of their day.
Gregory and Percival called for a professional
life of service to patients grounded in the professional virtues of the physician as moral fiduciary of the patient. This concept requires that
the physician be scientifically and clinically competent and use his or her knowledge and skills
primarily to benefit the patient and not primarily to advance the physician’s self-interest. Professional virtues create moral responsibilities for
physicians by blunting self-interest and making
the patients’ interests the primary consideration
in the physician’s practice and research. Two
such virtues are especially relevant.1 Self-sacrifice
creates the responsibility to make reasonable
From the *Department of Obstetrics and Gynecology, Weill Medical
College of Cornell University, New York, NY; and †Center for
Medical Ethics and Health Policy, Baylor College of Medicine,
Houston, TX.
Address reprint requests to Frank A. Chervenak, MD, The New
York-Presbyterian Hospital, Weill Medical College of Cornell University, 525 East 68th St, M-7, New York, NY 10021; e-mail:
fac2001@med.cornell.edu.
© 2003 Elsevier Inc. All rights reserved.
0146-0005/03/2706-0002$30.00/0
doi:10.1053/j.semperi.2003.10.002
Seminars in Perinatology, Vol 27, No 6 (December), 2003: pp 427-434
427
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Chervenak, McCullough, and Rosenwaks
sacrifices of self-interest, eg, income and prestige, as required to protect the health-related
interests of the patients. Integrity creates the
responsibility to practice medicine consistently
according to standards of intellectual and moral
excellence. Practicing medicine according to
the best evidence, as opposed to idiosyncratic
bias, is required by the professional virtue of
integrity.
An ethical framework for clinical decisionmaking, practice, and research integrates these
principles and virtues into a coherent approach
that guides and evaluates clinical judgment,
practice, and research. This framework treats
each principle and virtue as prima facie, ie, as
binding unless it is shown by argument to be
overridden by another principle or virtue.1,2
This approach avoids the intellectual gridlock
and clinical disutility of absolute principles and
virtues, ie, treating them as never allowing exceptions. A framework of prima facie principles
and virtues makes possible more nuanced and
therefore more clinically applicable judgments
about the physician’s moral responsibility in
matters of clinical ands research controversy.1
The Fetus as a Patient
Ethical issues in reproductive technologies are a
subset of obstetric ethics in which the concept of
the fetus as a patient plays a central role.1 This
concept therefore needs to be part of our ethical
framework. The concept of the fetus as a patient
should not be understood on the basis of the
independent moral status of the fetus, ie, some
feature(s) of the fetus that, independently of
other entities, including the pregnant woman,
physician, and the state, generates obligations of
others to it, because all attempts to establish
such status are doomed to failure. This failure
results from the irreconcilable differences
among philosophical and theological methods
that have been deployed over the centuries of
debate about the independent moral status of
the fetus. Instead, the moral status of the fetus as
a patient depends on 1) whether it is reliably
expected later to achieve the relatively unambiguous moral status of becoming a child and, still
later, the more unambiguous moral status of
being a person; and 2) whether the fetus is
presented for care. The fetus is a patient when
reliable links exist between it and its later achiev-
ing moral status as a child and then person, and
when it is presented to a physician.1
The first link between a fetus and its later
achieving moral status as a child and then person is being presented to a physician and viability is the ability of the fetus to exist ex utero with
the levels of technological support required to
supplant immature or impaired anatomy and
physiology through the neonatal period and
into the second year of life, times at which no
one disputes that childhood and then personhood exist. Viability is not an intrinsic characteristic of the fetus, but a function of both biology
and technology. In developed countries, fetal
viability occurs at approximately the 24th week of
gestational age, as determined by reliable ultrasound dating.7
The second link between a fetus and its later
achieving moral status as a child and then person is being presented to a physician and the
decision of the pregnant woman to continue a
previable pregnancy to viability and thus to
term. That is, the only link between a previable
fetus and its later achieving moral status as a
child and then person is the pregnant woman’s
autonomy, exercised in the decision not to terminate her pregnancy and to present the fetus
(and herself) to the physician, because technological factors do not exist that can sustain the
fetus ex utero.
There are 4 important implications of the
concept of the fetus as a patient. First, the concept does not rely on the concept of fetal rights
or fetal personhood, but, in particular, the right
to life. Second, for the previable fetus, including
in vitro embryos, the woman’s autonomous decision to confer the status of being a patient is a
necessary condition. Therefore, not all previable
fetuses or in vitro embryos are patients. Patienthood status is therefore not dependent on location (in vitro versus in vivo), but rather is dependent on the woman’s establishing a linkage
between the previable fetus or embryo and the
child that the fetus or embryo can later become.
Third, a woman is free to withdraw the status of
being a patient from the previable embryo even
when she has previously conferred such status.
Therefore, within beneficence-based clinical
judgment, abortion or fetal reductions are ethically justifiable options prior to fetal viability,
because these do not involve killing a patient,
Ethics in Reproductive Technologies
which is (usually) prohibited in medical ethics.1,8
Numbers of Embryos to be Transferred
During In Vitro Fertilization
How many embryos to transfer during in vitro
fertilization (IVF) cycles is a current controversy
in the practice of the new reproductive technologies.9-22 Four ethical factors shape this controversy. First, the issue is addressed by the medical
outcomes of pregnancy rate, live birth rate, and
the rate of multiple pregnancies stratified by
high-risk groups and techniques. This first factor
dominates the literature. However, 3 other factors have been discussed: the role of the patient’s preferences, costs, and market forces of
providers.23 The ethical framework set out above
creates the basis for integrating all 4 factors into
a coherent, clinically applicable account of the
doctor’s responsibility regarding the number of
embryos to be transferred in IVF.22
In IVF, the physician has beneficence-based
obligations to the woman who wants to become
pregnant and to fetal patients and future possible children who will result from the process.
Beneficence-based obligations to the woman balance pregnancy success rates against the healthrelated risks of pregnancy with multiple gestations. The replacement of more embryos
(provided that the replacement of more embryos results in higher pregnancy and live birth
rates) favors success rates, while the replacement
of fewer embryos (provided that the replacement of fewer embryos results in fewer multiple
gestations) reduces risks of multiple pregnancy.
Considered by itself, the principle of beneficence, applied to the pregnant woman’s healthrelated interests, does not automatically favor
either more or fewer embryos being replaced.
There are 2 important subgroups to be considered. If fetal reduction is not an option (ie,
the woman would not withdraw the status of
being a patient from any fetus), and the IVF
procedure results in possibly more than 2 gestations and definitely more than 3 gestations, the
health-related interests of the fetal patients are
adversely affected by increased morbidity and
mortality from prematurity risks.24 In this situation when fetal reduction is not an ethically
acceptable option for the woman, based on her
moral commitments and judgments, there is a
429
strong beneficence-based obligation to replace
fewer embryos.
In the situation in which fetal reduction is an
ethically acceptable option of the pregnant
woman, this strong beneficence-based obligation to replace fewer embryos is mitigated, but
not entirely. This is because fetal reduction has
an intrinsic risk of loss of the entire pregnancy.8
The principle of respect for autonomy is put
into clinical practice through the informed consent process. This process has 3 basic elements:
1) the physician’s obligation to disclose an adequate amount of information about the clinical
benefits and risks of IVF in terms of the number
embryos to be replaced, and high risk groups
and techniques; 2) the patient’s understanding
of this information; and 3) the patient’s process
of deciding, including making a voluntary decision.1,2,25
Beneficence-based clinical judgments and
recommendations depend on the competence
of physicians to evaluate patients’ health-related
interests as required by the concept of being a
moral fiduciary.5 Although pregnancy and childbirth have health-related aspects, the decisions
to become pregnant, how aggressively to pursue
treatment of infertility, and how many children
should result from infertility treatment appeal
predominantly to non-health–related values
such as personal preference, family traditions
and expectations, economics and social resources, and religious beliefs. Neither medical
education nor clinical expertise bestows authoritative judgment. These matters appropriately
fall under respect for the woman’s autonomy.
Thus, the woman’s preference concerning how
many children she would like to result from IVF
treatment must be taken into clinical account in
determining the number of embryos transferred.1
Decisions about IVF for the woman are cognitively demanding, as are many other clinical
decisions made by patients. When patients struggle with such cognitively demanding decisions,
the principle of respect for autonomy creates a
responsibility for physicians to structure the consent process in ways that empower the patient’s
decision-making capacities. Fisk and Trew9 have
recently suggested that “even with counseling,
the risks of triplets are generally underestimated
by parents.” They conclude that the number of
embryos to replace should not be left to the
430
Chervenak, McCullough, and Rosenwaks
woman’s choice. We do not agree. Instead,
women should be assisted as necessary to estimate such risks reliably and balance them
against the benefits of IVF. Fisk and Trew9 provide no evidence that women are incapable of
benefiting from such assistance or performing
this cognitively demanding task. They do suggest
that assisted reproduction technology (ART)
specialists are distanced from clinical practice.
To the contrary, we believe that most ART practitioners are especially cognizant of such risks.
Some patients may find it useful to consult with
a maternal-fetal specialist who has experience
with multiple gestations and can explain risks
and benefits and assist her in her decision-making process. These decisions especially apply to
the older patient when the transfer of 3 embryos
appears to result in higher pregnancy rates.21
Some may be skeptical about the pressures on
voluntary decision-making by women seeking
IVF, thereby weakening autonomy-based obligations. Again, we disagree, because autonomybased obligations remain intact and take the
form of efforts to shield women from undue
pressure from family members, and take the
time necessary to elicit her values and preferences from her, and assure her that the physician will support her in whatever decision she
ultimately makes.
Another crucial responsibility regarding respect for autonomy is for the physician to take
steps to ensure that the pregnant woman’s decision about conferring or withdrawing patient
status on the previable fetus(es) is ultimately
hers. She is free to take account of the preferences of her partner, husband, or other family
members and should be assured that they do not
control this decision. In particular, while the
husband and father’s interests are surely at
stake, there is obvious moral asymmetry in that
the burdens of pregnancy, fetal reduction, and
childbirth fall on the woman and not the husband.1
In fulfilling the disclosure of obligation of the
consent process, the physician is obligated to
present and explain only medically reasonable
alternatives, ie, those that are expected on balance to protect the patient’s health-related interests.1,25 Therefore, ineffective or harmful alternatives should not be offered. The patient
exercises autonomy to select from among the
medically reasonable alternatives, not to define
what those are. When adding embryos is not
reliably expected to increase pregnancy or live
birth rates, then that number adds no benefit,
but introduces unnecessary incremental risk of
multiple gestations and therefore is medically
unreasonable. When added embryos decrease
pregnancy or live birth rates, they are intrinsically harmful and also add to the risk of multiple
gestations, making them even more medically
unreasonable. It has long been known that good
ethics should be based on good facts. Currently,
the facts appear to support that pregnancy and
live birth rates increase when more than 2 embryos are placed, especially for certain high-risk
groups.22
There are major justice-based issues about
IVF and about assisted-reproduction technologies generally. Chief among these is whether
these services should be covered by insurance
and national health plans, and to what degree.
This is a very large issue because it concerns
rights or entitlements to health care and health
care policy, and whether infertility is or is not a
disease, goes far beyond the scope of this articles. The authors believe that infertility is a serious condition worthy of medical attention.
Faber19 has recently called attention to one
justice-based consideration that is directly relevant to the subject at hand. He points out that in
the United States most insurance plans do not
cover ART procedures, but do cover pregnancy.
Thus, patients take economic risks in starting a
pregnancy, but not in continuing it. Thus, from
the perspective of payers, a perverse economic
incentive is introduced that gives patients little
reason to take into account the overall subsequent costs of managing pregnancies initiated
by IVF and ART.19 This is obviously an incoherent policy that, like all incoherent health care
policy, strains against the demands of justice.
As in many other medical specialties, when
patient services in IVF produce a significant revenue stream, and when patient services bring
prestige to individual physicians and their sponsoring institutions, self-interest can become a
predominant consideration for the physician.
This threatens the physician’s professional virtues.
Professional integrity requires vigorous adherence to evidence-based standards and to the
responsibilities of the informed consent process.
In particular, the woman seeking IVF services
Ethics in Reproductive Technologies
should be provided with institution-specific information about that institution’s outcomes of
pregnancy rates, live birth rates, and rates of
multiple gestation per number of embryos transferred, stratified by high-risk group, embryo
quality, and techniques used, as well as national
information on the same parameters, so that the
patient can make an informed comparative
choice. However, there are limitations and perhaps even bias related to patient selection and
practice in registries that can affect outcomes.
Individual physicians and centers must be willing to accept the consequences of the virtue of
self-sacrifice when patients, on the basis of this
information, elect to go to centers with better
outcomes. After all, IVF services in the United
States function in a marketplace model and the
ethics of the market strictly require informed
consumer choice. Thus, failure to provide such
information violates the virtues of integrity and
self-sacrifice and the ethics of the market.
Professional integrity also requires that the
informed consent process be as free as possible
from the bias introduced by self-interest, eg, a
physician who starts the informed consent process by emphasizing the increased pregnancy
rates from added embryos while under-emphasizing the risks of multiple gestation, to gain
market advantage from high-pregnancy rates.
This is obviously inappropriate, and self-sacrifice
as well as integrity prohibit this morally corrupt
practice.
Gene Transfer Research
In the not-so-distant future, gene transfer technology will be combined with IVF and introduced into the clinical setting as human subjects
research, which will raise significant ethical issues.26-28 Recent studies on the experience of
subjects of research have shown that patients are
not always aware when they are subjects of research.29 It has been suggested that the language
used during the consent process may contribute
to this disturbing lack of understanding.29 In our
judgment, the use of the word “therapy” should
be avoided to prevent this lack of understanding. Phrases such as “innovative therapy,” “gene
therapy,” and “experimental therapy” therefore
should never be used in consent forms or in
discussions with women about their participation in gene transfer research. Instead, the con-
431
sent process and form should be explicit about
the fact that the clinical application of gene
therapy to the fetus at this time is research or
experimentation.
It is never obligatory for an individual who
can consent for himself or herself to consent to
become a subject for research. Nor is it obligatory for a surrogate, such as a parent, to consent
for a patient not capable of participating in the
consent process, eg, an infant or very young
child, to become a subject of research.25 Therefore, it follows that no woman has an obligation
to consent to gene therapy research on her in
vitro embryo, even when she gives the embryo
the status of being a patient. The consent process should make this moral fact very clear to the
woman and to others who might be involved
with her in the consent process.
Institutional review boards should scrutinize
consent forms and procedures to require efforts
on the part of investigators to prevent coercion
of a woman’s decision by internal factors such as
unreasoning desperation, and external factors
such as partners and family members. These
recommendations parallel the ethically justified
practice of protecting women from subtle coercion in decisions about using assisted-reproductive technologies generally.
Gene therapy research will be new and the
informed-consent process should be structured
with this fact in mind. Therefore, we recommend that the consent process should begin
with the research team inviting the woman to
state what she understands about the embryo’s
diagnosis, available alternatives for managing
that diagnosis, including nontransfer, and the
benefits and risks of those alternatives. She
should be asked what she understands the prognosis to be if gene transfer is successful. In particular, women will need to understand the distinction between gene transfer for uniformly
lethal conditions and gene transfer for conditions that result in serious morbidity. The research team should be attentive to factual errors
and incompleteness in the woman’s fund of
knowledge. Educating her about the protocol
should begin by making sure her initial fund of
knowledge is accurate, thus laying a solid informational foundation for the rest of the consent
process.
That process should continue with an explanation of the embryo’s genetic condition and
432
Chervenak, McCullough, and Rosenwaks
how the gene transfer research is designed to
address that condition. She should be given information about the results of animal studies,
especially about documented benefits and risks
identified in such studies. She should also be
informed about the unknown risks that transferred genes could function in unpredictable
ways (the law of unintended consequences).
She should then be assisted to identify her
relevant values and beliefs. This can be accomplished in a nondirective fashion by asking what
is important to her about becoming pregnant,
about having children, and about having children with health problems that can range in
their severity. She can then be asked to assess the
offered gene therapy research on the basis of
her values and beliefs, thus enhancing her autonomy in the consent process.
Throughout the consent process and in the
consent form, the options of abortion and nonintervention during pregnancy (assuming transfer is successful) should be presented as entirely
acceptable to the research team.30 We make this
recommendation to reinforce the nondirective
character of the informed-consent process for
gene therapy research.
Current US federal regulations continue to
require paternal consent.31 On the account we
have given of the fetus as a patient, the father of
the fetus does not determine whether the fetus is
a patient. There is an obvious moral asymmetry
between the father and the pregnant woman
during pregnancy such that his role in decisions
about interventions on the fetus should be a
function of the pregnant woman’s autonomy.
Even though the legal regulation is therefore
ethically without support, civic responsibility requires that the regulation be followed (until
such time as it is changed).
Gene transfer research will be used especially
to try to reduce the mortality of uniformly lethal
conditions, such as alpha thalassemia, as the
ability to diagnose them in vitro is created. The
traditional logic of beneficence that drives such
research has been that every reduction of mortality from such conditions is worth whatever
morbidity that might result for survivors. In the
clinical setting, especially in critical care, the
traditional logic of beneficence has been appropriately challenged when morbidities eliminate
or greatly impair developmental capacity of survivors. As McCormick32 put it over 30 years ago,
when critical care results in all of the patient’s
energies being used in an irreversible struggle to
survive, critical care intervention can be
stopped. The moral lessons for gene transfer
research are 2-fold. First, if animal studies reduce mortality but survivors are left with devastating morbidity, then human trials should not
be started until animal outcomes improve. Second, human trials should include, as a stopping
rule, high rates of occurrence of devastating
fetal morbidity.
Recall that the in vitro embryo is a patient
solely as a function of the autonomy of the
woman into whom the embryo will be transferred. For gene transfer on embryos, the exercise of such autonomy is greatly restricted in the
absence of prenatal diagnosis to determine the
effectiveness of the gene transfer. In particular,
some women may want to terminate a pregnancy
before viability, when there is no laboratory evidence of successful transfer. In our view, therefore, offering prenatal diagnosis should be required by Institutional Review Boards for gene
therapy interventions with previable fetuses. The
consent process should include careful explanation about the potential for false-negative and
false-positive results.
It is an accepted feature of study design in
general that clinical trials should be conducted
in such a way as to control for the idiosyncratic
effects of patients’ preferences on results. This,
for example, justifies a double-blind study design.
For gene transfer research this general rule of
study design raises significant ethical issues. On
the one hand, to get the cleanest results one
would not want any pregnancies in which gene
transfer occurred to result in elective abortions.
On the other, it would be desirable to prevent
adverse outcomes of gene transfer through abortion in a study population of women who would
accept this option.
To address the first problem, one would exclude women who indicated any willingness to
consider elective abortion. To address the second problem, one would exclude women who
were opposed to abortion. Both solutions share
a common and disabling ethical problem: They
decide for the woman whether the previable
fetus is a patient, thus unjustifiably overriding
her autonomy in favor of research considerations, a paternalistic abuse of research subjects.
Ethics in Reproductive Technologies
To avoid this unacceptable ethical problem
there should be no exclusion criteria for fetal
gene transfer based on willingness to countenance elective abortion. Study designs would
therefore have to include elective abortion and
birth of adversely affected infants as hard endpoints.
Germ-Line Risks
5.
6.
7.
Fletcher and Richter have raised the important
ethical concern for germ-line harm that could
result from the unknown harms of gene transfer.
They propose that somatic cell gene transfer
research “ought not be approved unless investigation in animal studies shows that the vector
does not convey copies of exogenous genetic
material into sex cells of fetuses.”27 This, in our
view, is a prudent recommendation designed to
prevent unnecessary harm to future generations.
As fetal gene transfer research matures, this position may need to be reconsidered, especially
when it is reliably thought that germ-line benefits convincingly outweigh germ-line harms. Any
attempt to address this question will be controversial.
27
8.
9.
10.
11.
12.
13.
Conclusion
14.
Clinical practice and research in newer reproductive technologies is best guided and evaluated by an appropriate ethical framework. We
have presented such a framework and have
shown it enhances both clinical insight and management, and the design and conduct of research. We believe that clinical practice and research of newer reproductive technologies
should incorporate ethics as an essential dimension.
15.
16.
17.
18.
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