Understanding the Clinical Utility of Genome Sequencing in Critically Ill Newborns.

Diagnostic genome sequencing (GS) in newborns may have many benefits. More accurate diagnosis could spur the development of innovative genomic therapies. A precise diagnosis could help doctors and parents anticipate clinical problems and inform a family's future reproductive choices. However, the integration of GS into neonatal care remains associated with a variety of ethical controversies, including concerns about informed consent, about interpreting uncertain results, about resource allocation and whether access to genomic services could exacerbate health disparities, and about the effect of genome diagnostics on people with disabilities. There also remains significant uncertainty about which babies should be tested and when and how the potential benefits of GS ought to be measured. Probably related to these challenges, some payors have been reluctant to cover the cost of GS for critically ill newborns. Much of the reluctance appears to turn on questions about the clinical benefit associated with GS and whether and for whom GS will be cost-effective. These situations point to the urgent need for careful assessments of the clinical utility of GS in critically ill infants. In this paper, we critically examine the ways in which the clinical utility of GS has been evaluated in this patient population. We focus on "change of management" (COM), a widely used measure of clinical utility for diagnostic GS. We suggest that this measure is often ambiguous because not all COMs can be attributed to genomic results and because not all COMs lead to patient benefit. Finally, we suggest ways that measurement of clinical utility could be improved.

Ethics knowledge, attitudes, and experiences of tertiary care pediatricians in Ethiopia.

BACKGROUND: Pediatricians in developing countries face different ethical dilemmas than do doctors working in settings with more resources. There are very few studies from developing countries analyzing pediatricians' knowledge and attitudes regarding the ethical dilemmas that arise in such settings. To address this gap, we explored the clinical ethical knowledge, attitude and experience of physicians who are working in the Department of Pediatrics and Child Health (DPCH) of St Paul's Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia. STUDY POPULATION: All pediatric resident doctors and pediatric consultants who were working in the DPCH of SPHMMC in December, 2020. METHOD: A structured pretested self-administered questionnaire was distributed to all 79 of the residents and consultants in the department during the period December 15-27, 2020. The questionnaire assessed the knowledge (23 questions), attitude (9 questions) and experiences (9 questions) of the study participants regarding a variety of bioethical issues. Data were analyzed using SPSS version 20.0 for windows. The mean, median, standard deviation, and interquartile range of respondents' scores were determined and compared using Fisher's exact test. RESULT: A total of 59/79 (75%) physicians completed the questionnaire. The mean age of the participants was 30.7 ± 4.1 years. Thirty six (61.0%) were female. At the time of data collection, more than half (57.6%) served < 5 years as a physician. The mean ethics knowledge score of the respondents was 12.3 ± 2.34 out of 23 knowledge questions. The lowest and highest knowledge scores were 8 and 19 respectively. Scores were highest on questions about confidentiality (94.9% correct) and lowest on questions about genetic testing and diagnosis (13.6% correct). Only 13 (22.4%) physicians agreed with the practice of children should never be treated without consent of the parent. CONCLUSION: Tertiary care pediatricians at one hospital in Ethiopia lack knowledge about current standards in bioethics. There is a need for more ethics education in this setting.

Parental Concerns on Short Stature: A 15-Year Follow-Up.

OBJECTIVES: To compare parental attitudes about short stature over time and determine possible factors that predict changes in attitudes. STUDY DESIGN: At baseline (1993-1994), we surveyed parents about their attitudes regarding their children's height. We compared parents of children (aged 4-15 years) referred to endocrinologists (referred, 154) with those of children with heights <10th percentile seen by pediatricians during regular visits (control, 240). At follow-up (2008-2009), 103 control and 98 referred parents completed a similar survey. We then made a logistic regression analysis to observe changes in perception. Primary variables included self-esteem, treatment by peers, and ability to cope with current height. RESULTS: At baseline, referred parents perceived a worse impact of short stature on their children than did controls. At follow-up, instead, referred parents were 3.8 times more likely to report improvement in self-esteem, 2.4 times more likely to report improved treatment from peers, and 5.7 times more likely to report overall ability to cope with height than were unreferred parents. Perception of psychosocial improvement was greater in the referred than the control group. Referral was a stronger predictor of an improved follow-up response than patients' current height or change in height. CONCLUSIONS: While incorporating parental attitudes into management decisions, clinicians should be aware that parental perceptions may change over time and that referral itself may lead parents to perceive psychosocial improvements over time.

Yes to Life: An Opportunity for Partnership Between Medicine and Religion.

Pope Francis recently spoke about perinatal palliative care and the dilemmas that parents of critically ill babies encounter. In his speech, the Pope beautifully captured what many parents feel. They love their baby even if they know that the baby cannot survive. They need compassionate care of the sort that will allow them to express that love, even if it is only for minutes or hours, and even if the expression of love takes the form of comforting the dying baby rather than intervening medically or surgically to try to prolong life. "Many times," the Pope said, "Those few hours in which a mother can cradle her child in her arms leave an unforgettable trace in her heart." For those who work in perinatal palliative care, this affirmation and endorsement of their efforts by the Church is a welcome offer for an important collaboration. Medicine and religion can work hand in hand, here, to help parents and doctors who struggle to do the right thing when all the choices seem bad.

The Belmont Report and Innovative Clinical Research.

A central pillar of the Belmont Report is that a bright line must be drawn between medical practice and biomedical research. That line may have been brighter 50 years ago. Today, the typical physician is likely to work for a corporation or health system that styles itself as a learning health system. Such systems increasingly emphasize the (research-like) use of data to measure quality, encourage efficiency, ensure safety, and guide a standardized approach to clinical care. While these activities are not considered research, they pose many of the same risks or conflicts of loyalty. In research, the doctor's fiduciary loyalty to the patient is compromised by a loyalty to the scientific process. In learning health systems, the doctor's loyalty is compromised by loyalty to the system and its metrics. In this world, it is not clear that research-as conceptualized by the Belmont Report, codified in the Common Rule, and overseen by IRBs-is a uniquely risky activity deserving of such uniquely strict oversight. Perhaps, instead, the divided loyalties and conflicts of interest faced by everyday clinicians working in learning health systems demand a protective framework similar to the one that we now have for the activities that we designate as "research." This article compares the risks of the various activities that might be called "research" and suggests a unified system of oversight for all of them.

Healthcare organizations and high profile disagreements.

In this paper, we examine healthcare organizations' responses to high profile cases of doctor-parent disagreement. We argue that, once a conflict crosses a certain threshold of public interest, the stakes of the disagreement change in important ways. They are no longer only the stakes of the child's interests or who has decision-making authority, but also the stakes of public trust in healthcare practitioners and organizations and the wide scale spread of medical misinformation. These higher stakes call for robust organization-level responses. There are responsible and thoughtful ways for healthcare organizations to directly engage with these cases. Hospitals should seek an alliance with the parents around the goal of public discussion and utilize web-based platforms to provide the public with information about medical conditions, experimental treatments, and how clinical ethics deliberation in hospitals works. We outline five important lessons for healthcare organizations to keep in mind when responding to such cases. Approached with care, these cases could become "teachable moments" for both healthcare organizations and society.

Pediatric Cardiology Specialist's Opinions Toward the Acceptability of Comfort Care for Congenital Heart Disease.

In order to evaluate physicians' willingness to seek legal action to mandate surgery when parents refuse surgery for various congenital heart lesions, we surveyed pediatric cardiologists and cardiovascular surgeons at 4 children's hospitals. We asked whether physicians would support parental refusal of surgery for specific heart defects and, if not, whether they would seek legal action to mandate surgery. We then analyzed associations between physicians' willingness to mandate surgery and national operative mortality rates for each lesion. We surveyed 126 cardiologists and 9 cardiac surgeons at four tertiary referral centers. Overall response rate was 77%. Greater than 70% of physicians would seek legal action and mandate surgery for the following lesions: ventricular septal defect, coarctation of the aorta, complete atrioventricular canal, transposition of the great arteries, tetralogy of Fallot, and unobstructed total anomalous pulmonary venous return. Surgery for all of these lesions has reported mortality rates of < 5%. Physicians were less likely to seek legal action when parents refused surgery for Shone complex, any single ventricle lesion, or any congenital heart disease accompanied by Trisomy 13 or Trisomy 18. Among experts in pediatric cardiology, there is widespread agreement about the appropriate response to parental refusal of surgery for most congenital heart lesions, and these lesions tended to be heart defects with lower surgical mortality rates. Lesions for which there was greater consensus among experts were those with the best outcomes. There was less consensus for lesions with higher mortality rates. Such surveys, revealing disagreement among expert professionals, can provide an operational definition of the current professional "gray zone" in which parental preferences should determine treatment.

Rethinking the "open future" argument against predictive genetic testing of children.

Professional consensus has traditionally discouraged predictive genetic testing when no childhood interventions can reduce future morbidity or mortality. However, advances in genome sequencing and accumulating evidence that children and families cope adequately with predictive genetic information have weakened this consensus. The primary argument remaining against testing appeals to children's "right to an open future." It claims that the autonomy of the future adult is violated when others make an irreversible choice to obtain or disclose predictive genetic information during childhood. We evaluate this argument and conclude that children's interest in an open future should not be understood as a right. Rather an open future is one significant interest to weigh against other important interests when evaluating decisions. Thus, predictive genetic testing is ethically permissible in principle, as long as the interests promoted outweigh potential harms. We conclude by offering an expanded model of children's interests that might be considered in such circumstances, and present two case analyses to illustrate how this framework better guides decisions about predictive genetic testing in pediatrics.

Ethical and Policy Considerations for Genomic Testing in Pediatric Research: The Path Toward Disclosing Individual Research Results.

DNA is now commonly collected in clinical research either for immediate genomic analyses or stored for future studies. Many genomic studies were previously designed without awareness of the ethical issues that might arise regarding the disclosure of genomic test results. At the start of the Chronic Kidney Disease in Children (CKiD) Cohort Study in 2004, we did not foresee the advent of genomic technology or the associated ethical issues pertaining to genetic research in children. Recent genomic studies and ancillary proposals using genomic technology stimulated the CKiD investigators to reassess the current ethical and policy environment pertaining to genomic testing and results disclosure. We consider the issues pertaining to next generation sequencing and individual results disclosure that may guide current and future research practices.

Ethical issues with testing and treatment for Krabbe disease.

Early-infantile Krabbe disease (EIKD) is an autosomal recessive, progressive, neurodegenerative disorder that usually leads to death in infancy. A study published in 2005 indicated that hematopoietic stem-cell transplantation (HSCT) was effective in the treatment for EIKD when used before the onset of symptoms. This finding suggested that newborn screening for EIKD, which would allow earlier diagnosis, might lead to earlier treatment and better outcomes. In 2006, New York was the first state to implement newborn screening for Krabbe disease; however, the results were not as good as proponents had hoped. In this paper, we present the history of efforts to diagnose and treat EIKD. Based on our findings, we question the efficacy of newborn screening for Krabbe disease. We present two arguments. First, testing itself is too imprecise. Even with the most rigorous testing standards, such as those used in New York, many of the children who are identified as being 'at risk' for EIKD remain asymptomatic. It is unclear if they will remain asymptomatic forever and, thus, whether the tests should be considered 'false positives', or whether they will eventually develop the disease. Second, we question the efficacy of early HSCT. We recommend placing a moratorium on mandatory newborn screening for EIKD. WHAT THIS PAPER ADDS: Current tests to identify which children are likely to develop Krabbe diseased are inadequate. Many children identified as being 'at risk' for early infantile Krabbe disease remain asymptomatic. Psychosine appears to be more specific than low galactosylceramidase levels for diagnosing early infantile Krabbe disease.

When Deeply Held Personal Beliefs Conflict with Collective Societal Norms.

This essay analyzes the conflicts that arise between an individual's deeply held beliefs and the collective norms of society. Sometimes these conflicts are framed in religious terms. The author argues that such a framing is too narrow and inappropriately puts the focus on a specific set of (largely Christian) beliefs about matters related to sexuality. This essay attempts to broaden the discussion in order to highlight the ways in which conflicts between individual beliefs and practices, on the one hand, and prevailing societal norms, on the other, create the tension that can lead to societal change.

Pediatric neurosurgeons' views regarding prenatal surgery for myelomeningocele and the management of hydrocephalus: a national survey.

OBJECTIVE: The Management of Myelomeningocele Study (MOMS) compared prenatal with postnatal surgery for myelomeningocele (MMC). The present study sought to determine how MOMS influenced the clinical recommendations of pediatric neurosurgeons, how surgeons' risk tolerance affected their views, how their views compare to those of their colleagues in other specialties, and how their management of hydrocephalus compares to the guidelines used in the MOMS trial. METHODS: A cross-sectional survey was sent to all 154 pediatric neurosurgeons in the American Society of Pediatric Neurosurgeons. The effect of surgeons' risk tolerance on opinions and counseling of prenatal closure was determined by using ordered logistic regression. RESULTS: Compared to postnatal closure, 71% of responding pediatric neurosurgeons viewed prenatal closure as either "very favorable" or "somewhat favorable," and 51% reported being more likely to recommend prenatal surgery in light of MOMS. Compared to pediatric surgeons, neonatologists, and maternal-fetal medicine specialists, pediatric neurosurgeons viewed prenatal MMC repair less favorably (p < 0.001). Responders who believed the surgical risks were high were less likely to view prenatal surgery favorably and were also less likely to recommend prenatal surgery (p < 0.001). The management of hydrocephalus was variable, with 60% of responders using endoscopic third ventriculostomy in addition to ventriculoperitoneal shunts. CONCLUSIONS: The majority of pediatric neurosurgeons have a favorable view of prenatal surgery for MMC following MOMS, although less so than in other specialties. The reported acceptability of surgical risks was strongly predictive of prenatal counseling. Variation in the management of hydrocephalus may impact outcomes following prenatal closure.

Clinical Ethics in Pediatrics: An International Perspective.

In this article, we first review the development of clinical ethics in pediatrics in the United States. We report that, over the last 40 years, most children's hospitals have ethics committees but that those committees are rarely consulted. We speculate that the reasons for the paucity of ethics consults might be because ethical dilemmas are aired in other venues. The role of the ethics consultant, then, might be to shape the institutional climate and create safe spaces for the discussion of difficult and sometimes contentious issues. Finally, we report how pediatric clinical ethics has evolved differently in a number of other countries around the world.

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.

Fragile lives with fragile rights: Justice for babies born at the limit of viability.

There is an inconsistency in the ways that doctors make clinical decisions regarding the treatment of babies born extremely prematurely. Many experts now recommend that clinical decisions about the treatment of such babies be individualized and consider many different factors. Nevertheless, many policies and practices throughout Europe and North America still appear to base decisions on gestational age alone or on gestational age as the primary factor that determines whether doctors recommend or even offer life-sustaining neonatal intensive care treatment. These policies are well intentioned. They aim to guide doctors and parents to make decisions that are best for the baby. That is an ethically appropriate goal. But in relying so heavily on gestational age, such policies may actually do the babies a disservice by denying some babies treatment that might be beneficial and lead to intact survival. In this paper, we argue that such policies are unjust to premature babies and ought to be abolished. In their place, we propose individualized treatment decisions for premature babies. This would treat premature babies as we treat all other patients, with clinical decisions based on an individualized estimation of likelihood that treatment would be beneficial.

Specialty-Based Variation in Applying Maternal-Fetal Surgery Trial Evidence.

INTRODUCTION: The Management of Myelomeningocele Study (MOMS) compared prenatal with postnatal surgery for fetal myelomeningocele (MMC). We sought to understand how subspecialists interpreted the trial results and whether their practice has changed. MATERIALS AND METHODS: Cross-sectional, mailed survey of 1,200 randomly selected maternal-fetal medicine (MFM) physicians, neonatologists, and pediatric surgeons. RESULTS: Of 1,176 eligible physicians, 670 (57%) responded. Compared to postnatal closure, 33% viewed prenatal closure as "very favorable" and 60% as "somewhat favorable." Most physicians reported being more likely to recommend prenatal surgery (69%), while 28% were less likely to recommend pregnancy termination. In multivariable analysis, neonatologists were more likely to report prenatal closure as "very favorable" (OR 1.6; 95% CI: 1.03-2.5). Pediatric surgeons and neonatologists were more likely to recommend prenatal closure (OR 2.1; 95% CI: 1.3-3.3, and OR 2.9; 95% CI: 1.8-4.6) and less likely to recommend termination (OR 3.8; 95% CI: 2.2-6.7, and OR 4.7; 95% CI: 2.7-8.1). In addition, physicians with a higher tolerance for prematurity were more likely to report prenatal closure as "very favorable" (OR 1.02; 95% CI: 1.00-1.05). DISCUSSION: In light of the MOMS trial, the vast majority of pediatric subspecialists and MFMs view prenatal MMC closure favorably. These attitudes vary by specialty and risk tolerance.