Chromosomal microarray analysis in prenatal diagnosis: ethical considerations of the Belgian approach.

Detection of genetic aberrations in prenatal samples, obtained through amniocentesis or chorion villus biopsy, is increasingly performed using chromosomal microarray (CMA), a technique that can uncover both aneuploidies and copy number variants throughout the genome. Despite the obvious benefits of CMA, the decision on implementing the technology is complicated by ethical issues concerning variant interpretation and reporting. In Belgium, uniform guidelines were composed and a shared database for prenatal CMA findings was established. This Belgian approach sparks discussion: it is evidence-based, prevents inconsistencies and avoids parental anxiety, but can be considered paternalistic. Here, we reflect on the cultural and moral bases of the Belgian reporting system of prenatally detected variants.

Prenatal genetic testing for cystic fibrosis: a systematic review of clinical effectiveness and an ethics review.

PURPOSE: We aimed to assess the clinical value of prenatal testing for cystic fibrosis (CF) and whether ethical considerations would affect endpoint selection. METHODS: To determine effectiveness, we conducted a systematic literature review whose protocol outlined search strategies across eight databases, study inclusion criteria, and prespecified literature screening, data extraction, and synthesis processes. We conducted a scoping search on ethical considerations. RESULTS: The genetic test showed good diagnostic performance. A change in clinical management was observed: termination of pregnancy (TOP) occurred in most cases where two pathogenic variants were identified in a fetus of carrier parents (158/167; 94.6%). The TOP rate was lower in pregnancies where CF was diagnosed after fetal echogenic bowel detection (~65%). TOP and caring for a child with CF were both associated with poor short-term parental psychological outcomes. Ethical analyses indicated that informed decisions should have been the main endpoint, rather than CF-affected births prevented. CONCLUSION: CF testing leads to fewer CF-affected births. It is difficult to assess whether this means the test is valuable, since patients may not value TOP primarily in terms of maternal or fetal health outcomes, psychological or otherwise. The value of testing should arguably be measured in terms of improving patient autonomy rather than health.

Attitudes of paediatric and obstetric specialists towards prenatal surgery for lethal and non-lethal conditions.

BACKGROUND: While prenatal surgery historically was performed exclusively for lethal conditions, today intrauterine surgery is also performed to decrease postnatal disabilities for non-lethal conditions. We sought to describe physicians' attitudes about prenatal surgery for lethal and non-lethal conditions and to elucidate characteristics associated with these attitudes. METHODS: Survey of 1200 paediatric surgeons, neonatologists and maternal-fetal medicine specialists (MFMs). RESULTS: Of 1176 eligible physicians, 670 (57%) responded (range by specialty, 54%-60%). In the setting of a lethal condition for which prenatal surgery would likely result in the child surviving with a severe disability, most respondents either disagreed (59%) or strongly disagreed (19%) that they would recommend the surgery. Male physicians were twice as likely to recommend surgery for the lethal condition, as were physicians who believe that abortion is morally wrong (OR 1.75; 95%CI 1.0 to 3.05). Older physicians were less likely to recommend surgery (OR 0.57; 95%CI 0.36 to 0.88). For non-lethal conditions, most respondents agreed (66% somewhat, 4% strongly) that they would recommend prenatal surgery, even if the surgery increases the risk of prematurity or fetal death. Compared with MFMs, surgeons were less likely to recommend such surgery, as were physicians not affiliated with a fetal centre, and physicians who were religious (ORs range from 0.45 to 0.64). CONCLUSION: Physician's attitudes about prenatal surgery relate to physicians' beliefs about disability as well as demographic, cultural and religious characteristics. Given the variety of views, parents are likely to receive different recommendations from their doctors about the preferable treatment choice.

Treatment Decisions for Babies with Trisomy 13 and 18.

Many babies with trisomy 13 and 18 die in the first year of life. Survivors all have severe cognitive impairment. There has been a debate among both professionals and parents about whether it is appropriate to provide life-sustaining interventions to babies with these serious conditions. On one side of the debate are those who argue that there is no point in providing invasive, painful, and expensive procedures when the only outcomes are either early death or survival with severe cognitive impairment. Others suggest that, although mortality is high and cognitive impairment universal, babies with these conditions have an acceptable quality of life. In this paper, we will discuss both points of view. We will review the ways in which these conditions are portrayed in pediatrics textbooks and on social media sites that offer support to parents. We will then suggest an appropriate way to deal with clinical decisions for babies with these trisomies.

Life and Medical Ethics in Pediatric Neurosurgery.

Ethical issues in the field of pediatric neurosurgery, including prenatal diagnosis, palliative care for children with an intractable serious disease, and medical neglect, are discussed. An important role of medicine is to offer every possible treatment to a patient. However, it also is the responsibility of medicine to be conscious of its limitations, and to help parents love and respect a child who suffers from an incurable disease. When dealing with cases of medical neglect and palliative care for an incurable disease, it is critical to diagnose the child's condition accurately and evaluate the outcome. However, to treat or not to treat also depends on the medical resources and social-economic status of the community, the parents' religion and philosophy, the policies of the institutions involved, and the limits of medical science. Moral dilemmas will continue to be addressed as medical progress yields treatments for untreatable diseases in the future.

Qualifying choice: ethical reflection on the scope of prenatal screening.

In the near future developments in non-invasive prenatal testing (NIPT) may soon provide couples with the opportunity to test for and diagnose a much broader range of heritable and congenital conditions than has previously been possible. Inevitably, this has prompted much ethical debate on the possible implications of NIPT for providing couples with opportunities for reproductive choice by way of routine prenatal screening. In view of the possibility to test for a significantly broader range of genetic conditions with NIPT, the European Society of Human Genetics (ESHG) and American Society of Human Genetics (ASHG) recommend that, pending further debate, prenatal screening for reproductive choice should only be offered where concerning serious congenital conditions and childhood disorders. In support of this recommendation, the ESHG and ASHG discuss a number of ethical issues on which they prompt further debate: the informational privacy of the future child, the trivialization of abortion, the risk of information overload, and issues of distributive justice. This paper responds to this call with further reflection on each ethical issue and how it relates to the moral justification of providing couples with opportunities for meaningful reproductive choice. The paper concludes that whilst there may be good reasons for qualifying the scope of any unsolicited prenatal screening offer to serious congenital conditions and childhood disorders, if prenatal screening is justified for providing couples with opportunities for meaningful reproductive choice, then health services may have obligations to empower couples with the same opportunity where concerning other conditions.

What If the Prenatal Diagnosis of a Lethal Anomaly Turns Out to Be Wrong?

Advances in prenatal diagnosis create a unique set of clinical ethics dilemmas. Doctors routinely obtain genetic screening, radiologic images, and biophysical profiling. These allow more accurate diagnosis and prognosis than has ever before been possible. However, they also reveal a wider range of disease manifestations than were apparent when prenatal diagnosis was less sophisticated. Sometimes, the best estimates of prognosis turn out to be wrong. The infant's symptoms may be less severe or more severe than anticipated based on prenatal assessment. We present a case in which a prenatal diagnosis was made of severe osteogenesis imperfecta, leading to a decision to induce delivery at 31 weeks. On postnatal evaluation, the infant's disease did not appear to be as bad as had been anticipated. We discuss the ethical implications of such diagnostic and prognostic errors.

Maternal Plasma DNA and RNA Sequencing for Prenatal Testing.

Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false-positive or false-negative NIPT result, or no result, also referred to as a "no-call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA.

Medical and ethical challenges in the case of a prenatally undiagnosed massive congenital brain tumor.

Fetal and neonatal brain tumors are rare. Prenatal ultrasound aids early tumor detection. Nonetheless, we encountered a preterm neonate born at 32 weeks gestation with a massive supratentorial glioma, which was undetected on ultrasound at 19-6/7 weeks gestation. The patient presented at birth with unanticipated massive macrocephaly. Resuscitation and stabilization were difficult, but the medical team felt that futility of care was not established and opted to transfer the baby to an academic center for further imaging and specialist consultations. Diagnosis of an extensive, inoperable tumor was confirmed and support withdrawn. Postmortem histologic examination and immunohistochemical stains identified the majority of tumor cells as glial in origin. This case report illustrates well how a severe and potentially fatal anomaly, which remained undetected prenatally, presented the medical team and family with multiple medical, ethical and emotional challenges at birth; decisions regarding futility of care in the neonatal transport setting are difficult.

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.

Prenatal screening, reproductive choice, and public health.

One widely held view of prenatal screening (PNS) is that its foremost aim is, or should be, to enable reproductive choice; this is the Pure Choice view. The article critiques this position by comparing it with an alternative: Public Health Pluralism. It is argued that there are good reasons to prefer the latter, including the following. (1) Public Health Pluralism does not, as is often supposed, render PNS more vulnerable to eugenics-objections. (2) The Pure Choice view, if followed through to its logical conclusions, may have unpalatable implications, such as extending choice well beyond health screening. (3) Any sensible version of Public Health Pluralism will be capable of taking on board the moral seriousness of abortion and will advocate, where practicable, alternative means of reducing the prevalence of disease and disability. (4) Public Health Pluralism is at least as well-equipped as the Pure Choice model to deal with autonomy and consent issues.

A new ethical landscape of prenatal testing: individualizing choice to serve autonomy and promote public health: a radical proposal.

A new landscape of prenatal testing (PNT) is presently developing, including new techniques for risk-reducing, non-invasive sampling of foetal DNA and drastically enhanced possibilities of what may be rapidly and precisely analysed, surrounded by a growing commercial genetic testing industry and a general trend of individualization in healthcare policies. This article applies a set of established ethical notions from past debates on PNT for analysing PNT screening-programmes in this new situation. While some basic challenges of PNT stay untouched, the new development supports a radical individualization of how PNT screening is organized. This reformation is, at the same time, difficult to reconcile with responsible spending of resources in a publicly funded healthcare context. Thus, while the ethical imperative of individualization holds and applies to PNT, the new landscape of PNT provides reasons to start rolling back the type of mass-screening programmes currently established in many countries. Instead, more limited offers are suggested, based on considerations of severity of conditions and optimized to simultaneously serve reproductive autonomy and public health within an acceptable frame of priorities. The new landscape of PNT furthermore underscores the ethical importance of supporting and including people with disabilities. For the very same reason, no ban on what may be analysed using PNT in the new landscape should be applied, although private offers must, of course, conform to strict requirements of respecting reproductive autonomy and what that means in terms of counselling.

Prenatal screening: an ethical agenda for the near future.

Prenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non-invasive prenatal test (NIPT), the tendency to widen the scope of follow-up testing, as well as the possible future scenarios of genome-wide screening and 'prenatal personalised medicine'. The article ends with recommendations for further debate, research and analysis.

Bioethical issues of preventing hereditary diseases with late onset in the Sakha Republic (Yakutia).

BACKGROUND: Prenatal diagnosis of congenital and hereditary diseases is a priority for the development of medical technologies in Russia. However, there are not many published research results on bioethical issues of prenatal DNA testing. OBJECTIVE: The main goal of the article is to describe some of the bioethical aspects of prenatal DNA diagnosis of hereditary diseases with late onset in genetic counselling practice in the Sakha Republic (Yakutia) - a far north-eastern region of Russia. METHODS: The methods used in the research are genetic counselling, invasive chorionic villus biopsy procedures, molecular diagnosis, social and demographic characteristics of patients. RESULTS: In 10 years, 48 (76%) pregnant women from families tainted with hereditary spinocerebellar ataxia type 1 and 15 pregnant women from families with myotonic dystrophy have applied for medical and genetic counselling in order to undergo prenatal DNA testing. The average number of applications is 7-8 per year. There are differences in prenatal genetic counselling approaches. CONCLUSION: It is necessary to develop differentiated ethical approaches depending on the mode of inheritance, age of manifestation, and clinical polymorphism of hereditary disease.

Valoración ética del diagnóstico de enfermedades fundantes de discapacidad en la vida prenatal / Valoração ética do diagnóstico de enfermidades causadoras de descapacidade na vida pré-natal / Ethical evaluation of the diagnosis of diseases causing disability in prenatal life

La finalidad del diagnóstico prenatal genera un dilema controversial. Algunos autores sostienen que favorece el mejor desarrollo y adaptación del niño por nacer y sus familias, porque, al definir el estatuto moral del feto como inherente, debe recibir las mismas consideraciones morales que el niño ya nacido. Otros consideran que son medidas preventivas que disminuyen la prevalencia de enfermedades genéticas, al evitar el nacimiento de niños con estas patologías. Así, el niño por nacer no es considerado como persona y la discapacidad se interpreta como un daño para el niño y su familia, y debe ser evitada. Hay tensión al determinar si el diagnóstico prenatal es una práctica médica al servicio del hombre, con el objetivo de limitar el daño y sufrimiento humano, o bien una práctica eugenésica liberal. Tres conceptos se involucran en este conflicto: el de persona, el de discapacidad y el de prevención de enfermedades. El objetivo del artículo es reflexionar acerca de la interpretación de estos conceptos en diferentes visiones bioéticas, para alcanzar una mejor compresión de los mismos y aplicar los avances tecnológicos respetando la condición humana.

The goal of prenatal diagnosis causes a controversial dilemma. Some authors sustain that it favors better development and adaptation of the child to be born and family, since, by defining the moral statute of the fetus as inherent, he/she must receive the same moral considerations that the child already born. Others consider that avoiding the birth of children with these pathologies is a preventive measure to diminish the prevalence of genetic diseases. Thus, the child to be born is not considered a person and the disability is interpreted as damage for the child and his/her family, which must be avoided. There is tension to determine whether prenatal diagnosis is a medical practice to the service of human beings with the goal to limit damage and human suffering, or rather an eugenic liberal practice. Three concepts are involved in this conflict: the person, disability and prevention of diseases. The goal of this article is to reflect about the interpretation of these concepts in different bioethical views, in order to reach a better understanding of them and applying technological advances while respecting human condition.

A finalidade do diagnóstico pré-natal gera um dilema controvertido. Alguns autores sustentam que favorece o melhor desenvolvimento e a adaptação da criança por nascer e suas famílias, porque, ao definir o estatuto moral do feto como inerente, deve receber as mesmas considerações morais que a criança nascida. Outros consideram que são medidas preventivas que diminuem a prevalência de enfermidades genéticas, ao evitar o nascimento de crianças com estas patologias. Assim, a criança por nascer não é considerada como pessoa e a descapacidade se interpreta como um dano para a criança e sua família, e deve ser evitada. Há tensão ao determinar se o diagnóstico pré-natal é uma prática médica a serviço do homem, com o objetivo de limitar o dano e sofrimento humano, ou uma prática eugênica liberal. Três conceitos são envolvidos neste conflito: o de pessoa, o de descapacidade e o de prevenção de enfermidades. O objetivo do artigo é refletir acerca da interpretação destes conceitos em diferentes visões bioéticas, para alcançar uma melhor compreensão deles e aplicar os avanços tecnológicos respeitando a condição humana.

[Words before actions- the significance of counselling in the Praena-Test era]. / Worte vor Taten - der Stellenwert der Beratung in der Ära des Praena-Tests.

Due to new offers in prenatal diagnostics pregnant women are forced to make choices. In Switzerland physicians are obliged to inform previous to prenatal tests and to obtain informed consent. Considering the complexity of this information and the consequences of a positive result, counselling is challenging, especially in an intercultural context. A questionnaire-based study compared information processing, test interpretation and emotional response of pregnant women from Switzerland and adjacent countries with Turkish women. Knowledge of the latter was significantly lower and they found counselling more unsettling, but their acceptance of prenatal tests was significantly higher. An empathetic approach and the right words are decisive, and counselling will even gain importance when considering the increase in options patients are confronted with.

Les nouvelles offres dans le diagnostic prénatal contraignent les femmes enceintes à faire des choix. En Suisse, les médecins ont le devoir d'informer au sujet des tests prénataux et en obtenir le consentement. Compte tenu de la complexité, ce conseil est exigeant, avant tout dans un contexte interculturel. Une étude basée sur des questionnaires a comparé les connaissances et les réactions émotionnelles des femmes enceintes de Suisse avec des femmes venant de la Turquie. Cela a montré que les connaissances de ces dernières étaient moindres et qu'elles se sentaient plus insécurisées tout en montrant une acceptation significativement plus élevée relativement au diagnostic prénatal. Une attitude empathique et des mots bien choisis sont décisifs et leur importance va encore prendre de l'ampleur avec l'augmentation des options à disposition des patientes.

Displasia tanatofórica: una reflexión bioética a partir de un caso clínico / Thanatophoric dysplasia: case-based bioethical analysis

El presente artículo muestra un caso de displasia tanatofórica, diagnosticado en el período prenatal bajo criterios ultrasonográficos. Se describe la evolución del embarazo hasta el nacimiento, así como la evolución postnatal del producto. Este reporte busca invitar a la reflexión bioética y retomar sus principios apelando a la otredad y a la dignidad humana, en particular del binomio madre e hijo y su entorno familiar. En este sentido, un diagnóstico precoz permite acompañar a los padres para afrontar el proceso evolutivo de esta patología, e incluso un desenlace fatal.

This paper presents a case report of thanatophoric displasia diagnosed in the prenatal period using ultrasound standards. The course of the case pregnancy, birth process, and postnatal period is described. This report invites bioethical analysis using its principles, appealing to human dignity, diversity and otherness, particularly in the mother-child dyad and their family. An early diagnosis allows parental support as they face the course of this condition and its potentially fatal outcome.

Including ethical considerations in models for first-trimester screening for pre-eclampsia.

Recent efforts to develop reliable and efficient early pregnancy screening programmes for pre-eclampsia have focused on combining clinical, biochemical and biophysical markers. The same model has been used for first-trimester screening for fetal aneuploidies i.e. prenatal diagnosis (PD), which is routinely offered to all pregnant women in many developed countries. Some studies suggest combining PD and pre-eclampsia screening, so women can be offered testing for a number of conditions at the same clinical visit. A combination of these tests may be practical in terms of saving time and resources; however, the combination raises ethical issues. First-trimester PD and pre-eclampsia screening entail qualitative differences which alter the requirements for disclosure, non-directedness and consent with regard to the informed consent process. This article explores the differences related to the ethical issues raised by PD and pre-eclampsia in order to elucidate which factors are relevant to deciding the type of information and consent required in each context from the perspective of the ethical principles of beneficence and autonomy. Furthermore, it argues that ensuring respect for patient autonomy is context dependent and, consequently, pre-eclampsia screening and PD should be performed independently of one another.