**Lasker Forum on Ethical Challenges in Biomedical Research and
Practice**

**[Assisted Reproductive Technology]{.underline}**

**Case Study**

**For Discussion Only**

**May 2003**

***Background.*** The Genesis Fertility Clinic is a privately owned
facility offering assisted reproductive services. These include
artificial insemination and surrogacy services, but the issues presented
by this case involve in vitro fertilization (IVF) technology, including
egg harvesting, embryo culture, preimplantation diagnosis, and cryogenic
embryo preservation. Genesis is led by Dr. Oldwest (hereafter, Dr. O.),
a confident, experienced physician with a reputation for clinical
innovation and an aggressive concern for his patients. Mr. and Mrs.
Hopeful (hereafter, the H's) arrive at Genesis after a history of
unsuccessful efforts to conceive, accompanied by medical histories
confirming that Mr. H's sperm are viable. While the cause of their
infertility has never been specifically determined, the couple is
desperate to conceive and bear a child of their own and they request
IVF. Dr. O. explains that it should be possible to achieve IVF by
inducing multiple ovulation through hormone injections and aspirating
the ova, which would then be fertilized with Mr. H's sperm in a special
culture medium. Some of the embryos would then be introduced into Mrs.
H's uterus while others would be cryogenically preserved.

###### **The Doctor**

Genesis has its own assisted reproduction lab where the embryos are
developed and cultured prior to transfer into the uterus of Dr. O's
female patients. Dr. O and his colleagues have known since the beginning
that the media employed to culture embryos *in vitro* is extremely
important to the pregnancy success rates he achieves in his clinic. The
culture formulations are responsible for adequately nurturing the new
embryo and promoting rapid and healthy development so that a sufficient
number of embryos are produced that have the maximum chance of creating
a pregnancy. Dr. O avidly follows the scientific literature and is eager
to apply advances in embryo culture; thus, over time, the culture media
used in Dr. O's lab has become complex and state-of-the-art. Dr. O has
been careful, however, to make only those changes in the lab's culture
media that, in his opinion, have been shown to be effective and safe in
studies on laboratory mammals and that are consistent with what is known
about the human pregnant state. Recently, his colleagues have
incorporated into the lab's formulas some growth factors that have been
shown in multiple animal studies to support embryo growth in culture for
longer periods of time. This produces more mature and viable embryos,
promising higher pregnancy rates for his patients while transferring
fewer embryos \-- making pregnancy safer for both mother and fetus. Dr.
O is so confident of the superiority of these new formulas that he has
filed for patent protection and believes that he may be able to generate
substantial licensing revenue from the sale of his formulations via a
separate commercial venture. He has also submitted manuscripts to a
prestigious medical journal to inform the medical community of his
innovations.

The one problem arises from statements in the scientific literature by
some embryologists that growth factors of the class used by Dr. O might
cause growth and other abnormalities in children born of an IVF
procedure using these culture media ingredients. However, Dr. O
considers these fears to be highly speculative; such fears are raised
whenever new ingredients are added to embryo culture media and have
become almost an obligatory caution added to the end of scientific
papers disclosing animal advances in this field. The growth factors used
by Dr. O are those that are produced by the newly pregnant human female
and are, therefore, ones to which the embryo would be exposed under
normal conditions. Thus Dr. O believes that he is creating a more
physiologically normal environment for the embryos created in his lab.
Over the prior year, Dr. O has used the culture media in his last eleven
IVF procedures and all four infants born from those procedures have been
healthy and normal.

1.  Should Dr. O's culture work be considered research or clinical
    practice? Is it ethical for Dr. O. to "test" his own invention on
    his own patients? If so, under what conditions?

2.  Should work such as Dr. O's be subject to regulatory oversight? How,
    and by what agency or agencies?

3.  Dr. O has been invited to present his paper at an ART symposium. He
    intends to report his experience with his new culture media. What
    are his disclosure responsibilities in this paper?

4.  Is Dr. O. obliged to report his past use of and his experience with
    his modified culture medium and the speculative risks to the H
    family as part of an informed consent procedure? What, specifically,
    should he disclose?

5.  Is Dr. O. obliged to disclose his financial interest in the culture
    media he is using? What about his reputational interests?

### *The Patients*

Mr. and Mrs. H. are shown an informed consent form by Dr. O. It explains
the risks of the hormonal treatments used to induce ovulation, and those
associated with the aspiration of the ova. It also supplies information
about "failure rates" of the IVF procedure as a whole. Mrs. H. has read
extensively about the procedure on the Internet, and asks about the
risks associated with multiple births; Dr. O. explains that in order to
increase the success rate for the procedure he will have to implant
multiple embryos. Multiple births pose some risk to the mother, and
increase the likelihood that one or more of the siblings may be Low
Birth Weight. Dr. O. then summarizes the risks associated with LBW --
but points out that pregnancy termination would be an option if that
were a prospect. Mrs. H. discloses that she would have a very difficult
time agreeing to the termination of the life of any living implanted
embryo. Dr. O. goes on to explain that because her own genetic history
suggests certain risks, her embryos should be subjected to
pre-implantation genetic diagnosis (PGD) so that those carrying
identifiable defects could be eliminated. Even though PGD is very
expensive (sometimes equaling the cost of the IVF procedure), he tells
the couple that he would be reluctant to perform IVF without doing PGD
because the ability to diagnose problems in embryos greatly increases
the chance of producing healthy children. Dr. O states that, although he
will explain these tests to the couple, given the complexity of the
matter, the decisions of what tests are reliable enough to employ and
which embryos to select for implantation based on test results, as well
as on embryo development rate and morphology, should be left to his
discretion. Finally, Dr. O. has just read a recently published medical
study conducted by British researchers that showed that normal weight
children born of IVF techniques have a higher incidence of neurological
abnormalities than those born naturally. However, the study conclusions
had been criticized because of the relatively low number of children
studied and the fact that the study failed to resolve the question of
whether the increase in abnormalities was caused by the infertility
procedures or the infertility itself or some other factors. Furthermore,
it was difficult to extrapolate British results to the U.S. since some
of the techniques used in IVF are different. Based on these
uncertainties, Dr. O. decided not to disclose this confusing information
to his patients.

1.  Should the consent form and/or Dr. O's explanation also include the
    epidemiological uncertainty associated with later-life in those IVF
    children who are normal with respect to birth weight?

2.  What evidence should be in place in order to require such a duty to
    disclose? Would the British study qualify in this instance?

3.  How much control over this process is Dr. O. justified in
    maintaining, and how much should the patients participate in such
    medical decisions as what PGD tests to employ, which embryos, and
    how many, should be selected for implantation? Whose interests are
    at stake in these decisions?

#### The Parents, later

Mr. and Mrs. H. indicate that they would like the medical record to
state that their consent to IVF is conditioned on Dr. O.'s agreement and
that of the clinic's administration to the following conditions: that
any viable, healthy embryos that will not be implanted will be
cryogenically preserved; that Mr. and Mrs. H. will be jointly
responsible for decisions about the future use and custody of their
frozen embryos; and that no genetic information obtained through PGD or
any other means will be shared with another person or entity (including
but not limited to an insurance carrier). With some reluctance about the
third condition, Dr. O. agrees. The IVF is successful. Multiple embryos
develop and look reasonably viable. Some are cryopreserved and three
embryos are implanted. Three pregnancies result, two of which are
eliminated *in utero* since Dr. O. determined that Mrs. H's subsequently
developed pregnancy problems put her at high risk with a multiple
gestation. The decision to undergo the pregnancy reduction procedure was
very difficult for Mrs. H. She had consulted with her religious advisor,
her husband, and her sisters. After much anguished contemplation, she
agreed to termination based on Dr. O.'s assurance that the risks of
multiple pregnancies were medically unacceptable for her and for the one
fetus selected for retention. Although Mrs. H. recognizes that Dr. O.
had discussed with her in advance the risks of multiple pregnancies, she
cannot help repeating her wish that she had fully understood, from the
beginning, the impact of making the reduction decision. She also says
that her joy connected with the anticipation of birth is significantly
diminished because of her distress over the thought of those two "lost
babies".

1.  Research conducted subsequent to this procedure implicates a
    particular genetic marker in an important medical disorder. Dr. O
    runs the new genetic test on all of the preserved embryo PGD tissue
    in his lab (he has stored over one thousand samples) and he finds
    the marker in Baby H's PGD tissue. Because of the importance to
    medical understanding and the public health, Dr. O. wants to release
    the data for incorporation into a national database along with
    medical information about the Hopeful's. Should he?

2.  Dr. O also wonders what his obligations are concerning informing the
    H's about this finding in Baby H's tissue. Does this suggest that
    Dr. O should have considered his testing as research and obtained
    prior consent from the H's? Aside from any new privacy obligations
    under HIPAA[^1], what would constitute prudent practice when
    physicians obtain, store, and then test human tissue such as in this
    case?

3.  If Dr. O does inform the H's about the genetic finding, they will be
    told that there is an association between the presence of the
    genetic marker and the development of a particular type of mental
    disorder. In addition to informing the H's about potential health
    risks, does Dr. O have a duty to mitigate the harms (including
    psychological and social) that the H's might experience as a result
    of learning about the genetic test findings?

***Additional Issue***

***The Child, much later***

Baby Hopeful is now 19 and over his life-time, there have been subtle
indications that he was not normal neurologically. His doctors have
tested him periodically and noted mild cognitive deficits but, since
Baby H's verbal, social, emotional, and other scores had improved as he
aged, doctors' advice to the Hopefuls was that their child would
eventually score within the normal range by the end of adolescence.
However, the cognitive test scores never quite reached a normal range
and have remained set since the age of 15. Baby H's condition now has a
name (High Functioning Autism Syndrome, HFAS) and is considered a form
of childhood developmental disability, a variant of autism that had
previously fallen into a category of unclassified disorders called
Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS). HFAS
has left Baby H somewhat socially withdrawn with weak communication
skills and with some emotional lability. These problems presage
difficulties with education, employment, and social interactions. On the
advice of legal counsel, Baby H has sued his physicians for failing to
diagnose this condition in a timely manner. Among the list of injuries
claimed is a lost opportunity to engage in therapy when it had the best
chance of success. Baby H's lawyers know that this is only a potentially
viable claim since researchers have not yet identified a single
\"trigger\" that causes autism but among the non-genetic possibilities
are early embryonic or fetal exposure to chemicals and other
non-physiologic substances. To increase the chances of prevailing in
their claim, Baby H's lawyers also sued Dr. O and the Genesis clinic on
the theory that the IVF procedure carried risks that were, or should
have been, known by Dr. O. but were not properly disclosed to his
parents in the informed consent process. Indeed, Dr. O had substantially
changed his embryo culture formulations since they were used for Baby H.
Since it was likely that the claim against Dr. O would be dismissed as a
legally disfavored "wrongful life" claim, a second legal theory against
Dr. O was newly developed for this lawsuit. According to the pleading,
Dr. O. should be punished for failing to treat his patients as research
subjects, which was akin to acting in reckless disregard for Baby H's
health and well being by performing the IVF itself and/or by using
untested culture media. If the culture formulations had been treated as
experimental, the lawsuit papers claim, there would have been more
extensive pre-clinical testing and more human subject protections in
place that would have protected Baby H from premature exposure to the
damaging embryo culture chemicals.

1.  Increasingly, courts are asked to address claims relating to
    evolving medical understanding. In addition, medical advances or the
    implementation of new medical technologies can lead to novel alleged
    harms, in turn generating new legal theories to redress them. What
    can society do to prepare courts for such novel cases?

2.  How could such possible after-the-fact tangles be avoided
    prospectively by the clinic and the parents? What requires
    structural change in the process?

[^1]: HIPAA is the Health Insurance Portability and Accountability Act
    which goes into effect in April 2003 and governs privacy and
    security of health care information.