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ISSUES IN ASSISTED REPRODUCTION
Jock Findlay*
“There are in fact two things, science and opinion; the former begets
knowledge, the latter ignorance” Hippocrates (460BC – 357BC)
Introduction
Success of ART.
Assisted reproductive technology (ART) was first developed
for the treatment of infertile couples, principally the female
partner with problems such as blocked tubes, failure of
ovulation, and endometriosis, but also for men with
oligospermia and motility disorders. Initially called In Vitro
Fertilization or IVF, it consisted of collecting eggs from a
woman after ovarian stimulation, fertilizing the eggs in vitro
with sperm and then transferring one or more of the embryos
into the uterus of the woman. This was followed by successful
use of cryopreserved embryos, donor gametes, and overcoming a major portion of
male factor infertility using intracytoplasmic sperm injection (ICSI). Although the
success rates were relatively low (<10% of embryos transferred) to begin with, there
have been many improvements in the technology since the first successful transfer in
1977 and birth in 1978, such that there now are over 3 million babies born worldwide
following ART.
ART has opened up a number of medical, legal and ethical issues.
ART not only includes the medical and laboratory procedures used to treat infertility,
it also encompasses a range of other issues including patient’s rights, scientific and
technological change, professional autonomy, ethical concerns, standards for
treatment and community concerns and expectations. Recent developments include
the use of ART by individuals who are not infertile but have social or lifestyle reasons
for accessing the treatment. It is for all these reasons that there has been vigorous
debate about the necessity or otherwise of regulating access to and treatment by
ART.
Regulation versus no regulation
There are those who advocate that ART is simply another medical procedure which
should not be regulated any differently from any other medical procedure. In this
context, the principles of reproductive freedom and individual autonomy should
prevail, and the decision to treat should be made by the doctor and patient and be
subject to the proper standard of care that can be promulgated by professional self
regulation through guidelines and codes of practice. Furthermore, in the absence of
community consensus on the ethics and use of ART, it is argued that moral and
ethical decisions should be made by the individuals to be treated and not imposed by
law. Regulation by law can inadvertently prevent important research and impede the
application of new and better technologies for treatment.
On the other hand, there are those that advocate that ART is different from other
forms of medical treatment because it involves the creation of children, especially
when the health and welfare of persons to be born as a result of treatment are
considered paramount, as is the case in many jurisdictions. This raises complex
moral and social issues. Regulation can also ensure other purposes:
• Protecting patients and children to be born and the medical staff providing
treatment, against risk of harm,
• Providing counselling to support patients and to ensure they are able to
make informed decisions about treatment based on a sound knowledge of
the topic,
• Prohibiting harmful practices such as transfer of multiple embryos or
reproductive cloning,
• Establishing community trust and confidence in ART,
• Ensuring fair and transparent decision-making processes,
• Defining the status of children and parents in situations where donated
gametes or embryos are used,
• Ensuring access to information about a donor conceived person’s genetic
origins,
• Transparency of expenditure of public funds, and
• Providing a process for consultation and review of advances in technology
and medical practice, and community values that may influence the
legislation.
Australia does not have national legislation regulating ART practice. ART regulation
varies between States and Territories. The National Health & Medical Research
Council (NH&MRC) of Australia issued “Ethical Guidelines on the Use of Assisted
Reproductive Technology in Clinical Practice and Research 2007”1 which inform a
national industry self-regulatory accreditation system monitored by the Reproductive
Technology Accreditation Committee (RTAC) of the Fertility Society of Australia2. The
majority of patients treated at ART clinics with RTAC accreditation are eligible for
pharmaceutical rebates by the Commonwealth Government. Victoria, South Australia
and Western Australia which have legislation require clinics to have RTAC
accreditation.
In Victoria, the proscriptive nature of the Infertility Treatment Act 19953 has made the
legislation difficult to apply to emerging practices, technological developments and
changes in community attitudes. It establishes the Infertility Treatment Authority
(ITA)4 which regulates ART practice. The functions of the ITA include licensing of
places for treatment and approved research, approval of ART practitioners,
maintenance of statutory time limits for gamete and embryo storage, approval of
import and export of gametes and embryos to or from Victoria, maintenance of donor
registers, and reporting to Parliament. Access to treatment is determined by an
approved doctor who decides that the woman will only achieve a pregnancy or
prevent transmission of a disease or genetic abnormality only if she undergoes a
treatment procedure. Although not specifically included in the Act, Preimplantation
Genetic Diagnosis (PGD) is allowed and is regulated by the ITA in Victoria.
A recent report on “ART and Adoption” by the Victorian Law Reform Commission
(VLRC)5 “concluded the continued regulation of ART in Victoria is justified. The use
of ART raises issues which go beyond the interests of particular individuals and may
affect the whole community”. However, the VLRC also highlighted the need for
legislation “to be able to respond to technological change, to address emerging
problems and to respond to shifts in social attitudes”. Accordingly, it recommended
that changes to the Infertility Treatment Act should “promote a responsive and
flexible regulatory regime” that holds as the primary guiding principle, the health and
welfare of persons to be born as a result of ART. These recommendations are under
consideration by the Victorian Government at the time of writing.
Given the trend towards greater demand for ART for social reasons, a case can be
made to review the necessity to regulate the provision of ART services by qualified
medical staff and access to ART by those with clearly defined medical infertility for
what could now be considered as ‘routine IVF”. More emphasis in the regulatory
frame could then be given to those who wish to access ART for social reasons in the
context of community attitudes, and whether or not such treatment should be
subsidized by the State.
Multiple versus single embryo transfers
Issues with numbers
Transfer of multiple embryos was common in many ART units and still is in some,
particularly in the USA. This was done to obtain the highest possible pregnancy rate,
and therefore the highest take home baby rate. Success rates with transfer of one or
even two embryos were low, primarily because of the inappropriate quality of the
embryos formed in culture and the status of the uterine environment following ovarian
stimulation. However, there are severe consequences of multiple pregnancies such
as higher risks of abortion, fetal death, premature birth, and low birth weight of babies
with the high associated costs involved, as well as the issues of raising multiple
siblings (see 6). One solution to this problem has been surgical fetal reduction which
itself increases the risks of harm to the mother and the remaining fetuses. More
recently, there have been significant advances in knowledge about the optimum
culture media conditions needed for in vitro development of embryos leading to
successful single embryo transfer (SET) and pregnancy, with its consequent benefits
to the mother and child. This has resulted in a dramatic reduction in the multiple
pregnancy rates and a consequent reduction in the complications and the need for
fetal reductions.
This has been the topic of recent Bertarelli Foundation meetings which explored the
issues around single and multiple pregnancies after ART. However, there are
limitations to the use of SET. The success rates after SET, albeit almost equivalent to
natural conception, are confined to women with high fertility during their reproductive
age from 25-38 years. After the age of 38 years, fertility falls dramatically and transfer
of multiple embryos is common to improve the chances of achieving a pregnancy.
There are recommendations in the literature and guidelines from professional bodies
for the ART industry to move to SET within certain age brackets.
Short and long term outcomes
Irrespective of the number of embryos transferred, babies conceived through ART
are born earlier at a lower birth weight than their naturally conceived counterparts (6).
The reasons for this are not clear but the consequences are known. Premature, low
birth weight babies have a lower survival rate and more developmental complications
in the neonatal period than naturally conceived babies. There are reports of
increased abnormalities at birth in babies conceived through ART, although others
have not confirmed these observations6. Furthermore, the “Barker Hypothesis” states
that low birth weight and prematurity are associated with an increased risk of health
complications such as cardiovascular disease and diabetes in later life. More
research on this topic involving ART children using properly controlled designs is
warranted. Early trials examining the rates of development of physical and mental
capacities of children conceived by ART suggest no difference to naturally conceived
children (see reference 6). However, the trials need repeating and extending to older
children and adults, on an international scale.
Recent evidence suggests a higher incidence of rare genetic disorders in ART babies
such as Angelman’s Syndrome and Beckwith-Weideman Syndrome (see reference
6). These are due to epigenetic changes in genes raising questions about the
influence of the in vitro conditions under which embryos are formed and transferred
on the epigenetic control of gene expression; it underlines the need for more
research.
Eligibility for treatment
Social versus medical infertility
Jurisdictions that have legislation regulating ART generally restrict access to infertile
couples or individuals, or to individuals who may pass on a genetic abnormality or
disease to their offspring. Eligibility is determined by medical definitions of infertility,
abnormality and disease. Anomalies do arise, however. For example, under Victorian
law, a woman is eligible for treatment if she is medically infertile and her male partner
is fertile, or if she is fertile and her male partner is infertile. However, a single woman
who is fertile is not eligible for treatment. In this case, the partnership confers
eligibility if one member is infertile. This does not extend to same sex couples. In
Victoria, a woman in a lesbian relationship is only eligible for treatment by ART if she
is medically infertile. The lack of a precise definition of the meaning of medical
infertility can also be a problem. There is a need for consistency in the law regarding
access and clarity in the medical definition of infertility.
Defining the ‘family unit’
There is an increasing desire by same sex couples and single women who are fertile
to have children. Many of them would prefer not to access ART to achieve a
pregnancy because they object to the ‘medicalisation’ of the process, and in some
cases being subject to legislative regulation. These individuals generally achieve
pregnancy using a known sperm donor in the confines of their home without the
certainty of success or the sperm being ‘screened’. Some would access ART,
particularly for donor sperm (or eggs) certified to be free of diseases such as
HIV/AIDS and hepatitis. This was made possible in Victoria recently (see reference
4), coupled with a requirement that the child’s birth is registered allowing it to trace its
biological origins later in life if desired. To date there have been no pregnancies
recorded from the small numbers who used this treatment.
Access to ART by same sex couples or single women invites debate on the definition
of the ‘family unit’ and the desirability or otherwise of a ‘father’ in the birth
relationship. This is an issue that has divided community opinion. It is often
countered by statements that children raised by single mothers or same sex couples
show no signs of being worse (or better) off than those in a heterosexual family unit.
In the UK, it is the subject of current debate as to whether or not the legislation
should require that there should be a ‘father’ in a relationship to allow a woman to
access ART. The identification of the sperm donor or father also has implications for
the names on the birth certificate of the child. This is a complex subject that would
benefit from more research.
Deferred conception by egg freezing
It is a well established biological phenomenon that as women age, the quality of their
eggs deteriorates, exemplified by the decreased rates of pregnancy and increased
rates of chromosome abnormalities or genetic aneuploidies, characterized by an
increased risk of Down’s Syndrome in their children. Age at first birth in women in
most developed societies is now more than 30 years as a result of later partnerships
and career choices. As a result, women are experiencing a reduction in fertility if they
defer child bearing to their late thirties. One way to avoid this problem is to freeze
eggs at an earlier age for later use. This will be feasible if egg freezing technology
and viability after thawing is followed by acceptable pregnancy rates, but it opens the
question of access to ART services needed by these fertile women for social
reasons. There is also a small but significant risk to those women, some of whom
may be single at the time, who choose this option because of the stimulation program
to increase the number of eggs recovered and surgical egg recovery. There is a need
for community debate as to whether or not deferred conception by egg freezing
would be an acceptable use of ART.
Reproductive tourism
Reproductive tourism is the expression used for describing the use by clients of ART
services in centres and countries that have either no or little regulation of ART,
coupled with costs that are well below those in the clients’ home country. This allows
clients to avoid eligibility criteria, but does not provide them with the safeguards that
may be in place in their own country. It can also open local donors to significant risks
and even harm, for example, infertility as a result of stimulation and surgical egg
recovery. While it would be difficult to penalize individuals from returning home
pregnant, it is possible, as in the UK, to regulate the import of gametes collected
under conditions that do not meet stringent criteria such as the collection methods
and records of donors.
Donor conception
Conception using donor gametes, particularly sperm, is now a common practice in
ART services, especially if ICSI is not an option. It attracts social, ethical and moral
issues, many of which can be discussed through appropriate counselling resulting in
informed consent to the use of donor gametes. However, the other side of the
equation is the health and welfare of the child born as a result of donor conception.
Right to know biological origins
Some jurisdictions, such as Victoria, enshrine in legislation the rights of children born
through ART to know their biological origins if they so choose (see reference 3). This
implies that the donor is not totally anonymous, indeed, in Victoria the donor has the
right to know of any offspring born as a result of the donation, and may after the child
reaches 18 years of age ask the ITA to approach the young adult for more
information. This exchange of non-identifying information is facilitated through the
existence of confidential registers administered by the ITA, and may after counselling
and agreement from both parties, allow the donor to meet with the child. This can be
a traumatic experience for any person who has not been told by his or her parents,
that they were conceived with donor gametes or a donor embryo. Data shows that
only about 30% of parents tell their children that they were donor conceived. This has
resulted in a very successful Time to Tell campaign in Victoria encouraging parents
to tell their children and providing them with the knowledge and support to do so.
There is an opposing argument that neither the donor nor children born as a result of
their donation should have the right to access information about each other, and that
in doing so, this will avoid the stress on the parents and children and increase the
likelihood of persons agreeing to act as donors. On the other hand, there is a very
slight chance that it could lead to a consanguineous relationship of two individuals
conceived using the same donor. Furthermore, there may be medical reasons for the
child to know of any genetic diseases carried by its biological parent(s). This is a
complex issue needing more research, not the least of which involves the basic
human drive to know of ones biological origins.
Limits on donation
It follows from the discussion above that there should be limits on the number of
times donor gametes are used. In Australia, a single sperm donation is limited to 10
families to minimize potential contacts and consanguineous relationships. This limit
would need adjustment in a small community. However, the scientific basis for
derivation of this limit has been questioned and recently reviewed7. There appear to
be no time limits on the viability of cryopreserved donor sperm; successful pregnancy
has been reported using sperm stored for more than 20 years. Similarly
cryopreserved embryos remain viable for many years. The technology for freezing
eggs is still developing but will undoubtedly become routine in due course.
Should donors have the right to restrict who receives their gametes or embryos? This
is a complex ethical and legal question that needs more debate. One particular
problem is the potential of directed donations to be inconsistent with laws against
discrimination. In Australia, directed anonymous donation of gametes and embryos is
not allowed, but is allowed in the case of known donors. In New Zealand, embryo
donation has been equated more with adoption; the donating and receiving couples
are counselled and required to exchange anonymous information before they agree
to meet and then agree on the terms before the donation is carried out.
Preimplantation genetic diagnosis (PGD) – who gets access?
PGD is a technology that combines IVF with genetic testing. It involves the biopsy
and removal of single cells from embryos formed in vitro. The biopsied cells undergo
genetic testing, and embryos are selected for transfer on the basis of the results.
PGD was initially conceived as a way for couples at risk of a known genetic condition
to reduce the risk of transmitting that condition to their offspring. As well as testing in
relation to genetic disease, PGD is also used for chromosomal analysis to increase
the efficiency of IVF for certain classes of infertile patients (aneuploidy screening).
PGD has now been performed in over thirty thousand cases and resulted in birth of
many thousands of children free of genetic and chromosomal disease, and is clearly
becoming part of genetic practices and ART.
The NH&MRC “Ethical guidelines on the use of ART in clinical practice and research
2007” (see reference 1) point out that the uses of PGD have profound ethical
significance including:
• what counts as a serious genetic condition is controversial;
• there are different perceptions of disability;
the practice of selecting against some forms of abnormality may threaten the
status and equality of opportunity of people who have that form of
abnormality;
• the procedures may involve the disposal of healthy embryos; and
• the procedures may have technical limitations (such as the failure
to identify the genetic abnormality of interest)
The NH&MRC guidelines further recommend that PGD should not be used for
• prevention of conditions that do not seriously harm the person to be born,
• selection of sex of an embryo except to reduce the risk of transmission of a
serious genetic condition, or
• selection in favour of a genetic defect or disability in a person to be born.
‘Serious’ genetic conditions
Most guidelines and legal documents do not define “a genetic abnormality or a
disease”. In Victoria, it is the ITA’s legal advice that Parliament intended the words to
receive a broad, purposive interpretation. Confirmation by a doctor with qualifications
in genetics satisfies the condition for admission. Such a person will make each
decision in the context of the medical expertise available to them. The responsibility
is entrusted to the specialist with qualifications in human genetics, and such a
specialist would be required to document the clinical grounds upon which admission
to treatment is based. The Act therefore imposes the responsibility for gate-keeping
on the doctor with specialist qualifications in human genetics.
Disability
The definition of a ‘serious genetic condition’ becomes more complex when applied
to disability. On the one hand, the prospective parents might have a strong desire to
remove a genetically-based disability from the family germ line. On the other hand, it
can send a message to those born with disabilities that they may have been better off
not being born8. Selection against carriers of late onset ‘disabilities’ such as breast
cancer and Huntingdon’s disease9 raise particular ethical concerns; such individuals
can enjoy a normal life before the onset of the disease so on what grounds should
embryos carrying the disability be selected against?
‘Saviour siblings’
Technology is now available to simultaneously test for genetic disease and
histocompatibility leukocyte antigen (HLA) embryo matching (see reference 9). This
procedure may be utilised where embryos are tissue type matched with a living child
who has a genetic condition, and where blood is harvested from the umbilical cord to
provide stem cells for transplantation to the affected sibling. In such cases, PGD is
utilised to select embryos that do not have a genetic mutation that affects the family,
and also to select an HLA compatible stem cell donor from these embryos.
The intention generally is that the interests of the person born or to be born are
paramount. Every effort is made to both save an existing life and create a new life.
However, it is clear that the application of the technology in this way is novel, and
raises many ethical and social considerations beyond the immediate interests of the
couple seeking the procedure, or the terminally ill child. Key considerations, which
must be brought into an ethical consideration of an application (see reference 4), and
which can be covered in counselling, include:
i) the motivation and level of understanding of the parent in seeking to have an
additional child. If this motivation is solely for the purposes of furthering the
interest of an existing sibling, then this may raise concerns. However, if the
child is wanted for his/her own worth, then this may be justifiable. It can be
very difficult to identify the motivation for parents, faced with a terminally ill
child, and a desire to complete their family;
ii) the issues which may arise where the birth of a child does not resolve the
genetic condition for the existing sibling;
iii) the status of the child within the family and the relationships, which grow,
with the growth of all children within the family.
These matters should be the subject of consideration by an Ethics Committee.
Social selection for sex and desired traits
Social sex selection or family balancing is allowed in some jurisdictions but not in
Australia (see reference 2). PGD is generally not allowed for selecting desired traits,
for example, hair or eye colour or athleticism, in a person to be born. Knowledge of
the human genome, indeed an individual’s genome, will make such selections more
feasible in future with the consequent demand for the service. Communities need to
debate the ethical and other issues around these possibilities in readiness.
Donation for research
Gametes collected and embryos formed as part of an ART treatment procedure can
be made available for research. Pressure for such donations has increased recently
as a result of changes in regulations that allow research on human embryos and
cloning by somatic cell nuclear transfer (SCNT), particularly for the production of
embryonic stem cells. Despite legalizing this type of research in some jurisdictions, it
is predicted that there will be a shortage of human eggs for SCNT.
Altruistic versus shared donation of eggs
One potential source of eggs is an altruistic donation as part of an ART procedure.
The patient undergoes ovarian stimulation followed by egg pickup, after which the
good eggs are fertilized in vitro. It is possible before fertilization takes place for the
patient to donate eggs to research. The benefit is that the patient is not exposed to
any more risk than that associated with her ART treatment, compared to the altruistic
donor who is not on an ART program. The problem is that very few women are
prepared to donate eggs to research when they want as many as possible to improve
their chances of getting pregnant. In an attempt to overcome this resistance to
donation, clinics in the UK can reduce the service costs for their patients to have
ovarian stimulation and egg pickup if they are prepared to donate some of their eggs
for research. Critics of this option say that this constitutes comodification and
exploitation of the patient. They argue further that this constitutes payment for
gametes, not services, which is prohibited in some jurisdictions. Either way the final
decision must be the patient’s after being provided with the appropriate information
and making informed consent.
This is never likely to be a major source of human eggs for research, because of
desire of the patient to get pregnant with her own eggs, and the likelihood that the
degree of ovarian stimulation and hence egg numbers will be reduced as the
technology improves. A potential but as yet untested source of eggs could be those
frozen for future use (deferred conception) but no longer required. An alternative
solution to the shortage of human eggs is to allow the formation of hybrid embryos
using animal eggs which is possible in the UK, but banned in Australia (see reference
1). However, this has raised considerable community opposition in some countries,
because opponents claim that it blurs the distinction between humans and animals,
and creates embryos that are destined to be destroyed once the stem cells are
extracted.
“Science is the father of knowledge, but opinion breeds ignorance.”
Hippocrates
Conclusions
One in 8 couples is infertile with the cause equally distributed between the female
and male partners. ART has gone a long way to overcoming this infertility but it is not
a ‘cure all’. New and improved technologies and changes in community attitudes10
(10) now open the way for ART to be applied in ways that we had not envisaged 30
years ago. In particular, it can now be used for treating social infertility and selecting
for or against diseases and certain traits in persons to be born.
Regulation of ART in some jurisdictions has been driven by social, ethical, moral,
religious and political views. In those with proscriptive legislative regulation, it has
been found that the laws can quickly become out of date as the technology and
community attitudes change. Therefore, where regulation is desired by the
community, it is better that it is a framework flexible form that can easily adjust to new
developments. Alternatively, legislation could include a sunset clause that ensures
review within a set time frame. Furthermore, there is a case to consider only
legislating around the more controversial areas of the application of ART, leaving the
‘traditional’ use of ART to treat infertility in the same way as any other medical
procedure. The exception to this would be in cases where donor gametes or embryos
are used.
There will always be differences between countries, and even states and territories,
in the degree to which they regulate ART. This underlines the necessity for the health
and ethical professionals who work in ART to develop and promulgate consistent
guidelines that can be applied in as many jurisdictions as possible. This would not
only raise the level of success and professionalism in ART, it would also reduce the
potential exploitation of individuals and reduce the risks associated with reproductive
tourism.
Many areas of ART need more research. It is important that the principles of
evidence-based medicine apply to ART in all its aspects, including social and ethical
matters.
“Life is short, art long, opportunity fleeting, experience treacherous, judgment
difficult.” Hippocrates
______________
* Professor Jock Findlay, AM PhD DSc, Prince Henry’s Institute of Medical Research, Clayton
Victoria, Australia
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