Human Reproduction Update Advance Access originally published online on December 3, 2007
Human Reproduction Update 2008 14(1):83-94; doi:10.1093/humupd/dmm037
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Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders
1 Department of Health, Ethics and Society, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands 2 Bioethics Institute Ghent, Ghent University, Belgium 3 Department of Genetics and Cell Biology, Faculty of Health,Medicine and Life Sciences, Maastricht University, The Netherlands
4 Correspondence address. E-mail: a.bredenoord{at}zw.unimaas.nl
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Abstract |
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Abstract
IntroductionThis paper aims to address the ethical issues regarding prenatal diagnosis and preimplantation genetic diagnosis (PGD) of mitochondrial disorders. Owing to the absence of effective treatment, the prevention of the transmission of mitochondrial disorders is considered to be of key importance. The characteristics of mtDNA, such as heteroplasmy and the genetic bottleneck, make it difficult to estimate recurrence risks correctly and to provide an accurate prognosis for many mtDNA mutations. A limited number of mtDNA mutations allow reliable predictions, though results in the ‘grey zone’ are problematic. Both prenatal diagnosis and PGD for mtDNA disorders are complicated by the interpretation of the test results. As a consequence, these applications confront both clinical practice and society at large with several ethical questions and issues for further debate, among which the acceptability of suboptimal genetic testing, the value and research use of embryos, the evaluation of late abortion, the ethics of PGD for disorders with an incomplete penetrance and variable expression, the possible transfer of embryos with residual health risks, the acceptability of risks and drawbacks of genetic reproductive technology in general, and the scope and limits of reproductive autonomy and professional responsibility.
Key words: ethics / prenatal diagnosis / preimplantation genetic diagnosis / mitochondrial disorders
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Introduction |
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Mitochondrial disorders or diseases due to the defects of oxidative phosphorylation are mostly severe disorders, caused by defects in energy production and affecting at least one in 8500 individuals. Usually the most energy demanding tissues such as the central nervous system, heart and skeletal muscles, liver and kidney are affected. Mitochondrial disorders cause chronic morbidity and can be fatal. They can be discerned in three groups (Thorburn and Dahl, 2001
):- Diseases with a known pathogenic mutation in a nuclear-encoded gene.
- Diseases with a respiratory chain enzyme defect in which no pathogenic mutation has yet been identified (i.e. deficiencies with an unknown genetic cause).
- Diseases with a known pathogenic mutation in an mtDNA-encoded gene.
Disorders from the first group follow a Mendelian pattern of autosomal recessive, dominant or X-linked disease inheritance. Diseases due to mtDNA-defects (Group 3), however, have some specific characteristics. First, mutations are usually heteroplasmic, i.e. there is a mixture of normal and mutant mtDNA, the level of which can differ among tissues. If the mutant load, i.e. the ratio of mutant to normal mtDNA, exceeds a tissue- and individual-specific threshold, clinical features become manifest, although exact genotype–phenotype correlations are usually lacking even within families. Second, the mtDNA is exclusively maternally inherited. The percentage heteroplasmy of point mutations in the offspring is related to the mutation percentage in the mother (Chinnery et al., 1998), but extreme shifts in mutation percentages are observed due to the genetic bottleneck (White et al., 1999a,b,c; Carelli et al., 2002), which occurs during oocyte development. These characteristics make it difficult to provide an accurate prognosis for many mtDNA mutations and to estimate recurrence risks correctly. Owing to the absence of effective treatment (Chinnery et al., 2006), the prevention of the transmission of mitochondrial disorders is of key importance (White et al., 1999a; Graff et al., 2000; Chinnery and Turnbull, 2001; Dahl and Thorburn, 2001; Thorburn and Dahl, 2001; Thorburn, 2004; Jacobs et al., 2005a,b; Brown et al., 2006; Schapira, 2006; Spikings et al., 2006). Prenatal diagnosis for most mtDNA mutations is, however, troublesome. Three criteria have been proposed to select those mutations for which reliable prenatal diagnosis can be offered (Poulton and Turnbull, 2000):
- There is a close correlation between the level of mutant load and disease severity.
- There is a uniform distribution of mutant mtDNA in all tissues.
- There is no change in mutant load with time.
These criteria seem reasonable, since together they determine the predictability of the phenotype, but it is evident that only few mutations meet these requirements. The correlation between the level of mutant load (genotype) and phenotype is low or unknown for many mtDNA diseases. Furthermore, exact threshold values cannot be defined, and interpreting intermediate levels of mutant load is problematic (the so-called ‘grey zone’) (Poulton and Turnbull, 2000; Poulton and Marchington, 2000; Thorburn and Dahl, 2001; Brown et al., 2006).
Preimplantation genetic diagnosis (PGD) can be an alternative for prenatal diagnosis. PGD presupposes IVF with or without ICSI. One or two cells are dissected for genetic analysis. This usually happens at the 8-cell stage, but PGD is sometimes performed on polar bodies. After the genetic analysis, only the unaffected embryos will be transferred (Health Council of the Netherlands, 2003; Sermon et al., 2004). However, the characteristics of mtDNA genetics are complicating PGD as well. As both prenatal diagnosis and PGD to prevent mtDNA and mitochondrial disorders with unknown genetic cause raise specific ethical questions, this paper aims to clarify the central ethical issues involved. Furthermore, we will pay an attention to the issues that need further scrutiny and debate now that the field of mitochondrial genetics is rapidly growing.
As specific moral issues are mainly raised by prenatal diagnosis or PGD for diseases with an unknown genetic cause (Group 2) and mtDNA-caused disease (Group 3), and to be more precise about the specific moral questions, another classification is first proposed to guide the ethical debate. This classification is based on the characteristics of the specific mutations.
1. De novo mutations with a low recurrence risk
At least one-third of adults with mtDNA disease have a de novo or sporadic mutation. Parts of these are point mutations, but the majority of these patients have a single mtDNA deletion with no or a low recurrence risk (Chinnery, 2002). Observations by Chinnery et al. (2004) suggest that clinically unaffected mothers are highly unlikely to have more than one affected child, but affected women have, on average, a 4% risk of having a clinically affected child. Examples are the three deletion syndromes: progressive external ophthalmoplegia, Kearns Sayre syndrome and Pearson’s syndrome. Prenatal testing has been performed for mtDNA deletions, mainly for reassurance, but interpretation of the result in case of a mutation found in the chorionic villous sample would be complex and dependent on the nature of the mutation.
2.Inherited mutations
a. Stable mutations, with a predictable outcome. Prenatal diagnosis or PGD is generally accepted for the few mutations that, broadly speaking, provide reliable predictions and meet the three criteria proposed by Poulton and Turnbull (2000). The main examples are the mutations m.8993T>G and m.8993T>C, leading to the neurodegenerative diseases NARP (neurogenic muscle weakness, ataxia, retinis pigmentosa) and Leigh syndrome. Both mutations have a strong genotype–phenotype correlation and show very little tissue-dependent or age-dependent variation in mutant load (White et al., 1999b,c; Dahl et al., 2000). When a test result shows mutant load <60%, the child is very likely to be healthy. When a test result shows mutant load >90%, the child is very likely to be affected. For results in between these are much less clear, as for these mutations a grey zone exists between 60 and 90% mutant load (Tatuch et al., 1992; Ciafaloni et al., 1993). Prenatal diagnosis for both mutations is feasible and has been offered with good results (Harding et al., 1992; White et al., 1999a,b; Leshinsky-Silver et al., 2003; Steffann et al., 2007), although outliers have been reported as well (Enns et al., 2006).
b. Unstable mutations, with an unpredictable outcome. Sufficient data show that for some mutations making reliable predictions is very troublesome. They do not meet the Poulton and Turnbull criteria. An example is the m.3243A>G mutation leading to MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), one of the most common mtDNA disorders (Poulton and Turnbull, 2000). The m.3243A>G mutation is problematic, because there is no clear genotype–phenotype correlation and the mutation load differs among tissues and changes in time. Previous research has shown that there is a rough relation between the severity of the clinical phenotype, the maternal mutation load and the frequency of affected offspring, but this is not sufficiently predictable for individual cases and exceptions do occur (Chinnery, 2002; Chou et al., 2004). In spite of this, and considering the limitations, prenatal diagnosis for the m.3243A>G mutation is being offered (Bouchet et al., 2006).
c. Mutations with an unknown outcome. For private or family-specific mutations, insufficient information is available to judge if these mutations allow sufficient reliable predictions and meet the Poulton and Turnbull criteria. This makes it difficult to identify potentially healthy offspring. Oocyte sampling might be useful as a preliminary step to determine the distribution of the mutation load and the number of mutation-free oocytes. Although it is not sure that the information obtained is representative for the oocyte and possible future embryo, it could be used for preconception counselling (Poulton and Marchington, 2002). An example is the m.9176T>C mutation. Prenatal diagnosis for this mutation (leading to Leigh syndrome) seems technically reliable, but the prognostic predictions are not straightforward (Jacobs et al., 2005a,b).
Homoplasmic mutations are present in 100% of the mtDNA. Homoplasmic mutations are genetic risk factors for the development of, e.g. Leber hereditary optic neuropathy (LHON, hearing loss or cardiomyopathies). Prenatal testing to assess the mutant load is useless, as the mutation load will always be 100%. However, in some cases prenatal testing might nevertheless be considered for other reasons. For example, for LHON, sex selection could be performed to exclude males. Males have a 50% lifetime risk of blindness compared with that of 10% for females. Most male and female patients experience visual loss in their late teens or early 20s (Man et al., 2002). The recurrence risks are well established from previous pedigree analyses (Chinnery, 2002).
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Prenatal diagnosis for mtDNA disorders: ethical issues |
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Prenatal diagnosis for Mendelian and chromosomal disorders has been extensively discussed, predominantly because of the link with selective abortion (see e.g. Katz Rothman, 1986
; Sutton, 1990; Clarke, 1998a,b; de Wert, 1999; Buchanan et al., 2000; Steinbock, 2002; Wertz et al., 2003). There is, at least in Western countries, a strong consensus that prenatal diagnosis can be morally justified. But what about prenatal diagnosis for mtDNA disorders? Prenatal diagnosis for most mtDNA mutations is complicated by the interpretation of the test results. All publications in the field emphasize the difficulties in making reliable predictions. These particularly regard intermediate levels of mutant load, when ambiguous information must be dealt with. The criteria of Poulton and Turnbull (2000) suggest that a prenatal test should have a strong predictive character, i.e. it should be possible to predict the phenotype with a high degree of certainty. At this moment, for most mtDNA mutations the predictive character of the test results is troublesome. Only testing for the heteroplasmic stable inherited mtDNA mutations (category I.2.a) yields high chances that the test results are able to predict the phenotype, at least when the test result shows mutant load outside the grey zone, thus, in other words, <60 or >90%.
Whether genetic testing is acceptable, partly depends on the interpretation of two ethical core concepts: non-directive counselling and informed consent. Key publications in the field of mtDNA disease all emphasize the importance of adequate genetic counselling and carefully obtaining informed consent (e.g. Poulton and Marchington, 2000; Thorburn and Dahl, 2001; Bouchet et al., 2006; Brown et al., 2006). However, both concepts are ambiguous and open for discussion. Different interpretations of these concepts will lead to different views regarding the acceptability of prenatal diagnosis for mtDNA disease. Every person involved in mtDNA genetics and reproductive decision-making, whether physician, researcher or otherwise, has, explicitly or implicitly, an ethical opinion about these concepts.
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Non-directive counselling |
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Non-directive genetic counselling is the standard in clinical reproductive genetics. Freedom of choice and patient autonomy are essential goals of genetic counselling (Wertz et al., 2003
). However, the meaning of (non-) directivity is unclear: when is a genetic counsellor inadmissibly directive? Does non-directivity imply the providing of unconditional support, whatever the clients request (de Wert, 1999)? What should be the ethos of genetic counselling (Clarke, 1998a; Wertz et al., 2003)? Furthermore, it has been emphasized that the social context in which individuals make reproductive decisions is relevant, both on the socio-political level and in a private context (Clarke, 1998b). When health care professionals counsel patients about preventing an mtDNA disorder, they should be aware of the scope and limits of non-directive counselling. Personal opinions about prevention, prenatal diagnosis and PGD may influence their counselling and the decision-making process of their clients. This is particularly important when difficult and precarious decisions seem unavoidable, like in the case of the m.3243A>G mutation leading to MELAS (category I.2.b).
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Informed consent |
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There is a strong consensus that informed consent is a necessary condition for medical interventions in general and genetic testing in particular. Consent should be based on the understanding of adequate and accurate information (Kuhse, 2002
). This process of informed consent should also encompass the pre-test counselling phase (Abramsky, 2003). Indeed, deciding whether or not to have a genetic test at all is one of the most important steps in the decision-making process. This counts even more for mtDNA disorders, as there are many uncertainties to be explained to and understood by the parents. In other words, all intricacies should be assessed right from the start. Nevertheless, the exact prerequisites of informed consent are subject to discussion. Is informed consent a sufficient condition, or merely a necessary condition?
At one end of the scale, any treatment or intervention is acceptable when adequate informed consent is obtained. Informed consent is interpreted as a procedure, with guaranteed ethically acceptable outcomes, provided the procedure of informed consent is carried out correctly and adequate (pre-test) counselling has occurred. Applied to the context of testing for mtDNA mutations, it would be sufficient to clarify ‘prior to’ testing the possible drawbacks of testing. These possible drawbacks include the considerable amount of uncertainty and the possible false-negative and false-positive results. Thus, even when there is hardly any predictive information, such as for the private point mutations, or when it is known that only ambiguous information is at hand, as for the m.3243A>G mutation, testing would be justified if clients give informed consent. Parents should be enabled to make their own decision, because it mainly affects their lives and not the doctor’s. When parents request prenatal diagnosis for the m.3243A>G mutation, one could decide to offer this and leave the decision up to them, after adequate counselling (Chou et al., 2004). Clearly, this interpretation leaves maximal space for reproductive autonomy. This is usually defined as the right to control one’s own procreation unless the state has a compelling reason for denying a person that control (Dworkin, 1993; Harris, 1998). The scope and precise substance of ‘compelling reasons’ is, of course, the subject of discussion. Most will accept this (negative) right to control one’s own procreation, but whether this also implies a positive right of assistance to realize those rights and a correlating duty of the physician is less clear (Nys et al., 2002).
At the other end of the scale, it is argued that informed consent is a necessary condition, but not sufficient. This position adds some substantial preconditions. To be a good doctor, the professional standard requires several conditions that have to be met before a treatment can be offered. The criteria proposed by Poulton and Turnbull (2000) can be perceived this way. Authors who commit themselves to these criteria thus acknowledge that mere informed consent is not enough. There are additional criteria; the amount of false-negative and false-positive results should be limited and the test should have a sufficient predictive character. If not, it should not be offered, even when parents insist.
This more restrictive attitude towards the offering of tests can be founded on several theoretical notions. The first background theory regards the concept of futility, the goals of medicine, and more in particular the goals of prenatal diagnosis. According to this view, the available data for most point mutations are simply insufficient to construct a balanced informed consent. Even more, testing for these mutations might be called medically futile. The main aim of prenatal diagnosis is to inform parents about the health of the fetus, enabling them to make informed reproductive choices. If this information is inaccurate, the goals of prenatal diagnosis are lost; the test does not provide clarity and reassurance, but uncertainty and distress. From a moral point of view, testing will become increasingly problematic as the test results become more unreliable.
A second base of a more restrictive attitude towards testing may be classic paternalism. Although autonomy is a worthwhile ideal, in reality illness, uncertainty and other circumstances make people dependent and restrict freedom and autonomy (Gaylin and Jennings, 2003). Informed consent as a sufficient condition is therefore, according to this view, unacceptable. Paternalism may be legitimate, because people are in a far from ideal situation, strongly desiring healthy children. This may affect their autonomous decision-making capacity and therefore, it is not acceptable to burden people with such difficult decisions. Furthermore, patients have to be protected against too high a percentage of false-negative and false-positive or insufficient predictive test results.
A middle road to introduce new applications of prenatal diagnosis (and PGD) may be to introduce the test only as part of scientific research. When in doubt about the acceptability of a new application, it could be performed in an experimental setting, with very small numbers of patients. This may be an appropriate format when only very limited information is available about specific mutations, such as the private point mutations (category I.2.c), but also for the unstable mutations (I.2.a). After evaluation of the experiences of the people involved, a better-founded decision can be made about whether or not to continue. In this situation, the ethics of medical scientific research would provide guidance. Of course, careful criteria of inclusion should be formulated.
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Terminating pregnancy |
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If the prenatal test indicates the presence of mutant mtDNA, termination of pregnancy is an option. Besides the general ethical, psychological and social difficulties of terminating a pregnancy on genetic grounds (Katz Rothman, 1986
; Korenromp et al., 1992; Warren, 1998; Tooley, 1999; Gillon, 2001; Wertz et al., 2003), considering selective abortion after prenatal testing for an mtDNA mutation is further complicated by the uncertainty of the data and the possibility of repeating the testing in the third trimester, which might result in a late termination of pregnancy. Selective abortion based on uncertain data
The uncertainty of the test results may cause additional difficulties when considering the termination of pregnancy. None of the publications in the field of the prevention of mtDNA disease pay attention to this. These additional difficulties arise, first, from a psychological perspective. Couples who decide to terminate the pregnancy when there is (some) uncertainty about the severity of the defect or the accuracy of the diagnosis are at higher risk for prolonged grieving after the termination. When the genetic defect of the fetus could not be diagnosed with certainty or when the severity of the defect was uncertain, couples’ doubts about the rightness of the decision increase. It seems optimal when as few uncertainties as possible about the effects, prognosis and life expectancy of the future child are left (Korenromp et al., 1992; Garret and Margerison, 2003). For most mtDNA mutations, this is exactly the problem, for both the expression and the penetrance of the disease are uncertain and hard to predict.
Furthermore, ethical difficulties may arise when due to suboptimal data an unaffected fetus may be aborted. Whether it matters ethically that the decision to terminate the pregnancy is based on uncertain data, depends on the moral status assigned to a fetus. Broadly, we can discern three standpoints (Bewley, 2003; Tooley, 1998; Gillon, 2001; Pennings and de Wert, 2003). The first position holds that the embryo is a person from conception onwards, with full human rights, deserving full protection (Sacred Congregation for the Doctrine of Faith, 1987). A variant holds that the embryo, even if not yet considered to be a person, still deserves full protection because of its inherent potential to become a person. Clearly, (selective) abortion is, then, unacceptable. The second position, the gradualist or intermediate view, considers the fetus to have some independent moral status, which is increasing throughout pregnancy (Gillon, 2001). By adopting the gradualist view, the general intuition that an abortion becomes more problematic the later it is performed can be explained (MacMahan, 2002). Selective abortion, then, is considered to be justified only when other interests overrule the moral value of the fetus. These interests might be the health of the mother and the prevention of severe harm to the future child. Terminating a possible unaffected fetus due to suboptimal data might complicate the balance. Also the value assigned to reproductive autonomy is important here. Finally, the third position states that the fetus has no independent moral status. Whether it should be treated with respect and care depends on the intentions of the couple, in particular the woman. Those adhering to the third position have no moral problems with selective abortion if this is the parents’ decision. Of course, psychological problems may remain.
Prenatal tests to prevent mtDNA disease, at this moment, are far from perfect. Fetuses that could have developed into healthy children may be aborted. Some will accept this as an unavoidable side-effect of fallible technology. Others will consider this a bridge too far. This, however, is not unique for mitochondrial genetics. Other examples exist where pregnancies are terminated when there is a chance that the future child would have been healthy; e.g. Duchenne’s muscular disease. For some couples, the only type of prenatal diagnosis is fetal sexing, with the option of terminating the pregnancy when the fetus is male. This means that in half of the cases a healthy fetus is aborted (Garret and Margerison, 2003). Another example may be prenatal exclusion testing for Huntington’s disease. This test is applied when potential carriers wish to exclude transmission of the mutation to their offspring, but at the same time do not want to know their own genetic status. Here also, an unaffected fetus is aborted in 50% of the cases (while full testing would have avoided this) (de Wert, 2002; Jacopini et al., 2002; Zoeteweij et al., 2002). These practices set a possible precedent for mtDNA mutations.
Previously, we made a distinction between mitochondrial disorders caused by a known pathogenic mutation and mitochondrial disorders with an unknown genetic cause, but with a biochemical deficiency. For the latter group, biochemical (enzyme-based) tests may be offered. There are, however, limitations to such testing because, again, the reliability is not optimal. This means false-negative results and a lot of ‘noise’ in the testing results (Bouchet et al., 2006). A normal test result in week 10 cannot exclude an affected child (Faivre et al., 2000). A possible solution would be sequential testing. Some (Faivre et al., 2000; Steffann et al., 2007) suggest performing an additional amniocentesis in weeks 28–30 of gestation, e.g. to avoid false-negative results due to possible late expression of the biochemical defect. Testing at several times, including the third trimester, may technically be the best option to decrease the uncertainty, but it raises some new ethical issues. First, these tests may cause fetal loss. Second, when a test in week 28 shows an adverse outcome, a late, i.e. third trimester, abortion needs to be considered.
In the discussion about late abortion, the legal and moral status of late abortion should be discerned. Whereas in some countries late abortion is prohibited, other jurisdictions do not make a distinction between early and late abortion (e.g. World Health Organisation, 2003; Visser et al., 2005). For the ethical discussion, the moral status of the fetus is a crucial point. For people assigning absolute or high moral status to the embryo right from the start, the timing of abortion is ethically irrelevant. Those assigning no independent moral status to the fetus will leave the decision in the hands of the couple, more specifically the mother. Late abortion is most complex for those who assign a growing moral status to the fetus (the gradualist view). After all, as the fetus develops, its moral value evolves as well (Sprang et al., 1998).
Viability, usually defined as the (potential) ability of the fetus to survive outside the uterus, is often regarded as a highly relevant moral dividing line (Chervenak et al., 1995; Sprang et al., 1998). It is presumed to exist after 24 weeks of gestation and not prior to 20 weeks. The weeks in between form a grey zone (Human Fertilisation and Embryology Act, 1990; Gans Epner et al., 1998). Others deny or question the ethical importance of viability (Fost et al., 1980; Rhoden, 1986; Grimes, 1998). In any case, late abortion causes an additional grief for both parents and staff (Boxall and Turner, 2003). The further the pregnancy is progressed, the more difficult the decision to terminate becomes for couples (Korenromp et al., 1992). No doubt, developments in preventing mtDNA disease require further reflection regarding the moral weight of viability and the ethics of late abortion.
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PGD for mtDNA disorders: ethical issues |
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Although many ethical issues raised by PGD are the same as for prenatal diagnosis, PGD is not just a simple alternative to prenatal diagnosis. After all, there are preliminary moral issues surrounding assisted reproductive technology in general, and IVF and ICSI in particular. Most authors and practitioners do not support these objections to assisted reproductive technology (e.g. de Wert, 1998a
; Kuhse, 2002; Pennings and de Wert, 2003). The objections to PGD mainly regard risk and safety issues, the discarding of embryos, the selection of embryos, the slippery slope and fears for eugenics (King, 1999). Notwithstanding these objections, there is a strong consensus that PGD is justifiable as well, at least for severe genetic disorders (Fasouliotis and Schenker, 1998; Buchanan et al., 2000; Verlinsky and Kuliev, 2000; Steinbock, 2002; Robertson, 2003; Klipstein, 2005; Kuliev and Verlinksy, 2005a,b; MacMahan, 2005; Dresser, 2006). There also seem to be some obvious advantages of PGD compared with prenatal diagnosis, such as the possibility to avoid a termination of pregnancy (Fasouliotis and Schenker, 1998; Verlinsky and Kuliev, 2000; Lashwood, 2003). One could say this advantage comes even more to the fore when selective abortion is complicated by the uncertainty of the data.
As far as we can see from the literature, PGD for mtDNA disease has currently been reported only once. It has been successfully applied in a family with the m.8993T>G mutation (Steffann et al., 2006) and seems technically feasible for other mtDNA mutations as well (Brown et al., 2006). However, since the chance of making reliable predictions is higher, the opportunities for the stable inherited heteroplasmic mutations (category I.2.a, including the m.8993T>G mutation) seem better than for the other mutations (Steffann et al., 2006). The uncertainty that, at this moment, is inherent in prenatal diagnosis of most mtDNA mutations complicates PGD for mtDNA disorders as well. Some ethical topics are similar to those we have discussed in the context of prenatal diagnosis, especially the issues of genetic counselling and informed consent. We will not repeat these issues here. But PGD also raises ‘additional’ ethical questions. Whereas in case of prenatal diagnosis, informed consent and reproductive autonomy may be restricted on grounds of two background theories, PGD brings in a third background theory, regarding the special responsibility the physician takes in this field. Furthermore, PGD might give greater choice to couples, which also can raise new issues. Before we will discuss the implications of these contextual factors of PGD combined with the uncertainty of mtDNA genetics, the issue of embryo research will be briefly considered.
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Embryo research |
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Preclinical embryo research can be useful for two reasons: first, to develop reliable pre-implantation diagnostic tests and, secondly, to study mtDNA inheritance, i.e. for scientific research regarding early-embryonic development and the distribution of mtDNA. One publication in the field explicitly refers to this need for embryo research (Steffann et al., 2006
). To investigate mtDNA inheritance, the embryos should carry an mtDNA mutation. Embryo research needs debate for several reasons.
First, views regarding the moral status of the embryo are important, both for the evaluation of research using surplus embryos and because it may be necessary, due to the unsuitability of surplus embryos, to create embryos. Although we notice a slow move towards a more liberal regulation, creating embryos for research purposes is at this moment for many countries unacceptable. 1t is also prohibited by the Convention on Human Rights and Biomedicine (Council of Europe, 1997; Strong, 1997; Olsthoorn-Heim, 2006). A second point is whether asking women to donate oocytes for research is morally justified. Dean et al. (2003) note that obtaining oocytes or embryos from women with mtDNA mutations is difficult. One could of course ask a carrier of an mtDNA mutation to create and give up embryos for research, but the question remains whether this is justified. Oocyte donation for research is a topic of international debate, for two reasons. First, what about the proportionality, also in light of the health risks for the donor. And secondly, there is debate regarding how to ensure voluntariness and how to avoid undue pressure (Hyun, 2006; Mertes and Pennings, 2006). To assess the proportionality, two distinctions may be morally relevant. A first distinction can be made between oocyte donors who are subfertile, opting for IVF anyway and oocyte donors who will undergo IVF solely to donate oocytes for research. The development of in vitro maturation is morally relevant here as well, since it implies that hormonal stimulation is no longer necessary. A second distinction can be made between healthy women donating an embryo for research purposes and patients donating, thus, women carrying an mtDNA mutation. In the latter case, the woman may already have a treatment relationship with a particular physician or hospital. This may be both an argument for and against donating. Defenders of oocyte donation for research argue that due to this treatment relationship the woman will be particularly motivated to make a contribution. Others fear undue influence and pressure by the physician to donate embryos. Clearly, further debate about embryo research and oocyte donation for research, also in the context of mtDNA genetics, is needed.
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The responsibility of the health care professional |
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Assisted reproductive technology is characterized by the fact that the doctor is involved in the normally two-person enterprise of making a baby (Purdy, 1998
). There is a strong consensus that the involvement of the fertility specialist in the conception of the child implies some kind of responsibility towards this child (Health Council of the Netherlands, 2003; Human Fertilisation and Embryology Authority, 2003; Purdy, 1998; de Wert, 1998b, 1999). However, the precise implications of this professional responsibility, its extent and limits, are much less clear, both for the fertility specialist and for the geneticist (Clarke, 1998b). Furthermore, a tension can exist between the responsibility of the health care professional and the reproductive autonomy of the parents. What if parents, carrying an mtDNA mutation, ask for medically assisted reproduction? Some emphasize the monopoly position and social role of the physician, leading to a prima facie obligation to assist parents asking for help (Harris, 1999). If a procreative choice or technology can lead to suboptimal circumstances for the resulting children, this does not automatically mean that reproductive autonomy should be restricted immediately. Objections have to be strong and convincing (e.g. Robertson, 1994; Burley and Harris, 1999). Although the starting point is to maximize well being, doctors may do less than the best and thus cooperate to suboptimal outcomes when there are ‘good reasons’ (Savulescu, 1999). Similar tensions between professional responsibility and reproductive autonomy can arise once a physician and the parents agreed about starting an IVF/PGD trajectory (de Wert, 1999; Pennings et al., 2003). It can be argued that the final decision is the responsibility of the woman, because in most cases she is the main caregiver to her (disabled) child (Wertz et al., 2003) and because denying women effective means of controlling their own fertility has harmful consequences for families, women and children (Warren, 1998). Others, however, argue that making these decisions is a joint enterprise, and that the professional may still be entitled to refuse assistance, taking into account the welfare of the child (de Wert, 1999). Both the ESHRE PGD Consortium (2005) and the Human Fertilisation and Embryology Act (1990) require the welfare of the child to be considered in the decision to offer assisted reproductive technologies. But how to make it operational in everyday practice? |
The welfare of the child |
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There is an ongoing debate about the practical application of ‘the welfare of the child’ (Blyth and Cameron, 1998
; Brewaeys, 1998; Mumford et al., 1998). Three different evaluation standards are used to assess whether offering assisted reproductive technology is acceptable [see Table 1] (Pennings, 1999; de Wert, 1999). Here, we will translate them to the question whether offering IVF/PGD is acceptable, based on the quality of life, or the expected health status, of the resulting child. The first is the ‘maximum welfare principle’: one should not knowingly and intentionally bring a child into the world in sub-ideal circumstances. Based upon this principle, the overwhelming majority of the candidate parents would be excluded. All possible deviations from the ideal life are criteria of exclusion. According to this principle, most if not all mtDNA mutations should probably be excluded for PGD, as, first, in the majority of cases, a healthy child cannot be guaranteed and, secondly, due to the maternal inheritance, the mother may develop the disease (except for mutations de novo). A sick mother deviates from ideal circumstances. The second standard to assess the welfare of the child is the ‘minimum threshold principle’, or, more particularly, the ‘wrongful life’ or ‘worse than death’ criterion: the only reason not to bring a child in the world is when the child would have been better off not to live at all. This principle entails a minimal conception of the responsibility of the health care professional and leaves almost absolute space for reproductive autonomy. According to this principle, offering IVF/PGD is acceptable for all mtDNA mutations as long as the test result is predictable. In case the test result may be suboptimal, the expected life standard of the resulting child may not be worse than death. Thus, when living with LHON, in the worse case scenario the child would become blind at young age. Although a serious impairment, most would agree that this still remains a life worth living. Physicians should therefore, based on this standard, offer IVF/PGD. Whether other mtDNA mutations will enable the child to live a life worth living is debatable and also depends on the severity of the disease. In particular for mutations with a highly variable expression, such as the m.3243A>G mutation leading to MELAS, making judgments is complicated. Finally, the third, intermediate, principle is the ‘reasonable welfare principle’: assistance of the health care professional is justified when there is reasonable chance of having a reasonably happy child (or acceptable life standard). A contra-indication for assisted reproduction would be a ‘high risk of serious harm’ (de Wert, 1999; Benatar, 2006). Whether a child with one of the mtDNA mutations will have an acceptable life standard depends on the harm-probability ratio of the specific mutation.
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Thus, if one adheres to the maximum welfare principle, PGD to prevent any mtDNA disease would be unjustified, since, currently both a healthy child and the long-term availability of a healthy mother cannot be guaranteed. Both other criteria, however, leave ample room for discussion.
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Responsible parenthood and parental responsibility |
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Obviously, discussions about responsible parenthood are not exclusive for mtDNA disease. This discussion regards all genetic diseases as a result of which one of the parents has a fair chance to become seriously ill (e.g. ESHRE PGD Consortium, 2005
). All mtDNA disorders follow a maternal mode of inheritance. A female carrier may have no or mild symptoms (especially if she has a lower mutant load), but she may also have a substantial mutant load and develop severe symptoms. Her life expectancy may be seriously reduced. The physician might consider not to offer assisted reproduction, because his or her professional responsibility requires that he or she should not burden a child with a possibly sick mother. Furthermore, the child might lose its mother at a young age. Counter-arguments are that one-parent families are often doing well. In other cases, we cannot predict the future health of the parents either. Furthermore, according to both the minimum threshold principle and the reasonable welfare principle, living with one parent or a sick mother is acceptable. Last but not least, for most mtDNA mutations, it is debatable whether the health of the mother is poor enough to justify a limitation of their reproductive autonomy. If the mother is affected, much depends on the bearing power of the prospective father. |
The transfer of embryos with residual risk |
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A successful IVF/PGD procedure normally provides the availability of several embryos. In that case, the couple can make a decision about which embryo to transfer, whereas with prenatal diagnosis the only choice is whether to terminate the pregnancy (Draper and Chadwick, 1999
). The most straightforward scenario would be if one or two embryos without detectable mutant load are available. In this case, we can assume these embryos will be transferred. However, in many cases, PGD of mtDNA disorders does not enable people to eliminate genetic risk, but only to reduce it, both for heteroplasmic and homoplasmic mutations.
Characteristic for mtDNA heteroplasmic mutations is that embryos and people often have a certain amount of mutant load, which can vary from 0 to almost 100%. Most authors regard only embryos with undetectable or very low amounts of mutant mtDNA as suitable for transfer (Thorburn and Dahl, 2001; Dean et al., 2003; Jacobs et al., 2005a,b). However, when performing PGD for, e.g. the m.3243A>G mutation, it is not inconceivable that only embryos with residual health risks may be available. Would it be morally justified, then, to transfer an embryo with some mutant load? And what should the cut-off point be? Clearly, the lower the cut-off point, the more embryos are discarded and, thus, the lower the take home baby rate—and vice versa. Another issue is whether and when the clinicians’ responsibility to transfer the best possible embryo would imply to start another IVF/PGD cycle in order to obtain mutant-free embryos. Savulescu (2001) defends the so-called ‘procreative beneficence’ principle, arguing that couples should select the embryo, i.e. expected to have the best life. They should use all the available information and choose the option that is the most likely to bring about the best outcome. This view raises the question how many IVF/PGD-cycles could (or should) justifiably be done before one chooses to implant an embryo with a certain mutant load.
The application of PGD for homoplasmic mutations, such as LHON, goes one step further as all embryos will carry residual health risks. Prenatal testing to assess the mutant load is useless, as the mutation load will always be 100%. Prenatal diagnosis could, however, be considered for sex-selection to exclude males. These males have a 50% lifetime risk of blindness compared to that of 10% for females. Why not transfer a female embryo, if the prospective parents insist and if a healthy embryo is out of the question? Should the physician insist on only replacing female embryos? No doubt, this application is controversial. In these cases, a conflict may arise between the prospective parents’ reproductive autonomy and the responsibility of the reproductive physician to take into account the welfare of the future child. Furthermore, the slippery slope argument should be considered, as applications like this may open the door for sexing for all disorders in which the mutation’s penetrance and/or the expression is lower or milder in one sex (Pennings, 2002).
In any case, PGD for mtDNA disease brings the classic application of PGD up for discussion. ‘It is one thing, it could be argued, for couples to refuse to undertake P[I]GD, but quite another for them to request that an affected embryo be implanted’ (Draper and Chadwich, 1999). Intuitively one could argue that the primary goal of PGD is quite the opposite: the birth of healthy children. However, sometimes this goal seems out of reach. Though PGD may not be ideal in these situations, some couples and clinicians nevertheless may consider PGD to be the best (or the least unfavourable) option.
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Polar body analysis |
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Polar body analysis can potentially be used in the diagnosis of mtDNA disease (Briggs et al., 2000
; Dean et al., 2003). The first polar body arises just before ovulation and can be used to determine the genetic status of the oocyte. To improve the reliability of the genetic analysis, it is possible to test the second polar body as well. This appears after the sperm cell has penetrated the oocyte. Limitations of polar body analysis are generally 2-fold. First, it only reveals chromosomal aberrations that already have taken place. New chromosomal deficiencies will not be detected. Second, with regard to Mendelian disorders, only the genetic material of the mother is analysed (Verlinsky and Kuliev, 2000; German National Ethics Council, 2003, Kuliev and Verlinsky, 2005b; Soini et al., 2006). These limitations, however, do not apply to the polar body analysis for mtDNA mutations, because only the maternal mitochondrial contribution needs to be determined. However, at the moment blastomere biopsy seems to have a higher diagnostic efficiency (Briggs et al., 2000; Dean et al., 2003).
To those who oppose embryo testing and selection, analysis of the ‘first’ polar body has an ethical advantage; after all it entails oocyte selection (Dean et al., 2003). In countries where PGD is prohibited, e.g. in Germany, polar body analysis is considered to be an alternative. Polar body analysis is, however, performed internationally on a very small scale, mostly combined with blastomere biopsy (German National Ethics Council, 2005). When carried out in combination with either second polar body or blastomere biopsy, the reliability may be higher, but the initial goal, by-passing embryo selection, is not met.
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Genetic testing of minors |
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Some authors genetically test children born after prenatal diagnosis or PGD. Some have measured post-natally the mutant load in the cord blood (White et al., 1999a
; Graff et al., 2000). Others do not assess the presence of the mtDNA mutation ‘for ethical reasons’ (Jacobs et al., 2005a,b; Bouchet et al., 2006). The reasons for or against testing are, however, not made explicit by these authors, although it seems that testing is performed to confirm the absence of mutant mtDNA (Graff et al., 2000). As genetic testing of minors is a controversial issue, it is important to carefully distinguish the reasons for and implications of testing. In this case, testing a (thus far) healthy child after birth could probably be done for two reasons. The first reason would be to remove the residual uncertainty and to confirm the test results. This will probably be the case when a ‘healthy’ child is expected. When the child, as expected, does not have mutant mtDNA, then the parents are reassured. However, when the mutation is present against all expectations, a neutral affirmation may turn out to be a tricky genetic prediction. Predictive genetic testing of minors is an ethically sensitive topic. There is a strong consensus that such testing is only acceptable when there are clear health advantages for the child. The situation is ethically less clear when the medical benefit is uncertain or absent, when there are no preventive or other therapeutic measures available, or when the disease will manifest at adult age. Arguments against predictive genetic testing of these minors regard the autonomy of the child, its privacy and the child’s right not to know (Clarke, 1998b; de Wert, 1999; Borry et al., 2006). For mtDNA disease, there are currently no real treatment options (Chinnery et al., 2006). The medical benefit of testing is therefore unclear and an alternative could be just to wait and see, as there are insufficient empirical data regarding the psychosocial consequences of predictive testing in minors (Evers-Kiebooms, 2006).
A second reason for testing may be the scientific surplus value: to increase our knowledge about mtDNA inheritance and the genotype–phenotype relation. However, none of the publications in the field mention this reason. In the case of a test performed for scientific reasons, the ethics of non-therapeutic medical research with incompetent subjects is the leading framework (World Medical Association, 1964; Council for International Organizations of Medical Sciences, 2002). In our opinion, it should be made clear whether testing children born after PGD and prenatal diagnosis for mtDNA disease is for medical purposes or for scientific purposes, since this would imply a different ethical framework. Owing to the sensitivity of this subject, further debate is needed about the pros and cons of genetically testing children born after prenatal diagnosis or PGD for an mtDNA mutation.
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mtDNA disease a new indication for PGD? |
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PGD was introduced as a technique to prevent monogenetic disorders that result in serious harm. Indications for PGD were similar to those accepted for prenatal diagnosis. In recent literature, attention has been paid to new applications of PGD, beyond the strict criteria for prenatal diagnosis (Kuliev and Verlinsky, 2005a
,b). Whether a wider scope of application is acceptable is open for debate (Pennings and de Wert, 2003; Robertson, 2003; UNESCO, 2003; Shahine and Caughey, 2005; de Wert, 2005; Health Council for the Netherlands, 2006; Niermeijer et al., 2006). It may be useful for the debate about the ethics of PGD for mtDNA disease to make a comparison with analogous cases, such as PGD for cancer susceptibility genes. PGD for adult-onset cancer predisposition genes, such as the BRCA mutations and HNPCC (hereditary non-polyposis colorectal cancer), is controversial for several reasons. First, due to the incomplete penetrance of most of the relevant mutations, some carriers will not be affected. Second, due to the later age of onset, people can often live for more than 30 years without developing the disease (but there are exceptions, such as Li-Fraumeni syndrome, causing a high risk of childhood cancers (Rice, 2006)). Third, for some disorders prophylactic or surveillance measures are possible, like a double mastectomy (Harris et al., 2005; Kuliev and Verlinsky, 2005a,b; Rice, 2006). Likewise, people with mutant mtDNA may have the chance of never or only later in life develop symptoms. However, they may become seriously ill as well, or even die at young age. Furthermore, effective therapy is currently not available. An important difference between the two types of disorders, however, is that PGD for mtDNA disease cannot always exclude residual health risks, whereas PGD for genes predisposing to cancer can guarantee the birth of children free from the particular hereditary cancer.
To people assigning a certain or high moral status to embryos, PGD is only ethically acceptable when done for good reasons, such as preventing offspring with serious genetic disease. When discussing new applications of PGD, the question therefore is whether the reasons are good enough to select and discard embryos (Robertson, 2003). Some fear a slippery slope. So far, PGD was mainly used for severe single gene disorders. In the near future, it may be increasingly used to select against mild diseases. Arguments in favour of extending the indications for PGD are, among others, reproductive autonomy and the prevention of harm. To substantially decrease the risk of cancer by means of PGD constitutes good preventive medicine (Braude, 2006). Performing PGD to prevent mtDNA disorders can also be perceived in this way, although the difficulty to predict the severity of the disease is a complicating factor. Countries have different views about extending the criteria for PGD. In 2006, the HFEA has included certain cancer susceptibility genes as legitimate reasons for PGD (Braude, 2006). PGD for mtDNA disease might therefore be accepted as well. In the Netherlands, the political discussion about extending the criteria for PGD is still ongoing (Handelingen Tweede Kamer, 2005–2006; Health Council of the Netherlands, 2006). Meanwhile, health care professionals have different views (UNESCO, 2003).
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Considering alternatives: genetic relatedness, harmto the child and proportionality |
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Thus far we have focused on prenatal diagnosis and PGD. However, some alternatives exist to prevent mtDNA disorders. Although (pro)nuclear transfer may become an option in the future (Rubenstein et al., 1995
; Roberts, 1999; de Wert, 1999; Thorburn and Dahl, 2001; Jacobs et al., 2005a,b; Spikings et al., 2006; Brown et al., 2006), currently available alternatives include oocyte donation and adoption. A practical problem is the scarcity of donor oocytes. Furthermore, for some, oocyte donation raises the same ethical questions as assisted conception in general, such as the meaning of family values, sexuality, parenthood, gender relations and commodification (e.g. Murray, 1996). Adoption would also be a solution for mtDNA disorders. However, these options result in unrelated or only partially related offspring. These strategies are, therefore, for a lot of couples less desirable. Some authors briefly mention these alternatives (Poulton and Marchington, 2000; 2002; Poulton and Turnbull, 2000; Thorburn, 2004) but they do not, or only briefly address the psychological and moral issues involved (Thorburn and Dahl, 2001; Jacobs et al., 2005).
The main moral question is whether genetic relatedness is that important that the use of costly, suboptimal and time-consuming techniques to prevent an mtDNA disease is justifiable when relatively ‘simple’ alternatives are available. Some would say that genetic relatedness, among others, is not the true determining factor for the child’s well-being (Golombok, 1998). Others mention social pressure, both to become parents, and to have children of one’s own (Strong, 1997). Furthermore, if we allow suboptimal outcomes to ensure genetic relatedness, then we have generated a strong argument in favour of reproductive cloning (Savulescu, 1999). After all, cloning ensures the highest degree of genetic relatedness. The importance of genetic relatedness is often assumed, but further reflection about the value and significance of the desire for a genetically related child is required (Graumann and Haker, 1998; Sparrow, 2006).
An intensive, costly and time consuming treatment for couples at risk can only meet the moral requirement of proportionality, also in light of scarce resources in health care and urgent global questions, when there is some degree of certainty about which embryo to transfer. The category of stable inherited heteroplasmic mutations (I.2.a, including the m.8993T>G mutation) is in this perspective different from the other categories. However, making proportionality operational in everyday practice is a complex issue. It may be helpful to distinguish between people needing IVF anyway because of infertility, and fertile people with a known risk of genetic disease, who want to avoid prenatal diagnosis and possibly abortion by having IVF and PGD. The latter couples make a claim to IVF not because they are infertile, but because this is a prerequisite to have PGD. With the development of PGD, new kinds of uses of IVF have arisen (Holm, 1998; Soini et al., 2006). IVF, which started as a fertility technique in the 1980s, has turned into a wheelbarrow for genetic services.
Women carrying a higher mutant load have a stronger likelihood of having a fetus with an intermediate or high mutant mtDNA. Some authors therefore suggest that PGD might, because of the hormonal stimulation, financial costs etc, be more suitable for woman with high mutant mtDNA (Dean et al., 2003; Poulton and Marchington, 2002; Jacobs et al., 2005a,b). Moreover, in case of a mutation with a low recurrence risk (or de novo), prenatal diagnosis may be a better option than PGD. After all, in these cases starting a IVF/PGD treatment may be disproportionate. Moreover, the chances to become pregnant are higher with natural reproduction and the risk of an affected child (and subsequently of considering a possible termination) are small.
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Concluding remarks |
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This paper aims to address the ethical issues regarding prenatal diagnosis and PGD of mtDNA and mitochondrial disorders with an unknown genetic cause. Extended ethical analysis and interdisciplinary debate will contribute to further guidance and to the adequate management of the challenging questions surrounding the prevention of the different mtDNA mutations. A limited number of mtDNA mutations, in particular the stable inherited mutations, allow reliable predictions, though results in the ‘grey zone’ complicate testing. Flaws in genetic and biochemical diagnosis of the other mtDNA mutations and the uncertainty that is currently inherent to this field, lead to complex ethical questions. From the unassailable fact that genetic testing in this field is far from perfect we cannot, however, jump directly to the conclusion that all applications are unsound. No doubt, an extended ethical debate and analysis is of utmost importance for the further development of good clinical practice.
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Funding |
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This work was supported by a grant from the European Union sixth Research Framework Programme (the MITOCIRCLE project contract no 005260).
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Acknowledgements |
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We would like to thank Dr C. de Die for her valuable comments.
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