Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 22, No. 1, pp. 219231, 2008

doi:10.1016/j.bpobgyn.2007.07.008
available online at http://www.sciencedirect.com

14

Ethical considerations of fetal therapy

Ray Noble * BSc, PhD, CBiol MBiol, FHEA

Director of Centre for Reproductive Ethics and Rights. UCL Institute for Womens Health

Charles H. Rodeck BSc, MBBS DSc(Med), FRCOG, FRCPath, FmedSci

Head of Department of Obstetrics and Gynaecology
UCL Institute for Womens Health, University College London, 8696 Chenies Mews, London WC1E 6HX, UK

Fetal therapy raises ethical concerns in relation to the balance of potential benefit and harm,
autonomy and informed consent, and the duties of the clinician to the pregnant women and fe-
tus. Invasive therapy should be recommended only when it has a realistic chance of saving the life
of the fetus and offspring or preventing serious and irreversible disease or disability. Clinicians
should respect maternal choice and assessment of risk, particularly if the therapy might be only
partially successful, leaving the offspring with a profound morbidity. Fetal therapy should not be
undertaken without maternal consent; nor should it be presented coercively as an option to
avoid a termination of pregnancy. Therapeutic procedures of unproven efficacy should be under-
taken only with the voluntary informed consent of the pregnant woman and according to
a clearly defined research protocol that has been approved by an appropriate research ethics
committee and where appropriate support and counselling can be provided.

Key words: autonomy; benefits; duties and obligations; ethics; fetal gene therapy; fetal therapy;
harms; informed consent; risks.

INTRODUCTION

Fetal therapies fall into four categories: transplacental drug treatment, gene therapy, in-
vasive procedures and fetal surgery. These present many common ethical issues, not
least because a given form of therapy might involve one or more of the other procedures.
However, specific ethical issues also arise, not the least of which is a consideration of

* Corresponding author. Tel.: 44 020 7679 6066.

E-mail address: r.noble@ucl.ac.uk (R. Noble).
1521-6934/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
220 R. Noble and C. H. Rodeck

what level of risk of harm might be considered acceptable in relation to potential benefit.
Ethical concern is raised in three key areas: the balance of potential benefit and harm,
autonomy and informed consent, and the duties of the clinician to the pregnant women
and fetus. In this chapter we argue that invasive therapy should be recommended only
when it has a realistic chance of saving the life of the fetus and offspring or preventing
serious and irreversible disease or disability. In recommending fetal therapy of proven
efficacy, clinicians should respect maternal choice and assessment of risk. This is partic-
ularly so if the therapy might be only partially successful leaving the offspring with a pro-
found morbidity. Such therapy should not be undertaken without maternal consent, and
nor should it be presented coercively as an option to avoid a termination of pregnancy. It
should be accepted that risk is not always easy to define or quantify in relation to per-
ceived potential benefits. Diagnostic and therapeutic procedures of unproven efficacy
should be undertaken only with the voluntary informed consent of the pregnant woman
and according to a clearly defined research protocol that has been approved by an
appropriate research ethics committee.

JUSTIFICATION FOR FETAL THERAPEUTIC INTERVENTION

Fetal therapy might be justifiable when: (1) there is reasonable certainty that the fetus
will suffer irrevocable and substantial harm without the intervention; (2) the interven-
tion has been shown to be effective; (3) the risk to the health and well-being of the
pregnant woman is negligible; and (4) the pregnant woman can give appropriate in-
formed consent to the intervention. In addition, the therapy should bring together
a team of consulting professionals in a collaborative and multidisciplinary approach
to care, both during and after the pregnancy, with clear strategies on communication,
diagnostic, therapeutic and care needs. Counselling should insure that parents under-
stand the range of possible outcomes for support after birth. Some fetal therapeutic
interventions, such as administration of steroids before birth to prevent hyaline mem-
brane disease and zidovudine to prevent the perinatal transmission of human immuno-
deficiency virus infection, are accepted practices of proven efficacy. Others, such as
fetal surgery to repair a diaphragmatic hernia, are not so proven, carry considerable
risk to the pregnancy and are not considered to be standard practice. Furthermore,
treatment after birth produces a high survival rate and there is little justification for
the considerable risks of fetal surgery.
An example of a therapy that might meet these criteria is the transfusion of fetal
blood to replace fetal red blood cells that are being destroyed by the Rh-sensitized
mothers immune system.1 This therapy could meet all four of the above criteria be-
cause a sensitized mothers immune system can destroy a large proportion of fetal red
blood cells, causing severe anaemia, fetal death or severe morbidity. Nevertheless, the
use of intrauterine fetal blood transfusions, although of proven benefit, carries risk to
both mother and fetus. In a severely affected fetus the transfusions might have to be
done repeatedly until the fetus is mature enough to be delivered safely. This poses
risks on each occasion including uterine infection, fetal infection, preterm labour, ex-
cessive bleeding and mixing of fetal and maternal blood, loss of amniotic fluid and fetal
death.1 If the woman refuses to undergo an intervention that poses a risk to her health
or to her fetus, her choice and assessment of risk should be respected. It should
equally be respected if she refuses for religious or other reasons.
One reason why antenatal intervention might not result in a better outcome than
conventional therapy is that any potential benefit can be negated by the substantial
 Ethical considerations of fetal therapy 221

fetal morbidity associated with the surgical procedure itself. Most pregnancies sub-
jected to antenatal fetal surgery end in preterm delivery. Fetal treatment to promote
the development of a hypoplastic lung by occlusion of the fetal trachea can be bene-
ficial, particularly in high-risk fetuses.2 Nevertheless, trial of this technique emphasizes
the potential complications of such interventions, especially premature rupture of the
membranes and preterm labour. In one randomized, controlled trial comparing fetal
tracheal occlusion with standard postnatal care, the mean gestational age at delivery
was 30.8 weeks with tracheal occlusion and 37.0 weeks with standard care. Fetal tra-
cheal occlusion did not improve survival or morbidity rates in this cohort of fetuses
with congenital diaphragmatic hernia.2

THE FETUS AS PATIENT: CONFLICT OF DUTY

Fetal therapy has the potential to alter the outcome of a pregnancy and profoundly
changes the choices available to the pregnant woman. Developments in fetal diagnosis
and therapeutic intervention present new ethical dilemmas and foster new attitudes to
both the pregnant woman and her fetus. The fetus is often regarded as a patient, if not
in its own right then at least with a quasi-independent consideration of interest.3 Ad-
vances in fetal medicine, particularly in ultrasound scanning, have been accompanied by
a changing view of the status of the fetus. If a baby can survive premature birth at youn-
ger gestational ages, then it is argued that there is little difference in moral status
between a late-gestation fetus and a newborn baby. Indeed, a fetus is referred to as
baby, as though it had a separate existence, or at least a separate consideration,
from that of its mother.
A fundamental of ethical clinical practice is a consideration of duty or obligation; the
nature of any duty, to whom it is owed and by whom; the extent of such duty and how
best it can be exercised. In particular, problems arise when there is a potential conflict
of duty. In fetal medicine there is a potential for conflict between the perceived duties
and obligations of the clinician and those of the pregnant woman; but also for a conflict
between duties owed by the clinician to the pregnant woman and perceived obliga-
tions to the well-being of the fetus or, specifically, the born baby. There is certainly
an ethical problem in deciding how best these perceived duties should be discharged.
The advent of fetal therapy and in-utero interventions has brought these potential
ethical problems into clearer focus.
It is argued that the duties of the obstetrician to the fetus arise because it is poten-
tially a born baby.4 A late-gestation fetus has a greater chance of being born alive and
so the obligations of the clinician to the well-being of the future child are greater. If
clinicians are considered to carry obligations of competence or negligence in relation
to the born baby, then it can be argued that they must carry such duties specifically to
the fetus, at least in late gestation. Thus, it has been argued that the status of the fetus
as a patient does not depend on an independent moral status.5 In this view, a human
being is a patient when a clinician has benefit-based ethical obligations to that being.4,6
A key to this concept of obligation to the fetus as a distinct patient is that of viability.
Thus there is a change in obligation of the physician once the fetus has a potential vi-
ability if born. The concept of viability attempts to make a distinction between the sta-
tus of a previable and viable fetus, where the former can be considered as a patient
only if the pregnant woman decides herself to confer such a status and the latter is
regarded as a patient regardless of the womans wish.6 However, there are several
problems with this concept of viability, in particular because it is not easily defined
222 R. Noble and C. H. Rodeck

or clearly demarcated in fetal development, especially where fetal therapy itself, such
as administration of steroids to mature the lung, might alter such a status. Viability is
dependent on the technological skills available and these will vary considerably in dif-
ferent circumstances and over time.7 The truth is that the fetus at any stage is depen-
dent on its mother in a way that a newborn baby is not; it cannot be treated other than
by invasion of the mothers body and thus it should not be treated without her con-
sent. The duties and obligations of others with respect to a born baby are distinct eth-
ically and legally because they can be discharged independently of the mother in the
interests of the baby. Developments in fetal medicine and fetal therapy present new
and difficult choices; the clinician has a duty to present such choices where they
have proven efficacy, and to inform the patient of the potential risks, but it is the preg-
nant woman who is the primary moral agent in relation to those choices and it is she
who bares the ultimate moral burden.
Reference to the fetus as a patient and the attempt to make an ethical distinction on
viability creates a potential conflict between clinician and mother.3 This can arise if
a woman refuses a diagnostic or therapeutic procedure considered by the clinician
to be beneficial to the fetus, or if her behaviour is considered harmful to the fetus.
In general, clinicians seek to avoid doing harm (principle of non-maleficence) and
always to do the best for their patient (principle of beneficence). Nevertheless, it
is the mother who ultimately must decide what is in the best interests of her fetus
and it is she who must give informed consent to any proposed treatment affecting
her fetus. Axiomatic to the womans right to consent to treatment is the right to re-
fuse treatment.8 Risks and benefits will be weighed differently by the pregnant woman,
particularly where this might involve religious or socioeconomic considerations, and it
is also the clinicians duty to apply the same ethical principles to the well-being of the
mother as patient as it is to the fetus, and to respect her autonomy. The right to in-
formed consent should not be predicated on agreement by the clinician or a judgement
on whether it is reasonable to withhold consent.8
In the UK, the Royal College of Obstetricians and Gynaecologists (RCOG) eth-
ical guidelines are clear: a patient is a person; a fetus is not a person.8 Furthermore,
in relation to UK law while the direct point has not been tested, there is consider-
able judicial authority to the effect that the interests of the fetus are necessarily
subordinated to the rights of the pregnant woman. A distinction between viable
and previable fetus does not alter the autonomy of the mother in relation to con-
sent to fetal therapy. Others have argued that obligations to the fetus must be ne-
gotiated with obligations to the mother, and that it is justifiable to move beyond
negotiation to respectful persuasion, and perhaps even to an ethics committee, as
part of a preventive ethics clinical strategy.6 Thus the concept of previable and vi-
able sets the scene for coercion of a pregnant woman to accede to fetal therapy or
to take the decision out of her hands if it is considered to be in the best interests
of the fetus.3 Such a contingent view of autonomy, where the pregnant woman has
the right to decide only if she behaves reasonably in the interest of her fetus, is
a potential source of discriminatory practice, where a woman has to demonstrate
that her behaviour is reasonable in the light of her circumstances. In relation to au-
tonomy, poor socioeconomic circumstances can be disempowering. Decisions that
might be considered reasonable could depend on family or other circumstances,
level of literacy, or ability to articulate wishes, concerns or interest. Clinicians
should also be mindful that the outcome of fetal therapy can be uncertain and,
whereas there might be a partial benefit to the fetus, this could create an unsatis-
factory outcome for the well-being of both mother and child. Arguably, the clinician
 Ethical considerations of fetal therapy 223

will not be the best judge of outcome in circumstances involving psychosocial or

religious factors. The choices available to the parents in relation to severe disorders
diagnosed in the fetus differ from those presented after birth. With the diagnosis of
a severe condition the parents might opt to terminate the pregnancy to prevent
suffering in the offspring; this is not an option available after birth.

FETAL GENE THERAPY

Fetal gene therapy (in-utero gene therapy; IUGT) offers a novel approach to the pre-
vention of severe manifestations of early-onset diseases. It has several key advantages
over gene therapy after birth, not least of which is that it might allow targeting of oth-
erwise inaccessible tissues with relatively low vector doses and it might avoid rejection
of therapeutic transgenic proteins.9 Developments in molecular screening techniques,
including DNA microarray technology, might expand the number of conditions diag-
nosed prenatally, with a consequent increase in demand for therapeutic intervention.
For many genetic disorders it will not be possible to use such therapies after birth. In
some disorders the damage occurs before birth and there might be good clinical rea-
sons to intervene in utero to attempt to correct the genetic damage.10 With sufficient
proof of principle from its use in animal models, the use of IUGT in humans is now
a real prospect.11 However, because of the potential for harm, it is vital that the key
issues are identified and addressed and that clear guidelines are established and fairly
applied in both research on humans and in clinical practice. Apart from problems of
safety and potential harm, issues arise in developing criteria for appropriate candidate
diseases or conditions, the process of recruitment and informed consent, and social
justice in relation to cost and access to treatment.
There have now been many human trials involving gene transfer techniques. Most of
these have been on adults or young persons and none has led to a successful gene
therapy in clinical practice, although there has been a successful reconstitution of im-
mune function in a child with the adenosine deaminase (ADA)-deficient form of severe
combined immunodeficiency (SCID) following haematopoietic stem cell (HSC) gene
therapy.12 Nevertheless there are good grounds in relation to efficacy for considering
the development of therapy prior to birth. The fetus presents a window of opportu-
nity because the immune system has not yet developed and it will be less likely to re-
ject a foreign agent; the fetus might become tolerant, allowing further treatment after
birth, again without the risk of rejection; and intervention in utero might permit
correction of a disorder before clinical manifestations have developed.
Fetal gene therapy has been proposed as most appropriate in disorders producing
irreversible illness or death in the pre- or neonatal period, such as type 2 Gauchers
disease, Krabbes disease and Hurlers disease. Such cases fulfil two ethical criteria:
(1) that there must be a clear advantage over postnatal gene therapy; and (2) that
there must be an advantage over any other form of therapy. However, fetal gene ther-
apy for such severe disorders presents specific and arguably the most complex of the
ethical issues, not least because two participants (mother and fetus) are recruited into
the trial, and one of which (the offspring) is unable to give consent to the procedure.
There is little evidence to suggest that gene therapy will be a magic bullet producing
total cure in all cases. If the condition of the fetus is one that normally leads to its
death before birth, a partially successful gene transfer might lead to a baby being
born with a severe/modified condition rather than a cure.
224 R. Noble and C. H. Rodeck

THE GENE THERAPY ADVISORY COMMITTEE (GTAC)

The 1992 report of the Committee on the Ethics of Gene Therapy (the Clothier Com-
mittee) recommended that gene therapy should be limited to life-threatening diseases
or disorders.13 To oversee and implement this, the Gene Therapy Advisory Committee
(GTAC) was established in 1993 as the UK national research ethics committee (REC)
for gene therapy clinical research under the Medicines for Human Use (Clinical Trials)
Regulations 2004. GTAC approval must be obtained before somatic gene therapy or
gene transfer research is conducted on human subjects.14 GTAC considers that gene
therapy has not yet developed to the stage where it can be considered as treatment.10
In its 1998 report taking account of the ethical and safety issues, GTAC concluded that
the use gene therapy in utero was unlikely to be acceptable for the foreseeable future.
Thus in the UK, all gene therapy is considered by the regulatory agency to be research,
and recruitment of patients into research trials takes place under strict rules set out by
GTAC, under principles elaborated by professional bodies and only after review of
clinical protocols by GTAC.
The GTAC subgroup on New and Emerging Technologies (NETS), reviewing the six
principles recommended by the Clothier Committee, concluded that these should
also apply to fetal gene therapy. These six principles state that:

1. Gene therapy is research and not innovative treatment.

2. Only somatic therapy should be considered.
3. In view of safety and ethical difficulties, germ-line interventions are off limits at
present.
4. Gene therapy should be restricted to life-threatening disorders for which no
current alternative effective treatments are available.
5. Patients should take part in gene therapy research trials only after a full explanation
of the procedures, risks and benefits and after they have given their informed con-
sent, if they are capable of doing so.
6. Recognizing that some people, including young children, might not be able to give
such consent, therapeutic research involving such patients must not put them at dis-
proportionate risk.

A fundamental principle in the ethical consideration of controlled clinical trials is that

of equipoise.15 This is usually applied to randomized, controlled trials in which it is not
known whether the trial treatment is better or worse than existing therapies or than
a control group. If it is known that it is no better, and if the potential harms are unclear,
then such a trial would be considered unethical. The trial treatment should have at the
least an equal potential therapeutic value to that which will be forgone by entry into
the trial and in relation to the perceived risks of harm. What this means is that there
should be good reason to believe that the new therapy will be better than existing treat-
ment. A similar principle can be applied to therapy in utero and the success of therapies
applied after birth. In the case of gene therapy this produces a problem because in those
conditions that might be considered to have the greatest likelihood of success, such as
cystic fibrosis, it is unclear whether the results in relation to potential harms would be
better than existing therapy. It is certainly arguable whether a partial success of gene
transfer would lead to a better outcome than if there had been no treatment at all;
the birth of a baby with a severe condition leading to death within months or a year might
be considered a worse outcome than if it had not been born alive.
 Ethical considerations of fetal therapy 225

INFORMED CONSENT AND HUMAN TRIALS FOR FETAL THERAPIES

Ethical research involving human participants is premised on two fundamental commit-

ments: (1) to improve human welfare by advancing knowledge and understanding of dis-
ease and treatment; but equally (2) to preserve and protect the dignity and health
interests of research participants. Clinical research aims to benefit individual partici-
pants and patient groups through the identification and testing of improved treatments,
and to benefit society by making them widely available. The justification for human trials
of new or potentially improved treatments is usually utilitarian in nature: the potential
for a greater benefit than existing treatments or choices being weighed against the risk
of harms. The potential risk of harm to participants has led to widespread agreement
that sound ethical standards must be observed in clinical research regardless of the per-
ceived benefits.16 The ends alone, no matter how good, are insufficient justification for
the means employed where they might unduly harm those involved. This is particularly
so when participants are unlikely to be the subsequent beneficiaries, or if they are likely
to carry a substantial burden of risk as participants in such trials. Research involving hu-
man subjects should thus be preceded by careful assessment of predictable risks and
burdens in comparison with foreseeable benefits to the subjects or to others (Helsinki
Declaration, article 10.16)16 and should only occur if the importance of the objective
outweighs the inherent risks and burdens to the subject (Helsinki Declaration, article
10.18).16 In this process, informed consent is a fundamental principle in any research in-
volving human participants; but consent can only be informed if the potential harms and
benefits are clearly understood or, if there is doubt, that the participants understand the
nature of such doubt. It should be clear what the proposed research or intervention
might achieve and who will be the likely beneficiaries.
In the case of human fetal therapy, it might appear that the beneficiaries are the par-
ticipants in the trial. However, this is not obviously the case, nor should it be assumed
to be the case. During the course of the trial, such participants might carry a burden of
risk considerably greater than those who might benefit from such treatment in the
light of knowledge gained from the trials. With uncertain success it would be wrong
to recruit participants on the grounds that their offspring might benefit. Arguably, at
this stage in the development of human fetal gene therapy, recruitment to such trials
should be considered to be an altruistic act by the participants, with the potential to
benefit others through the knowledge gained; a cure for the disorder of their offspring
specifically should not be offered as an inducement. It should be clearly understood
that the trial therapy might not succeed and they should be aware of the consequences
of choosing to take part in the trial. Furthermore, it is the parents who will have given
consent on behalf of their future offspring. Depending on outcome, there are potential
burdens on both the parents and offspring, particularly if the treatment is unsuccessful,
or if it is only partially successful.
Participation in human trials might affect immediate or subsequent choices in health
care. Assessing the impact of any human trial on choices is a fundamental ethical con-
sideration. Entering a fetal gene therapy, or other fetal intervention trial, might close
options for the parents that they might otherwise have chosen, particularly an option
to terminate the pregnancy to avoid giving birth to a profoundly handicapped offspring.
It is often presented as a benefit that fetal therapy might avoid the need for a termina-
tion of pregnancy. This presupposes that the potential success of therapy is sufficiently
high and sustainable. Furthermore, the outcome might not be known until after birth,
when the option for termination no longer exists.
226 R. Noble and C. H. Rodeck

A key issue in fetal gene therapy is whether sufficient is now known of the benefits
and risks to be able to recruit people for human trials with an appropriate level of in-
formed consent and in circumstances where the benefits clearly outweigh potential
harm. Eight years ago, in recognizing the potential of IUGT, the Recombinant DNA
Committee of the NIH concluded that In our present state of knowledge, it is pre-
mature to undertake any experiment involving human in utero gene transfer.17 It is un-
clear whether sufficient knowledge has now been gained for us to be confident that
any consent can be appropriately informed. But as we will argue, information on
risk and likely benefit alone is insufficient for appropriate consent to be considered
as informed; appropriate access to counselling and support is necessary to ensure
that there is sufficient understanding of the likely benefits and harms, and that support
is available in the event of a poor outcome. Furthermore, counselling in relation to
fetal gene therapy should be enabling in relation to all the choices and it should not
promote the potential benefits of gene therapy, nor should it be part of the trial re-
cruitment process. There is a particular problem with the term therapy in this regard
because it implies an inherent beneficence. At best, the term potential new treatment
should be used in recruitment to trials. As recommended by the GTAC, independent,
non-directive counselling should be made available.18
In any research trial, prospective follow-up is required to monitor any long-term
effects of the gene transfer. It would not be sufficient simply to judge the success
on immediate results in the fetus or neonate. This should be a requirement of the in-
formed consent process. Nevertheless, it is the offspring who will have been recruited
into the trial and it is their consent for continued participation that should be obtained
at some future date. It is most likely that repeat treatment would be required over the
lifetime of the individual, with potential risk of harm at each stage.

TERMINATION OF PREGNANCY AND RECRUITMENT

TO THERAPY TRIALS

A possible option would be to recruit parents who would not opt for a termination
even when the condition might be severe. This raises an issue of when and how par-
ticipants should be recruited to a trial. The problem with the term therapy is that it
implies an inherent benefit.19 Presenting it as an option or as an alternative to termi-
nation might place undue pressure on parents to consent to gene therapy because
they feel a moral obligation to do everything possible to avoid a termination, and to
do everything possible in the interests of their offspring. Given the uncertain outcome
of fetal gene therapy, this would be an inappropriate burden influencing the parents
decision at an emotionally difficult time. It should be clear to those recruited for
such trials that research is at a very early stage and the outcome is uncertain.
One approach to this dilemma would be to recruit only after a decision has been made
not to terminate. It should not be presented as an alternative to termination until trials
have established its efficacy and the risks are better known. Arguably the term therapy
should not be used. To avoid a potential conflict, the clinicians looking after the pregnancy
should not be involved in the trial, and certainly should not be involved in the recruit-
ment, as this might be seen to compromise their duty of care. A couple contemplating
the difficult decision of terminating a pregnancy needs time to consider the options
free of any other moral obligation to take part in a trial of an unproven therapy.
A nothing to lose or last chance approach to fetal gene therapy should be avoided.
People who are terminally ill might wish to participate in trials of new treatments
 Ethical considerations of fetal therapy 227

knowing that others could benefit from the knowledge gained a decision taken with
altruistic motives. They might also wish to take part because the new treatment, al-
though unproven, might give them some benefit. In such cases, they will be able to weigh
the potential benefits and harms in relation to their own circumstances, their needs and
specific motives and give an appropriate informed consent. It is tempting to conclude
that a fetus should be given a chance for life rather than to terminate where a potential
therapy exists. This runs on the concept that any chance of life is better than none. How-
ever, a partial success in such cases might lead to greater prolonged suffering in the
offspring and greater psychological and socioeconomic burdens on the parents.

SAFETY AND POTENTIAL HARM

The Clothier Committee, reporting in the UK in 1992, concluded that somatic human
gene transfer was no different to any other form of drug treatment and, as such, hu-
man trials of somatic gene transfer presented no new ethical problems.13 A similar
conclusion has been reached by other advisory bodies in Europe, the USA and else-
where. However, human trials of fetal gene transfer do present specific concerns
and distinct ethical problems. Gene delivery in utero carries specific procedural risks
not encountered in postnatal gene delivery including infection, fetal loss and induction
of preterm labour. Transplacental vector spread to the mother is also a risk factor,
with the potential for oncogenesis and germ-line transduction.11
The safety of gene therapy remains a major ethical concern in the development of
clinical trials. During the 1990s there were around 400 gene therapy trials involving
more than 4000 patients internationally. None of these trials has led to an approved
therapy. By 2000, the National Institutes for Health (NIH) in the US had recorded
691 serious adverse events during these trials, including six patient deaths.20
The injection of viral vectors into the amniotic fluid or peritoneal cavity of devel-
oping fetuses exposes the entire organism to the risks of insertional mutagenesis, on-
cogenesis and hence disruption of normal development. In November 2004, the UK
GTAC expressed concern about safety of some gene therapy vectors following
reports of the development of liver tumours in a preclinical study using lentiviral
vectors.21 Most of the tumours occurred in a group of mice that had been treated
in utero with a vector carrying the factor IX gene, although a small number of tumours
was also observed in animals that had been treated neonatally or had received vectors
carrying only marker genes.
Fetal gene therapy is unlikely to be a once and for all biogenic fix, and it is likely
that treatment will need to be repeated again and again during the course of a life-
time. This inevitably increases risk and burdens and should be part of any risk
benefit analysis. In most organs there is a turnover of cells as old ones die to be
replaced by new ones. For most gene therapy protocols the new cells are unlikely
to carry the modified gene. Key problems in developing gene transfer at therapeutic
level are getting the DNA into the target cells and getting the new DNA to express
appropriately. The most common method is to use viral vectors (genetically altered
viruses). The most promising are retroviruses, the DNA of which becomes part of
the genome of the cell infected and is replicated on cell division. This means it is
available through all generations of cells as they divide in the tissue and continue
to work over time. The problem is that these retroviruses can only work for targets
where the cells are dividing. Adenoviruses have an advantage in that they can infect
any cell and are used in developing therapies for cystic fibrosis. However, with
228 R. Noble and C. H. Rodeck

adenoviruses the DNA is not incorporated into the genome of the target cells and is
not replicated when the cells divide. Somatic cell gene therapy works only as long as
the transduced cells either live or give rise to new cells that also have the inserted
gene.
The potential benefits of fetal gene therapy are substantial but the potential for
harm is also considerable. Research trials should proceed with caution, although it
is not clear how such trials should be conducted as they do not fit clearly into the
stage 1 to 3 progression normally applied to clinical trials. First-stage clinical trials
for new treatments (phase 1) are conducted specifically to determine the safe dose
range, side effects and how the body copes with the treatment. Such trials are usually
conducted when there is sufficient preclinical evidence that the treatment is likely to
work. However, indications of safety obtained in animal models are difficult to transfer
to human pregnancy, particularly when interpreting results on safety obtained using
a model such as fetal sheep where pregnancy is much more robust and the fetus
unlikely to abort.
An ethical approach to clinical trials would ensure consistent standards for compar-
ison across different trials so that appropriate therapeutic values could be determined
and harm avoided; meaningful end-points or stages for determining efficacy; regular
evaluation of trial participants over time to ensure safety and sustainable outcome;
and a robust reporting of adverse outcomes.22 Sadly, this has not always been achieved
in the development of gene transfer trials.21
It has been argued elsewhere that expectation of gene therapy as a magic bullet
has fuelled the perception of gene therapy as the inevitable therapeutic goal.23 But
the truth might be that in general it has promised much but delivered little.24,25
The danger of this expectation is that fetal gene therapy becomes a goal in itself, where
legitimate ethical problems are to be overcome on the grounds that this must be the
better course for therapy to take. It tilts the utilitarian balance in considering benefits
and harms and, as a result, it lowers the ethical threshold for approval of clinical trials,
and subsequently for fetal gene therapy itself. Those engaged in development of fetal
gene therapy have their own societies, such as the American Society of Gene Therapy
and European Society for Gene Therapy (now European Society of Gene and Cell
Therapy), with the aim of promoting basic and clinical research in gene therapy.
A recent ESGT position paper on gene therapy states26:
Pre-clinical investigation carried out in animal models for many years and in
many different countries has provided little evidence that the use of genes or
gene-carrying vectors is more harmful or dangerous than conventional drugs
or therapies, supporting the initiation of clinical trials in human patients.
And with respect to human trials it argues: In general, no specific risk factor has
been associated to the use of genes, gene transfer vectors or gene transfer proce-
dures. Yet, for the same period of these trials, the NIH reports 691 serious adverse
events including six patient deaths.21 There needs to be a realistic assessment of the
anticipated benefits, acceptable risks and perceived need for gene therapy, and fetal
gene therapy in particular.

GERM-LINE GENE THERAPY

Unlike somatic gene therapy, the development of germ-line gene therapies offers the
prospect of eradicating gene-related disorders from the human gene pool. Germ-line
 Ethical considerations of fetal therapy 229

gene therapy is controversial because of its capacity for genetically engineering future
people, eradicating unwanted or adding desired traits. The argument is often pre-
sented in terms of a slippery slope.27 If diseases such as sickle-cell anaemia or can-
cers are to be eradicated by altering the human gene pool then it might be argued
that there would equal reason for doing so for other less-debilitating conditions or
traits, or for selecting traits on psychological or social preferences. The problem
here, then, is how a clear line could be drawn, or by what criteria certain conditions
might be excluded or included. Without clear criteria, it is feared that a line will not
hold.
This problem is generally recognized by governments and regulatory agencies,
which might prohibit the development of such therapies. Central to the concept of
moral equality and of human rights is that they are not contingent on any particular
characteristics; they are held simply on the ground that an individual is human. The
ethical problem lies in determining the nature of moral equality. Preferential selection
of traits as being good or bad, harmful or beneficial are considered to be value
judgements leading to discrimination on the grounds of whether humans do or do
not have such traits. But it is not clear why correcting a malfunctioning bit of DNA
should carry any greater moral impact in relation to such value judgements than
correcting the action of the protein the DNA builds.
It might be argued that, in reality, different societies or cultures do put a premium
on certain traits and that advantage is conferred on individuals who have them. Thus
we might value athletic, artistic or intellectual attributes and our society might reward
those who have these abilities. It is arguable that this reasoning misses the point that
we also value a diversity of such traits within the population. We do not expect, nor
require, that any given individual should be endowed with all these abilities. Nor do we
use them in determining human rights or access to justice. It is in the nature of human
survival that we share these attributes, not by each of us possessing them equally but
by all benefiting from the diversity of talents within a community. We do not expect
a long-distance runner also to be a leading sprinter but our society benefits from
both these traits.
Harris28 questions the notion that selection of characteristics at an individual level
carries the same moral problem as when this is applied by a society. To eradicate dis-
eases does not suggest that those who have such diseases are of less moral worth; else
we could contend that the use of any therapy to eradicate a given condition, such as
deafness, would imply that all those with such a condition all deaf people were of
less value than those who were not deaf. The distinction here is between a decision at
society level to alter the human gene pool to improve or make more perfect human
beings, which is arguably a different motive than selection to eradicate human suffering
resulting from disease.
The major concern with germ-line therapy remains the potential unseen and long-
term consequences. We know very little of the way in which mutations might produce
both harms and benefits. Genes that might be harmful in one set of circumstances
might confer an advantage in another. The classic example is the higher resistance
to malaria for heterozygote carriers of the sickle-cell gene mutation.26 Balanced selec-
tion maintains more than one variant of a gene in the population as a result of both the
harms and benefits they confer in different circumstances. Another classic example of
this in biology would be Biston betularia, the peppered moth, which has both dark and
white polymorphic states that confer selective advantage or disadvantage in relation to
the background.27 To manipulate the germ-line with insufficient knowledge of long-
term consequences would be a high-risk strategy.
230 R. Noble and C. H. Rodeck

SUMMARY

In this chapter we have argued that invasive fetal therapy should be recommended only
when it has a realistic chance of saving the life of the fetus and offspring or preventing
serious and irreversible disease or disability. In recommending fetal therapy of proven
efficacy, clinicians should respect maternal choice and assessment of risk. This is par-
ticularly so when the therapy might be only partially successful, leaving the offspring
with a profound morbidity. Such therapy should not be undertaken without maternal
consent, and nor should it be presented coercively as an option to avoid a termination
of pregnancy. It should be accepted that risk is not always easy to define or quantify in
relation to perceived potential benefits. Diagnostic and therapeutic procedures of un-
proven efficacy should be undertaken only with the voluntary informed consent of the
pregnant woman and according to a clearly defined research protocol that has been
approved by an appropriate research ethics committee.

Practice points

 Fetal therapy should be recommended only when it has a realistic chance of

saving the life of the fetus and offspring or preventing serious and irreversible
disease or disability.
 In recommending fetal therapy of proven efficacy, clinicians should respect
maternal choice and assessment of risk.
 Such therapy should not be undertaken without maternal consent, and nor
should it be presented coercively as an option to avoid a termination of
pregnancy.
 Diagnostic and therapeutic procedures of unproven efficacy should be under-
taken only with the voluntary informed consent of the pregnant woman and
according to a clearly defined research protocol that has been approved by
an appropriate research ethics committee.
 Counselling should insure that parents understand the range of possible out-
comes and for support after birth.

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