An easy test but a hard decision: ethical issues concerning non-invasive prenatal testing for autosomal recessive disorders

Prenatal testing based on cell-free fetal DNA in maternal serum is now possible for specific monogenic conditions, and studies have shown that the use of non-invasive testing is supported by prospective parents and health professionals. However, some ethical issues have been raised concerning informed consent and paternal rights. The objective of this study was to explore ethical aspects of the use of non-invasive prenatal diagnostic testing for autosomal recessive disorders. We used a qualitative cross-sectional design, based on Thematic Analysis, and recruited 27 individuals of reproductive age who were carriers of one of four conditions: thalassaemia, sickle cell disease, cystic fibrosis or spinal muscular atrophy. Data were collected via focus groups or interviews. Participants were aware of the potential for such tests to be viewed as routine and suggested that obtaining written consent and allowing time for consideration is needed to facilitate autonomous choice and informed consent. All participants felt that mothers should be able to request such tests, but fathers who declined carrier testing should be made aware that fetal test results may reveal their status. We suggest that a written record of consent for non-invasive prenatal diagnosis should be used as a standard to help reinforce the serious nature of the test results. Where the father''s carrier status could be revealed through fetal testing, he should be made aware of this before the results are available. Health professionals should discuss with the pregnant woman the best way to manage unsought information about the father''s carrier status to minimise family disruption.     

Non-invasive prenatal testing for single gene disorders: exploring the ethics

Non-invasive prenatal testing for single gene disorders is now clearly on the horizon. This new technology offers obvious clinical benefits such as safe testing early in pregnancy. Before widespread implementation, it is important to consider the possible ethical implications. Four hypothetical scenarios are presented that highlight how ethical ideals of respect for autonomy, privacy and fairness may come into play when offering non-invasive prenatal testing for single gene disorders. The first scenario illustrates the moral case for using these tests for ‘information only'', identifying a potential conflict between larger numbers of women seeking the benefits of the test and the wider social impact of funding tests that do not offer immediate clinical benefit. The second scenario shows how the simplicity and safety of non-invasive prenatal testing could lead to more autonomous decision-making and, conversely, how this could also lead to increased pressure on women to take up testing. In the third scenario we show how, unless strong safeguards are put in place, offering non-invasive prenatal testing could be subject to routinisation with informed consent undermined and that woman who are newly diagnosed as carriers may be particularly vulnerable. The final scenario introduces the possibility of a conflict of the moral rights of a woman and her partner through testing for single gene disorders. This analysis informs our understanding of the potential impacts of non-invasive prenatal testing for single gene disorders on clinical practice and has implications for future policy and guidelines for prenatal care.     

Non-invasive prenatal diagnosis for aneuploidy: toward an integral ethical assessment

The great promise of the pending introduction of non-invasive prenatal diagnosis (NIPD) for trisomy 21 (18 and 13) is that it enables one-step, early and safe testing for these abnormalities. The ethical debate so far has been limited to possible drawbacks of routine access to this type of testing: normalization of testing and abortion and adverse effects on autonomous decision-making. We address the ethical implications of the fact that routine NIPD affects the scope and strategy of current prenatal screening cascades. A decision is needed whether complementary (invasive) testing remains in place in order to avoid a loss of information as compared with current practice. If so, the supposed advantages of NIPD may be less significant than generally assumed. Accumulation of tests challenges informed consent and proportionality. Therefore, an ethical evaluation of the implications of NIPD for the prenatal screening strategy as a whole is needed.     

The California Prenatal Screening Program: “Options and choices” not “coercion and eugenics”

The California Prenatal Screening Program is designed to make prenatal screening available to the state's large and diverse population. The Program provides information to women which will allow them to make informed choices regarding prenatal screening and prenatal diagnosis. Since the Program's inception in 1986, women in California have had the option to participate in prenatal screening or to decline prenatal screening. The California Program offers prenatal diagnostic services to women whose screening tests indicate an increased risk for birth defects, including Down syndrome. Women can decline any or all of these follow-up services. Genetic counseling, diagnostic services, and the presentation of diagnostic results are performed by medical professionals (not State staff) who follow established guidelines for nondirective counseling. Program data clearly demonstrate that women in California have a wide range of options and make a wide range of choices regarding prenatal screening and prenatal diagnosis. California's comprehensive Prenatal Screening Program promotes optimal care for all women within all options and choices. The important and necessary communication among organizations and stakeholders involved in prenatal screening and diagnosis, and in related care for pregnant women and for people with Down syndrome, is not served by misrepresentation and inflammatory rhetoric.     

Ethical issues in early detection of HIV infection to reduce vertical transmission

Proposals to make prenatal HIV testing routine and universal dramatize ethical issues regarding early detection of HIV. These proposals would abolish pretest counseling and written informed consent for prenatal HIV testing. Ethical concerns include whether pregnant women are adequately informed that they may refuse such testing and whether patients have an opportunity to obtain more detailed information about the benefits and risks of HIV testing in this context. Several pertinent research questions need to be studied, including whether pregnant women find routine universal HIV testing acceptable and whether safeguards adequately protect women who receive testing. If analogous policies to enhance early detection of HIV are considered in other clinical contexts, the important clinical and ethical differences between vertical transmission and other situations of HIV transmission must be kept clearly in mind.     

Pharmacogenetic testing: not as simple as it seems

Pharmacogenetics has the potential to help guide treatment decisions by tailoring appropriate drugs and dosages to patients most likely to benefit. This straightforward clinical goal has led some to suggest that pharmacogenetic testing is free of ethical concerns. However, a number of potential risks and clinical uncertainties arise in considering the use of these new tools in clinical care. We propose a classification of pharmacogenetic tests to identify and prioritize the policy issues that will need to be addressed to ensure appropriate delivery of pharmacogenetic testing. We use the classification framework to consider the benefits and risks associated with ancillary information, timing of testing, and storage and retrieval of pharmacogenetic test results among health professionals. These issues have implications for informed consent and genetic counseling requirements, and for the role of health professionals.     

Will the introduction of non-invasive prenatal diagnostic testing erode informed choices? An experimental study of health care professionals

Objective

Informed choice is a fundamental concept within prenatal care. The present study assessed the extent to which the introduction of non-invasive prenatal diagnosis (NIPD) of Down's syndrome may undermine the process of making informed choices to undergo prenatal testing or screening for Down's syndrome by altering the quality and quantity of pre-test counselling.

Methods

231 obstetricians and midwives were randomly allocated one of three vignettes, each describing a different type of test: (a) invasive prenatal diagnosis (IPD), (b) non-invasive prenatal diagnosis (NIPD) or (c) Down's syndrome screening (DSS). Participants were then asked to complete a questionnaire assessing (1) the information considered important to communicate to women, (2) whether test offer and uptake should take place on different days, and (3) whether signed consent forms should be obtained prior to testing.

Results

Across the three test types, five out of the seven presented topics were considered equally important to communicate, including the information that testing is the woman's choice. Compared with participants receiving the IPD vignette, those receiving the NIPD and DSS vignettes were less likely to report that counselling and testing should occur on different days (IPD 94.7% versus 74.1% and 73.9% for NIPD and DSS respectively, p = .001) and that written consent was a necessity (IPD 96.1% versus 68.3% and 75.4% for NIPD and DSS respectively, p < .001).

Conclusion

This study provides the first empirical evidence to demonstrate that practitioners may view the consent process for NIPD differently to IPD. There is potential for the introduction of NIPD to undermine women making informed choices in the context of prenatal diagnostic testing for conditions like DS.

Practice implications

Given the importance of informed choice in reproductive decision-making, implementation of any programme based on NIPD should be designed to facilitate this.     

Ethics and fetal medicine

Summary Ethical issues in the clinical practice of fetal medicine are discussed, largely from the point of view of early prenatal medicine. The discussion concentrates on several aspects including the time when human life begins, the pros and cons of fetal medicine, and ethical guidelines for fetal medicine. The emphasis is placed on the importance of informed consent and an increase in genetical knowledge amongst the general public.     

Informed consent and patient videotaping.

PURPOSE: To determine whether videotaping consent forms used in family medicine residencies meet the criteria for informed consent, adhere to published guidelines for videotaping patients, and are written at a suitable reading level. METHOD: Three reviewers independently evaluated videotaping consent forms obtained from 20 family practice residencies to determine whether they included the elements of informed consent and conformed to published guidelines for ethical videotaping. The reading level of each consent form was also determined using a standardized assessment. RESULTS: Depending on the reviewer, only one to three of the 20 consent forms were judged adequate in providing a patient with enough information to make an informed choice. Specific aspects of voluntariness were absent from most of the forms. In addition, the reading level was, on average, well above recommended levels for patient comprehension. CONCLUSION: Most of the videotaping consent forms analyzed in this study did not provide adequate information to assist patients in making a voluntary, informed choice to be videotaped. The absence of this information raises the potential for violations of patient privacy and confidentiality.     

Pregnant couples at increased risk for common aneuploidies choose maximal information from invasive genetic testing

Genomic array detects more pathogenic chromosome aberrations than conventional karyotyping (CK), including genetic variants associated with a susceptibility for neurodevelopmental disorders; susceptibility loci (SL). Consensus regarding the scope of invasive prenatal diagnosis (PND) pregnant couples should be offered is lacking. This study examined pregnant couples' preferences, doubts and satisfaction regarding the scope of invasive PND. Eighty‐two couples choosing prenatal screening (PNS) and 59 couples choosing invasive PND were offered a choice between 5 (comparable to CK) and 0.5 Mb resolution array analysis outcomes, the latter with or without reporting SL. A pre‐test self‐report questionnaire and post‐test telephone interview assessed their choices in‐depth. Actual (PND) and hypothetical (PNS) choices differed significantly (p < 0.001). Ninety‐five percent of the couples in the PND group chose 0.5 Mb array, vs 69% in the PNS group. Seven percent of the PND group wished not to be informed of SL. Ninety percent was satisfied with their choice and wished to decide about the scope themselves. Pregnant couples wish to make their own choices regarding the scope of invasive PND. It therefore seems justified to offer them a choice in both the resolution of array and disclosure of SL.     

Ethical and legal constraints to children’s participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial

Background

Clinical trials involving children previously considered unethical are now considered essential because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation.

Findings

In Zimbabwe the parental informed consent document for children participating in clinical research is modeled along western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in obtaining informed consent from guardians of orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation. The situation contrasted with general clinical practice where consent for procedures on orphans is obtained from their caregivers who are not legal guardians.

Conclusion

The challenges faced in obtaining informed consent for orphans in this clinical trial underscores the need for the Zimbabwe ethics committee to develop an ethical and legal framework for pediatric research that is based on international guidelines while taking into account the cultural context. The Medical Research Council of Zimbabwe has since started the process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.     

Ethical and legal constraints to children's participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial

ABSTRACT: BACKGROUND: Clinical trials involving children previously considered unethical are now considered a necessity because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation. DISCUSSION: The Zimbabwean parental informed consent document for children participating in clinical research is modeled along western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in interpreting and obtaining informed consent for orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation if the Zimbabwean courts had not legally appointed them. The situation contrasted with general clinical practice where legal papers where not required for providing consent for surgical procedures for example. SUMMARY: Experiences gained from this clinical trial revealed that while there may be internationally established guidelines governing the process of obtaining informed consent for children participating in research, there may be need to be cognizant of the culture within which the research is taking place. This may call for the development of an ethico-legal framework that governs research-involving children in Zimbabwe that would facilitate their participation in clinical research, while ensuring that they are protected from exploitation. The Medical Research Council of Zimbabwe has since started developing that framework in a process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.     

Carrier testing in minors: a systematic review of guidelines and position papers

The objective of this article is to review all published normative ethical and clinical guidelines concerning the genetic carrier testing of minors. The databases Medline, Philosopher's Index, Biological Abstracts, Web of Science, and Google Scholar were searched using keywords relating to the carrier testing of children. We also searched the websites of the national bioethics committees indexed on the websites of WHO and the German Reference Center for Ethics in the Life Sciences, the Human Genetics Societies of various nations indexed on the website of the International Federation of Human Genetics Societies and related links, and the national medical associations indexed on the website of the World Medical Association. We retrieved 14 guidelines emanating from 24 different groups. All guidelines advanced the following preferences: (1) carrier testing should not be performed in children, and (2) testing should be deferred until the child can give proper informed consent to be tested. The guidelines varied in three areas: (a) the role of genetic services in ensuring that children are informed about their carrier status and associated risks when they are older; (b) exceptions to the general rule of withholding or deferring carrier testing; and (c) the communication of incidentally discovered carrier status. In the absence of compelling reasons, carrier testing of a child can reasonably be deferred until the child has the intellectual capacity needed to discern if and when to be tested.     

Informed consent and the "medical student psychiatrist"

The involvement of medical students in the clinical assessment of psychiatry patients raises concerns that have ethical and possibly legal implications. Responses to a 1986 questionnaire by 91 departments of clinical psychiatry in U.S. medical schools reveal that a substantial proportion (29.3%) of these departments were not fully compliant with established guidelines for obtaining informed consent from patients for students' participation in the patients' assessment and psychiatric care. Medical educators in psychiatry should recognize the importance of consent as a topic in the educational process and should establish policies that correct the discrepancies between institutional practices and informed consent guidelines.     

Arrays in postnatal and prenatal diagnosis: An exploration of the ethics of consent

The introduction of genome-wide arrays in postnatal and prenatal diagnosis raises challenging ethical issues. Here, we explore questions with regard to the ethics of consent. One important issue is whether informed consent for genome-wide array-based testing is in fact feasible, given the wide range of possible outcomes and related options. The proposed alternative of "generic consent" will have to be studied in practice. From an ethical point of view, the question is whether consent would still be sufficiently "informed" in a generic approach. Another issue that has not yet been given much attention is how far parents, or pregnant women and their partners, should be allowed to determine the range of possible outcomes that will or will not be reported back to them. The scope and limits of parents' and prospective parents' right to know or not to know are far from clear. The complex normative issues on the content and weight of these rights can only be answered by taking full account of the rights and interests of all the parties involved: prospective and actual parents, children, and relatives. This paper is the result of a working group meeting preceding the European Society of Human Genetics 2011 Conference, where these issues were addressed.     

Rapid aneuploidy detection or karyotyping? Ethical reflection

No consensus exists whether women at increased risk for trisomy 21, 13, and 18 should be offered stand-alone rapid aneuploidy detection (RAD) or karyotyping. In this paper, the ethical implications of a fast, relatively cheap and targeted RAD are examined. The advantages of RAD seem less robust than its proponents suggest. Fast test results only give a short-term psychological benefit. The cost advantage of RAD is apparent, but must be weighed against consequences like missed abnormalities, which are evaluated differently by professionals and pregnant women. Since pre-test information about RAD will have to include telling women about karyotyping as a possible alternative, the advantage of RAD in terms of the quantity of information that needs to be given may also be smaller than suggested. We conclude that none of the supposed arguments in favour of RAD is decisive in itself. Whether the case for RAD may still be regarded as convincing when taking these arguments together seems to depend on one''s implicit view of what prenatal screening is about. Are we basically dealing with a test for trisomy 21 and a few conditions more? Or are there good grounds for also testing for the wider range of abnormalities that karyotyping can detect? As professionals and pregnant women may have different views about this, we suggest that the best approach is to offer women a choice between RAD and karyotyping. This approach is most in line with the general aim of prenatal screening: providing opportunities for autonomous reproductive choice.     

Knowledge About Genetic Risk for Breast Cancer and Perceptions of Genetic Testing in a Sociodemographically Diverse Sample

Informed consent for genetic testing for breast–ovarian cancer susceptibility requires that women understand basic concepts about the inheritance of cancer susceptibility and the benefits and risks associated with genetic testing. Women awaiting routine medical services (N = 220) were surveyed about their knowledge of breast cancer and cancer genetics and their perceptions of genetic testing and personal risk. There were no racial differences in median income or mean level of education. Compared to Caucasian women, African American women knew significantly less about breast cancer and about genetic risk for breast cancer. African American women had different psychological, social, and economic concerns as evidenced by how they weighted the benefits and risks of genetic testing. This study is the first to assess several dimensions of informed consent for genetic testing among a sociodemographically diverse group. The findings should enable health professionals to target the African American and lower-income populations with the appropriate education and counseling.     

Update on the use of exome sequencing in the diagnosis of fetal abnormalities

Unexpected fetal abnormalities detected through ultrasound scanning in pregnancy may have a monogenic aetiology but are difficult to diagnose. Next generation sequencing now enables us to sequence fetal exomes, providing increased resolution and broader diagnostic capability compared to traditional cytogenetic prenatal tests, improving the yield and accuracy of diagnoses and allowing better counselling for expectant parents.Here we review published studies of exome sequencing (ES) for prenatal diagnosis over the last 5 years and address important questions for its clinical implementation, including clinical utility, which groups benefit most, and practical and ethical challenges for interpreting and reporting results.We observe that fetal ES substantially improves diagnostic yield relative to cytogenetic techniques. However, diagnostic rates vary widely between studies, largely attributable to differences in case selection. Recently several large studies report variations in diagnostic yield between phenotypic groups, with fetuses with multisystem abnormalities most likely to receive a diagnosis from fetal ES. Challenges for prenatal ES include the limitations of ultrasound-based fetal phenotyping, the need for rapid return of results in pregnancy, and technical limitations compared to whole genome sequencing. We also consider ethical issues around potential secondary findings and variants of uncertain significance and the complex counselling needs these present.Prenatal ES is a valuable tool to diagnose fetal abnormalities and, as it is implemented in the clinic, more large-scale research will serve to further delineate its clinical utility, as well as generating new knowledge about fetal phenotypes and informing guidelines for case selection, reporting results and genetic counselling.     

Ethical issues in susceptibility genetic testing for late‐onset neurodegenerative diseases

Genome‐wide association studies have revolutionized our understanding of the genetic architecture of complex traits and diseases over the last decade. This knowledge is enabling clinicians, researchers, and direct‐to‐consumer genetics companies to conduct disease susceptibility testing based on powerful methods such as polygenic risk scoring. However, these technologies raise a set of complex ethical, legal, social, and policy considerations. Here we review and discuss a series of ethical dilemmas associated with susceptibility genetic testing for the two most common late‐onset neurodegenerative diseases, Alzheimer's and Parkinson's disease, including testing in asymptomatic individuals. Among others, these include informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. Importantly, appropriate counseling is a deciding factor for the ethical soundness of genetic testing, which poses a challenge for the regulation of these tests and the training of healthcare professionals. As genetic knowledge about these diseases continues growing and genetic testing becomes more widespread, it is increasingly important to raise awareness among researchers, medical practitioners, genetic counselors, and decision makers about the ethical, legal, and social issues associated with genetic testing for polygenic diseases.     

Quality in genetic counselling for presymptomatic testing — clinical guidelines for practice across the range of genetic conditions

Presymptomatic testing (PST) is the performance of a genetic test on an asymptomatic individual at risk of a condition to determine whether the person has inherited the disease-causing mutation. Although relevant guidelines exist for specific diseases, there is no overarching protocol that can be adapted to any disorder or clinical setting in which such testing is offered. The objective of this European project was to develop a set of coherent guidelines for PST (for adult-onset monogenic conditions) for use by health professionals working in a range of disciplines, countries or contexts. To ensure the guidelines were appropriate and practice based, we organised a workshop attended by an expert group of practitioners with relevant health professional backgrounds from 11 countries. Models of service for offering PST were presented, the group then discussed different aspects of testing and the standard of care required to ensure that patients were prepared to make decisions and deal with results and consequences. After the workshop, several rounds of consultation were used with a wider group of professionals to refine the guidelines. The guidelines include general principles governing the offer of testing (eg, autonomous choice of the patient), objectives of genetic counselling in this context (eg, facilitation of decision making), logistical considerations (eg, use of trained staff) and topics to be included during counselling discussion with the patient (eg, consequences of both positive and negative outcomes). We recommend the adoption of these guidelines to provide an equitable structure for those seeking PST in any country.