Current controversies in prenatal diagnosis 2 should incidental
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  • 1. ISPD 2013 MEETING PRESENTATION Current controversies in prenatal diagnosis 2: should incidental findings arising from prenatal testing always be reported to patients? The-Hung Bui1*† , Frances Lucy Raymond2† and Ignatia B. Van den Veyver3† 1 The Karolinska Institute, Center for Molecular Medicine, Clinical Genetics Unit and Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden 2 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK 3 Departments of Obstetrics and Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA *Correspondence to: The-Hung Bui. E-mail: † All authors contributed equally. Funding sources: None Conflicts of interest: Ignatia B. Van den Veyver is a member of the Baylor College of Medicine Department of Molecular and Human Genetics, which houses the diagnostic Medical Genetics Laboratories that offer various forms of genetic testing, including for prenatal diagnosis, on a fee for service basis, but she does not derive personal revenue from this activity. INTRODUCTION (THE-HUNG BUI) Our ability to measure and quantify variation in human development is rapidly increasing, not least in the area of genetic investigation. However, our understanding of the implications of this variation is far behind our ability to describe it. A powerful motivation for research and development is the desire to improve knowledge and care of those who seek medical attention but also to interpret data correctly and to communicate findings with the appropriate evidence and to do no harm nor create undue anxiety. The discovery of an incidental finding as the result of a diagnostic or screening procedure has complicated nearly all aspects of clinical research and diagnostics.1–4 Traditionally, such findings were relatively rare, and decisions about how and when to report them were mostly left to the judgment of healthcare providers within the confines of individual physician–patient relationships. With recent technical advances in diagnostic methodologies, combined with more ready access and willingness to use them, incidental findings have become more common, and the findings themselves have become more complex.4 The debate on reporting of incidental findings is motivated by this massive increase in genetic information available and our current deficiencies of knowledge about the clinical significance of much of these data, rather than by general principles of communicating and observing incidental findings in prenatal diagnosis. The essence of the debate is whether all variants should be communicated to users of prenatal services or whether there are limits as to what should be returned and what would be the basis of this selection or restriction. THE CASE FOR REPORTING ALL INCIDENTAL FINDINGS (IGNATIA B. VAN DEN VEYVER) There are two main types of incidental findings in prenatal diagnosis and screening. First are those associated with prenatal imaging, including high-resolution ultrasound and fetal magnetic resonance imaging. While important, they are not reviewed in detail for this report but can be contrasted with those of the second category, which are the incidental findings that arise during genetic screening or a genetic diagnostic test. Reporting incidental findings in genetic research and clinical testing is currently highly debated,4–7 but debates or proposed guidelines typically exclude considerations relevant to prenatal testing.4,8 Nevertheless, we can learn from other genetic diagnostic circumstances to help address whether and how such findings should be reported prenatally. This is an important question that must be considered by the prenatal diagnosis community, individual prenatal healthcare providers, and parents who choose to undergo prenatal genetic screening and/or testing.9,10 To arrive at the best answer, we must first define what is an incidental finding and then consider practical and ethical aspects that are unique to prenatal screening and diagnosis, taking into account the purpose and goals of prenatal diagnosis. What are incidental findings? An incidental finding or secondary finding can be defined as ‘an observation (result) of potential clinical significance unexpectedly discovered in patients or in healthy subjects unrelated to the purpose of the diagnostic study or test’.8,11–13 This definition implies that an incidental finding carries with it clinically useful information that may benefit the health of the individual being tested, but that information was unrelated Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd. DOI: 10.1002/pd.4275
  • 2. to the primary goal of the diagnostic study. This can be difficult to define,5,8 and we must consider to whom ‘useful’ applies. Is it the fetus, or also the parents, siblings, or even the extended family of the fetus? We must also consider what clinically useful means.11,14 Should we only report findings that are of well- defined clinical relevance, and within that category, should we only report incidental findings for which an intervention is possible that has therapeutic benefit? What should we do with the findings of defined clinical significance but for which there is no known therapy? What should we do with the findings of uncertain significance that we know may have clinical impact but not in all cases? What should we do with incidental findings for which it is unknown but possible that there is clinical impact? What about genetic changes that are causative for late-onset adult disorders for which it has been argued that the ‘right to an open future’ should be a barrier to reporting such mutations prenatally or in childhood. These are complex questions that require thoughtful consideration. Purpose and goals of prenatal diagnosis The purpose of prenatal screening and diagnosis is to provide information to prospective parents about the current and future health of their unborn children. Considering that decisions regarding fetal and neonatal care resulting from prenatal diagnostic information may have implications not only for the fetus but also for the mother and the nuclear family, the diagnostic information provided should benefit the well-being of the family, including first not only the future child, but also the parents, siblings, and even other extended family members. In this context, well-being encompasses not only the physical but also the mental and social aspects. Under ideal circumstances, all prenatal diagnosis would be noninvasive and risk-free to the pregnant woman and fetus, would be oriented towards diagnosis rather than screening, and would be comprehensive or more broadly ‘disease- optimized’ rather than focused on a small number of disorders, such as common aneuploidies. We would also prefer that all tests are cost-effective; widely available; and easy to explain, interpret, and counsel about and that the results are conclusive, only relevant to the conditions for which we test without incidental findings of potentially uncertain significance. Clearly, we cannot achieve all of these goals, but it is our ethical responsibility as prenatal care providers to manage rather than to avoid these complexities of our profession, keeping in mind the best interest of the fetus and the family. Applying principles of medical ethics The four principles of medical ethics – autonomy, beneficence, non-maleficence, and justice (Table 1) – provide an ethical framework for healthcare professionals whenever difficult clinical decisions arise for which there may be real or perceived competing interests for providers or patients.15 The principle of autonomy embodies respect for the patient’s right to choose or to refuse treatment.15 This is at the core of the informed consent process for testing and treatment and carries with it the obligation for good communication between healthcare providers and patients. Important for a debate on reporting incidental findings is that patients (or their legal representative decision makers) cannot exert autonomy if not provided with full information4,5,16 and equally important is whether a generic consent that bins categories of results,14 although practical, can be considered fully informed.10 Beneficence requires that a practitioner act in the best interest of the patient.15 Within the context of fetal diagnosis, the individual being tested cannot be the one providing consent. Parents, who provide consent on behalf of the unborn child as the child’s representatives, are also bound by the beneficence principle to act in the best interest of the fetus.10 It has therefore been argued that the right of parents to know or not to know diagnostic information (autonomy) conflicts with the beneficence-based responsibility towards the fetus in the setting of prenatal diagnosis.17 Under these circumstances, beneficence is considered more important than autonomy.10 However, when the ultimate goal that prenatal diagnostic information should benefit the well-being of the fetus within the context of the family’s well-being is considered, the capacity of parents to exercise autonomy in their decisions is reconcilable with the principle of beneficence. The principle of non-maleficence together with beneficence encompasses the ‘first do no harm’ and ‘duty to warn’ responsibilities of the healthcare provider.4,15 This supports reporting of actionable incidental findings, that is, those results for which it is known that a preventive measure or intervention is available to reduce risk or improve health.8 Not reporting such prenatal diagnostic results to parents carries a risk of causing harm and is a strategy that is difficult to endorse. Furthermore, incidental results from prenatal diagnostic testing on the fetus may have direct implications for the health of the parent. For example, incidentally discovered cancer-predisposing mutations may be inherited from a parent, who can be placed on a cancer screening and prevention protocol.10,18 Equality of access to care and of distribution of health care resources, as well as respect for people’s rights and the law are components of the principle of justice. While important in multiple aspects of healthcare, it provides less guidance for the specific question of reporting incidental findings, which is more easily considered in view of the other three principles of medical ethics. Table 1 Principles of medical ethics Autonomy • Respect for the patient’s right to choose or refuse treatment • Obligation for informed consent, requires good communication Beneficence • A practitioner should act in the best interest of the patient • Clinical care should benefit the patient Non-maleficence • Is the ‘first do no harm’ principle • Carries with it the ‘duty to warn’ obligation Justice • Fair adjudication between competing claims – ‘Equality’ is central • Fair distribution of scarce health resources • Respect for people’s rights and for morally acceptable laws Reporting incidental findings in prenatal diagnosis 13 Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.
  • 3. The difficulty with incidental findings (variants) of unknown significance The aforementioned reasoning supports reporting incidental findings of known clinical significance that are actionable,8,11 but it may not be immediately obvious that the same applies to the findings or variants of unknown significance (VOUS)19 These are results that may be of clinical significance but with variable expressivity so that we cannot predict what the phenotype will be after birth, such as for example, a 16p11.2 deletion detected by chromosomal microarray. This is a relatively common deletion in individuals ascertained for developmental delay, intellectual disability, and autism. However, the phenotype associated with deletion 16p11.2 is highly variable, even within families, and apparently unaffected or very mildly affected cases exist. Thus, it is difficult to predict how severe these manifestations will be when it is detected prenatally. In other cases, there may be a genetic change for which there is not enough information as to whether the finding will result in a clinically significant phenotype, for example, an unclassified sequence variant in a known disease-associated gene for a disorder with no prenatal phenotype. Findings of uncertain significance are not unique or new to genetic testing and have always complicated prenatal diagnosis. While they often create difficult and complex counseling situations, they are health-related information that has the potential to be relevant to the well-being of the tested individual.9 The ethical principle of autonomy supports that the information is shared with parents to allow them to make decisions with the available information. A detailed discussion of VOUS is beyond the scope of this report, but they come with many practical challenges involving pretest counseling and informed consent procedures, definition and classification of VOUS, and who should report them.9,19,20 Whereas it is the responsibility of those developing new tests and the diagnostic laboratories that offer the tests to aim for testing platforms that avoid the discovery of true VOUS, they cannot be fully eliminated without compromising diagnostic power for important disorders. Therefore, when VOUS occur, we should be prepared to share this information with parents in the best possible way so that they can exert their autonomy in decisions about the care for their pregnancy and future child. Incidental discovery of late-onset untreatable disease and the ‘right to an open future’ It has long been held that children should not undergo presymptomatic genetic testing for late-onset disorders for which no cure is available, such as familial Alzheimer disease, Huntington disease, or spinocerebellar ataxias to preserve the child’s right to an open future and to an education that is unbiased by the prior knowledge that there will be impairment in later adulthood.21 Genetic societies have endorsed or developed guidelines in support of this approach,22 but this topic has become more debated recently.21 The same principles have been extended to prenatal and preimplantation genetic diagnosis, with adaptations that take into account the option of avoiding (through preimplantation genetic diagnosis) or terminating affected pregnancies, as well as the unavoidable presymptomatic discovery of the disorder in a carrier parent through fetal testing.23,24 Whereas these guidelines are very beneficial for targeted testing, they preceded the explosion of genome-wide genetic tests that are capable of incidentally discovering mutations that cause these conditions. Most laboratories have taken the approach of not reporting them in children and presymptomatic adults, but it remains an open question how best to handle them in prenatal diagnosis for two important reasons. First, when discovered during prenatal diagnosis, the disorder can be prevented if parents choose the option of not continuing a pregnancy. Second, it should be examined what the right to an open future signifies and whether we infringe autonomy by shielding information that may allow parents and young adults to make decisions about their future that take into consideration all aspects of their current or future health. It is not well established that not providing this predictive information is the only direction to preserve the right to an open future.25 Risks, benefits, and guidelines One argument put forward for not reporting incidental findings is the risk of causing parental anxiety about a finding that is of uncertain significance for which there are no interventions available. This is indeed an unavoidable consequence of reporting incidental findings but not one that is new to prenatal diagnosis. As providers we need to assume responsibility for this by providing expert counseling and support for the families we are caring for, rather than hiding this information from families. Advances in technologies for genetic testing will likely generate more incidental findings, creating the need for more genetic counseling professionals, and for better appreciation of their services. As a discipline, we must assume responsibility for training more genetic counselors and for motivating governments and regulatory instances to recognize their services with appropriate licensing and reimbursement. We must also proactively become involved in educating other providers, such as general practitioners and obstetrician– gynecologists, and various fetal care-related subspecialists, in the intricacies of newer genetic tests. Vice versa, we should be prepared to integrate their knowledge with how we most optimally interpret the test results and counsel patients. Some incidental findings from prenatal diagnosis may cause unnecessary or justified anxiety that may be prolonged while the child grows into adulthood. However, in this era, a paternalistic approach to medical care is no longer considered acceptable, and the ethical principle of autonomy therefore mandates the disclosure of the information.9 Furthermore, considering that the pace and scope of advances in medicine are unpredictable, we cannot have the foresight in many cases what the future benefit of knowing an incidental finding could be. From that perspective, putting the decision as to what constitutes the ‘right to an open future’ only in the hands of health professionals may conflict with autonomy and beneficence. In summary, reporting incidental findings in prenatal diagnosis is a complex issue, but it is not limited to the results of genetic testing and has been part of our field since the start. There are no good arguments to treat genetic testing differently The-Hung Bui et al.14 Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.
  • 4. from other diagnostic testing on how to manage these unanticipated results. In general, as the benefit or harm from reporting them will vary depending on the individual patient within his or her family structure, we have to assume the professional responsibility to report them and allow patients (parents) the autonomy to make decisions on the basis of the results. We also have the responsibility to do so under the most supportive counseling circumstances possible. Unfortunately, we do not yet have professional guidelines on how to handle these complex issues in prenatal diagnosis and most guidelines available or in preparation explicitly exclude prenatal diagnosis situations. Thus, it will be up to our professions to assume the responsibility for generating guidelines that are applicable to prenatal diagnosis. THE CASE AGAINST REPORTING ALL INCIDENTAL FINDINGS (LUCY RAYMOND) There are three areas that merit consideration when discussing whether incidental findings should be reported to patients: (1) The mandate to do no harm and the misuse or misinterpretation of the data. (2) How accurately does a genotype predict a phenotype in individuals? and (iii) Genetic data as a ‘product’ and the potential effect of parental information about a baby with respect to the ongoing relationship between parent and child. The misuse or misinterpretation of incidental findings Except in rare circumstances of X-linked genetic diseases or disorders of sex, knowing the gender of a fetus is of no medical importance. However, fetal selection by termination of pregnancy and preferences for one sex is still widespread in cultures where the perceived value of each gender is different.26,27 This is a powerful illustration that incidental knowledge of the genome is not always medical and is used as a social tool by some, whilst others would regard this as unacceptable. The identification of any variant of normal during pregnancy is always unsettling to couples and creates uncertainty. Sex chromosome anomalies (SCA) are usually reported to families as an incidental finding as a consequence of prenatal testing for autosomal aneuploidy. The rate of termination of pregnancy for SCA was initially high when introduced because of the lack of knowledge about the prognosis for these conditions and has gradually decreased over time as data have emerged from long term follow-up studies, which show a good prognosis.28 We predict that when new variants of unknown significance are detected with more detailed analysis of the fetal genome, the initial response to the lack of knowledge about prognosis together with the associated increase in uncertainty will result in an increased number of requests for termination of pregnancies. Only once longitudinal clinical follow-up data are available for children and adults with novel variants that emerge to be clinically reassuring will the termination request rate reduce as was seen for SCA. Whether the baby is normal is a major issue for many women during pregnancy.29 Once data on a fetus are generated and available, there is usually an obligation to communicate the results, as paternalistic decisions not to communicate results are rarely acceptable in contemporary medicine. Consequently, communicating test results with uncertain findings generates referrals and consultations where subspecialties are needed to communicate these complex data to patients. Nonroutine consultations between specialist professions and couples during pregnancy are almost never without anxiety for the family, however skilled the professional is at counselling. Reassuring someone that an abnormality is not serious or is of unknown significance is intrinsically contradictory. How accurately does a genotype predict a phenotype in individuals? In the context of a structurally normal fetus, the presence of a DNA sequence abnormality as a predictor of a disease in the child depends on the penetrance of the variant in the individual. This is both gene and sequence variant specific and is one of the key challenges of contemporary human genetics. Autosomal dominant conditions, such as tuberous sclerosis and neurofibromatosis type 1, are highly variable within families, and it is notoriously difficult to predict the phenotype on the basis of the genotype alone. This probably explains why few families opt for prenatal testing for these conditions as the genotype alone is a poor predictor of severity of disease. Even for autosomal recessive conditions in which penetrance of the disease is usually more predictable, the penetrance of the disease in the normal unaffected population is often hard to quantify, as little data are available. Currently, prenatal testing and termination of pregnancy are usually offered to couples with previously affected children, thus confirming both the pathogenicity and penetrance of the variants in the family. When prenatal analysis is available without knowledge of the penetrance of the variants within the family, the interpretation of the pathogenic significance of rare variants in disease-causing genes is highly challenging. Recent whole exome and genome sequence analysis of healthy fully informed adults has identified many variants that were previously thought to be highly penetrant disease genes, illustrating the difficulty of interpreting the clinical significance of rare variants in the normal population.12 One way forward may be to consider offering a limited list of genes or genomic abnormalities that predict highly penetrant, life-limiting conditions in which prenatal diagnosis is already offered in societies where termination of pregnancy is accepted as ethical. Even then, there will be over interpretation of variant data that has not yet been proven. Similarly, knowledge of sequence variants that would affect the obstetric management of a specific pregnancy is justified, for example, those that cause Rhesus D alloimmunization and thrombophilia. For diseases that are not life limiting or severe and for which in utero therapeutic options are not currently available, a postnatal assessment may be more appropriate when the phenotypic consequences of variants can be assessed. For postnatal reporting of incidental findings, the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) propose somewhat different strategies to address the issue of incidental findings.8,30 The American approach is to report all incidental findings to adults and children if identified, whereas the European suggestion is Reporting incidental findings in prenatal diagnosis 15 Prenatal Diagnosis 2014, 34, 12–17 © 2013 John Wiley & Sons, Ltd.
  • 5. to avoid the detection of incidental findings where possible by having agreed limitations on analysis. If within the agreed limits, incidental findings are identified, then appropriate commu- nication of the findings is indicated. For prenatal testing, both ACMG and ESHG have not yet provided recommendations. Genetic data as a ‘product’ and the relationship between parent and child In a consumer-driven society where health knowledge can be purchased, both the right to know about one’s unborn baby and the increasing conceptualization of the baby or child as a commodity are real. The rights of the child and the rights of the parent to know are dependent on cultural differences and attitudes towards parenting. Concepts of stewardship and obligation vary across cultures, but little research has been performed as to whether having extensive genetic knowledge about one’s child will influence the subsequent relationship between parent and child. For diseases such as Huntington disease, prenatal testing for information only is not currently offered, as it denies the right of the child to exercise his or her own right not to know his or her risk of disease.31 The principle of respect of the autonomy of the child has been in place since the Huntington disease gene was identified in 1994. A change in practice from this position needs careful consideration. The counter argument is that for some conditions, early intervention and therapeutics may ameliorate a disease if detected early, and this would potentially justify the knowledge gained. At this stage, this is true for very few diseases that would justify prenatal rather than postnatal detection. At this stage of knowledge, I would argue, that it is premature to report all incidental findings to parents, as we have insufficient evidence that this will improve health care outcomes. However, I would advocate the development of agreed-upon principles as to what would be appropriate to communicate to parents prenatally, such that parents would have the possibility of detailed information about a disease that is predictable on the basis of genotype. Alternatively, parents would have the option of termination of pregnancy in the event of detecting genomic abnormalities that predict severe life limiting genetic conditions that may have arisen de novo. I would advocate for the use of comprehensive postnatal genomic testing where there is evidence of a medical problem in a child, and I would not advocate that the health gains of opportunist screening for all incidental findings outweighs the loss of autonomy of the child when the child is clinically normal. CONCLUSIONS (THE-HUNG BUI) With the advent of genomic technologies such as array-based methods and whole exome or whole genome sequencing, the genetic causes underlying various pediatric and adult phenotypes in many patients are potentially identifiable. Applications of such technologies prenatally have the potential to provide ancillary disease risk information (incidental findings). This potential should be considered as such tests are brought into clinical use. Implications may vary with each type of test, but these tests should be evaluated individually within a framework that outlines the potential implications of ancillary information. Some have argued against an exceptionalist approach to genetic information, but unless actively recognized and included in practice guidelines and other policy-making activities, the potential harm of ancillary risk information might not be properly considered. Policy makers will need to consider when and how ancillary information should be provided to patients, whether formal informed consent procedures are needed, and how risks and benefits of ancillary risk information should be weighed. For the foreseeable future, however, each individual whose genome in part or whole is sequenced will have vast numbers of variants identified that are of uncertain clinical significance at our present state of knowledge. The major challenge to the implementation of the technology is properly interpreting the variants found upon analyzing any individual’s genome. Fortunately, interpretation of incidental findings may ease as we obtain more information about frequency and long-term outcome of certain variants of uncertain significance. To achieve this, it will be important that such information is collected and shared through easily accessible databases. Even with this in place, the management of incidental findings and the relevance for patient care decisions remain a controversial issue. There is a need for consensus guidelines on incidental findings in prenatal diagnosis and such a task should be considered by an organization such as the International Society for Prenatal Diagnosis. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Incidental findings can occur in many areas of diagnostic testing. • Incidental findings, including those of uncertain significance, have many complicated aspects or prenatal diagnosis and are not limited to genetic testing. • Whereas guidelines for which findings should be reported and how to report them are being developed in the pediatric and adult genetic testing, little to no guidance exists for prenatal diagnosis. WHAT DOES THIS STUDY ADD? • We report two opinions on how to address incidental findings on the basis of a debate at the 17th annual conference of the International Society for Prenatal Diagnosis. 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