Universal newborn screening and adverse medical outcomes: a historical note

Universal newborn screening programs for metabolic disorders are typically described as a triumph of medicine and public policy in the US over the last 50 years. Advances in science and technology, including the Human Genome Project, offer the opportunity to expand universal newborn screening programs to include many additional metabolic and genetic conditions. Although the benefits of such screening programs appear to outweigh their costs, some critics have claimed that historical examples of inadvertent harm ensuing from false-positive screening results and subsequent inappropriate medical treatment should make us wary of expanding universal newborn screening. In this essay, we report the results of a review of the published literature to assess whether the extension of screening from at risk populations to all newborns led to substantial morbidity and mortality from misguided medical treatment. We provide a historical overview of universal newborn screening programs in the United States, and then focus on six early NBS programs: congenital hypothyroidism, phenylketonuria, congenital adrenal hyperplasia, galactosemia, sickle cell disease, and maple syrup urine disease. Our comprehensive search of published sources did not reveal a widespread problem of harm ensuing from medical treatment of children with false positive screening test results.     

The role of National Library of Medicine web sites in newborn screening education

Expanded newborn screening programs and subsequent detection of rare genetic disorders challenge parents and their medical providers to learn about the treatment and management of these disorders. Many people seek medical information on the Internet but may encounter requests for registration or fees, or find that resources are out of date, difficult to understand, or buried in advertisements. The U.S. National Library of Medicine (NLM), a component of the National Institutes of Health, provides web-based resources that address the challenges of newborn screening education. These resources include MedlinePlus, Genetics Home Reference, ClinicalTrials.gov, and PubMed. NLM websites are not commercial, do not require registration or fees, and provide varied levels of information for a continuum of audiences from low-literacy consumers to health professionals. Using phenylketonuria as an example, this study describes the information that parents and their medical providers can find through NLM resources. NLM has embraced the digital age and provides the public with reliable, accurate, and up-to-date educational materials.     

Pilot programs in newborn screening

The term "pilot study" has been used over the years to describe the evaluation of the many elements involved in deciding whether a proposed condition should be added to a newborn screening (NBS) panel, and until recently, was unilaterally used to describe the evaluation of the assay to be used before the condition was officially adopted by a state for its newborn screening panel. Since Guthrie's introduction of screening for PKU, each time a new condition was added to the panel, the screening assay itself was validated through a population-based trial, in which the test was performed with de-identified samples to avoid association between the test result and the infant. This is considered by the laboratory as the "pilot phase" of adding a new condition. To advance the science of NBS, especially to accommodate new technologies that may provide new types of information (genetic versus physiological) for each new condition, pilot programs are essential. Involvement of the clinical community serves to improve these evaluations and provides the needed clinical validation of decisions made as a result of it. This paper describes the historical context of pilot programs in population-based NBS that utilize laboratory-based markers as indicators of concern; specifically, three applications that demonstrate different approaches to the use of pilots in adding conditions to a NBS panel are described.     

The utilization of genetic counselors within a newborn screening program

Genetic counselors have participated in the Michigan Newborn Screening Program on a contractual basis since 1988. Their role includes newborn screening education and training, newborn nursery site visits, and monitoring newborn screening in hospitals. Their impact has been to improve the quality of newborn screening services by reducing errors and increasing completion of data fields on newborn screening cards, improving hospital nursery cooperation and problem solving, and enhancing health department response to specific problems.     

National evaluation of US newborn screening system components

Newborn screening has existed as a state-based public health service since the early 1960s. Every state and most territorial jurisdictions have comprehensive newborn screening programs in place, but in the United States a national newborn screening policy does not exist. This results in different administrative infrastructures, screening requirements, laboratory and follow-up services, medical management approaches, and related activities across the country. Federal initiatives and support have contributed to limited evaluations of various aspects of individual newborn screening programs at the national level, but funding is an issue. The national evaluation strategies have taken various forms, all with the intent of improving the screening system through review of actions taken and suggestions for future improvements. While participation in the national evaluation effort for newborn screening laboratory practices includes all US programs, and this has aided in improving quality and harmonizing protocols, other national evaluation activities have been only moderately successful. National data reporting of quality indicators for various program elements must be comprehensive and timely, and the elements must be universally accepted in order to meet the evaluation and improvement needs of the national newborn screening system. A comprehensive real time national evaluation activity will likely require additional resources and enforcement incentives. Limited federal actions through grant incentives and selected reporting requirements provide a possible means of stimulating programs to participate in national harmonization efforts.     

Critical role of the March of Dimes in the expansion of newborn screening

Expansion of newborn screening (NBS) has been driven primarily by a combination of advances in technology and medical treatment, and the sustained advocacy efforts of consumers and voluntary health organizations. The longstanding leadership of the March of Dimes has been credited by many as a critical factor in the expansion and improvement of state NBS programs. From the historic vantage point of four decades of March of Dimes involvement with newborn screening, this report reviews the unique origin of the first newborn screening test, and identifies from this point of origin several of the elements which still define the evolution of advocacy for NBS today. It also documents activities at the federal level and in seven states that have lead to expanded screening for newborns. Advances in NBS technology and medical treatment have informed policy development. Mobilization of volunteers and focused advocacy activities have brought about expansion of screening opportunities for newborns across the United States. But more work is needed. Continued application of the effective strategies identified in this report will help assure that all families have the best possible chance of assuring that their newborns do not have to suffer the complications of conditions that we know can be treated effectively.     

Cost-effectiveness and test-performance factors in relation to universal newborn hearing screening

The first portion of this paper reviews current understanding of the cost of universal newborn hearing screening (UNHS), including capital and operating expenses, as well as the costs for follow-up testing on infants who do not pass the hearing screening test in the perinatal period. Capital expenses include the cost of equipment. Operating expenses include the costs for disposables and personnel. Follow-up costs relate to the diagnostic testing that must be performed in order to determine hearing status in those infants who do not pass the newborn hearing screening test. This section is followed by a more theoretical approach, in which test performance, prevalence, program costs, and "costs of hearing loss" are combined in a model that includes all costs of hearing loss, including screening, follow-up testing, and costs (benefits) associated with identifying hearing loss early in life. While some of the model's cost/benefit assumptions may be incorrect, the general approach of taking into account both costs and benefits provides a framework for evaluating the utility of UNHS in a more global manner. Model assumptions (costs, benefits, prevalence, sensitivity, specificity) can be changed to values deemed more appropriate, but the general approach is still informative. With the present assumptions, it is shown that initially, the costs of UNHS exceed its benefits. However, after only four years of operation, UNHS programs will result in a net savings to society. These savings increase rapidly, reaching a maximum annual benefit of seven billion dollars 75 years after initiation of the program, which is also the societal benefit for all years thereafter.     

Newborn screening for fragile X syndrome

Newborn screening for fragile X syndrome (FXS) is technically possible, and in the relatively near future accurate and inexpensive screening technologies are likely to be available. When that happens, will America's public health system adopt newborn screening for fragile X syndrome? This article addresses this issue by first placing screening for FXS in the context of the history and current status of newborn screening policy and practice. Lack of a proven medical treatment may stand as a barrier to newborn screening, but strong arguments can be made that early intervention provides important services for identified newborns and their families. Furthermore, other arguments could be used to justify newborn screening, including informed reproductive risk, medically necessary information, and consumer demand. Fragile X syndrome is offered as a prototype for many of the issues that will face society as more genetic disorders are discovered and new technologies for screening are developed.     

Changing perspectives on the benefits of newborn screening

The likelihood of benefit is fundamental to decision making about newborn screening. But benefit is construed in different ways by different stakeholders. This article begins with a review of benefit as considered historically by various expert panels and organizations. We then show how 78 conditions fared when experts recently rated them on benefit using a scoring system recommended by a task force of the American College of Medical Genetics. Finally, we analyze how benefit is reflected in the public comments submitted in response to the ACMG report. Results show that benefit has been and remains a core consideration for screening decisions. Historically the focus has been on improved physical health as a result of medical treatment; however, in only 4 of the 78 conditions rated does newborn screening prevent all negative consequences. In fact the majority of both core conditions (51.7%) and secondary targets (87.5%) recommended in the ACMG report were rated as having treatments that prevented only some negative consequences. All conditions rated had perceived benefits for family and society, but currently no conditions are screened on the basis of family or societal benefits alone. No agreed-upon threshold exists for what would be considered meaningful benefit, and stakeholder groups differ in their perceptions of benefit. We conclude by suggesting several key research studies needed to further inform public policy.     

NICHD research initiative in newborn screening

Recent changes in genetics research have created new opportunities to improve the scope and quality of newborn screening services. Changes in newborn screening should be supported and directed by an organized program of research. The NICHD Research Initiative in Newborn Screening includes the development of systematic methods to identify additional conditions appropriate for newborn screening; development and testing innovative interventions and treatments to improve outcomes; education of the provider workforce; development and implementation of appropriate information and communication systems for parents and providers; and, sponsoring an ongoing program of research and research training. Future needs will include the development of a national translational research infrastructure, prevention research and research into behavioral and social sciences issues. The NICHD Research Initiative in Newborn Screening is expected to be an ongoing and vital initiative that adapts itself to new scientific findings, technological developments, changes in the public and personal health care system, and our evolving understanding of the needs of affected individuals, families and the community.     

Current status of newborn screening: decision-making about the conditions to include in screening programs

Newborn screening is considered a highly successful public health program that has resulted in the reduction of mortality, mental retardation, and other serious disabilities in thousands of children since the introduction of screening for phenylketonuria (PKU) in the 1960s. Programs are based in state public health departments such that each state independently reaches decisions as to which conditions should be mandated for inclusion in programs, leading to considerable variability among the states as to what is being screened. New technologies and knowledge of the genetics of many conditions have greatly expanded the number of conditions with potential for inclusion in newborn screening.     

The regional genetic and newborn screening service collaboratives: the first two years

Newborn screening and genetic technologies are expanding and changing rapidly, increasing the demand for genetic specialty services. Because of the scarcity and geographic maldistribution of genetic specialty services, access to these services is a critical issue. This article discusses some of the efforts initiated by the Maternal and Child Health Bureau of the Health Resources and Services Administration, particularly the establishment of regional genetic and newborn screening collaboratives to improve access to these services and expertise.     

Treatment of Anxiety Disorders With Comorbid Depression: A Survey of Expert CBT Clinicians

Cognitive-behavioral therapy (CBT) is an empirically supported psychological treatment for anxiety disorders. These treatments have primarily been developed to target primary anxiety disorders, despite the fact that these disorders frequently co-occur with a diagnosis of depression. Empirical evidence provides guidance regarding how to treat an individual with a primary anxiety disorder with comorbid depression; however, there is limited data regarding how to translate these findings into clinical practice. Improving our understanding of how CBT is currently being used in practice among experts is integral to learning whether modifications to protocols lead to more or less effective treatments. Accordingly, we surveyed expert CBT clinicians about their assessment and treatment approaches and what challenges they face in formulating and treating mood and anxiety comorbidity. Most experts reported that their assessment includes a semistructured interview and self-report measures to determine breadth and hierarchical ordering of comorbidity severity. Symptom severity, client's goals, temporal onset of disorders, presence of suicide risk, and potential for early treatment success were reported as factors to consider when deciding where to begin treatment. Almost three quarters of experts surveyed indicated that they usually take some type of sequential treatment approach when treating primary anxiety disorders with comorbid depression. The top three reported challenges associated with treating comorbid presentations were client's motivation/energy, hopelessness/pessimism, and ongoing need for risk assessment. Implications for the nature and timing of CBT interventions in “real-world” clinical practice are discussed.     

Making the case for objective performance metrics in newborn screening by tandem mass spectrometry

The expansion of newborn screening programs to include multiplex testing by tandem mass spectrometry requires understanding and close monitoring of performance metrics. This is not done consistently because of lack of defined targets, and interlaboratory comparison is almost nonexistent. Between July 2004 and April 2006 (N=176,185 cases), the overall performance metrics of the Minnesota program, limited to MS/MS testing, were as follows: detection rate 1:1,816, positive predictive value 37% (54% in 2006 till date), and false positive rate 0.09%. The repeat rate and the proportion of cases with abnormal findings actually been reported are new metrics proposed here as an objective mean to express the overall noise in a program, where noise is defined as the total number of abnormal results obtained using a given set of cut-off values. On the basis of our experience, we propose the following targets as evidence of adequate analytical and postanalytical performance: detection rate 1:3,000 or higher, positive predictive value>20%, and false positive rate<0.3%.     

Toward a biopsychosocial model for 21st-century genetics

Advances in genomic research are increasingly identifying genetic components in major health and mental health disorders. This article presents a Family System Genetic Illness model to address the psychosocial challenges of genomic conditions for patients and their families, and to help organize this complex biopsychosocial landscape for clinical practice and research. This model clusters genomic disorders based on key characteristics that define types of disorders with similar patterns of psychosocial demands over time. Key disease variables include the likelihood of developing a disorder based on specific genetic mutations, overall clinical severity, timing of clinical onset in the life cycle, and whether effective treatment interventions exist to alter disease onset and/or progression. For disorders in which carrier, predictive, or presymptomatic testing is available, core nonsymptomatic time phases with salient developmental challenges are described pre- and post-testing, including a long-term adaptation phase. The FSGI model builds on Rolland's Family System Illness model, which identifies psychosocial types and phases of chronic disorders after clinical onset. The FSGI model is designed to be flexible and responsive to future discoveries in genomic research. Its utility is discussed for research, preventive screening, family assessment, treatment planning, and service delivery in a wide range of healthcare settings.     

Application of pharmacological fMRI to developmental psychiatric disorders

Functional magnetic resonance imaging of neural activity induced by pharmacological stimulation (phMRI) is a promising technique for revealing pathophysiology and etiology of developmental psychiatric disorders. Recent investigations of the dopaminergic system have made possible the use of phMRI as a non‐invasive assay for neurotransmitter function. This paper explores applications of phMRI for identification of neurophysiological trait‐dependent and clinical state‐dependent mechanisms that can define biologically valid diagnostic criteria for developmental psychiatric disorders. Further, applications of phMRI for investigations of neurochemical changes induced by long‐term drug exposure, alternative therapies and normal brain maturation are discussed. The paper ends by highlighting methodological challenges posed by experimental control of pharmacological stimulation that is essential for valid interpretation of phMRI results.     

Mandatory versus voluntary consent for newborn screening?

Virtually every infant in the United States undergoes a heel stick within the first week of life to test for a variety of metabolic, endocrine, and hematological conditions as part of state-run universal newborn screening (NBS) programs. The history of this mandatory public health program is examined, as well as whether the policy was morally justifiable. Three changes in NBS practice necessitate a re-evaluation of the mandatory nature of NBS. First is the adoption of NBS for hemoglobinopathies in the 1980s that led to the identification of many sickle cell carriers and carriers of other hemoglobin variants. In all other contexts, carrier testing requires consent, and there is no moral rationale why NBS ought to be exceptional. Second is the application of tandem mass spectrometry (MS/MS) to NBS in the 1990s that led to the identification of many metabolic conditions and variants, some of which were not treatable and others of which had unknown clinical relevance. To the extent that the conditions do not need emergent diagnosis and treatment, there is less justification for mandatory screening. Third, there is great interest in using residual blood spots for research, and the cornerstone of research ethics is the voluntary consent of the participant (or his or her proxy). These three changes support revising mandatory NBS with a tiered consent process to best balance respect for parental autonomy and the promotion of children's health.     

Young Adults’ Pre-Existing Knowledge of Cystic Fibrosis and Sickle Cell Diseases: Implications for Newborn Screening

Parental distress following newborn screening is thought to result from inadequate preparation for screening results which can result in maladjustment to screening results after birth. Although prior awareness of relevant genetic disorders such as cystic fibrosis and sickle cell diseases, and preparedness for screening is suggested to enhance information uptake and reduce parental distress, little is known about how young adults’ prior knowledge prepares them for screening or affects the assimilation and retention of screening information. Thirty-four young adults, without familial genetic disease or screening experience took part in one of seven focus groups which examined knowledge of cystic fibrosis and sickle cell diseases and ability to assimilate new disease information. Thematic analysis revealed that adults had limited understanding of how cystic fibrosis and sickle cell diseases were inherited or how symptoms manifest, leaving them inadequately prepared for screening results if they do not engage with information interventions. Further, they selectively assimilated new disease information and had difficulty understanding new information in the absence of prior disease knowledge. Young adults’ prior disease knowledge should be considered within a newborn screening context and written materials should consider the inclusion of carrier statistics to improve information relevance.     

Orientation discrimination and cortical function in the human newborn

There is some controversy concerning whether or not the visual abilities of the newborn are mediated entirely through subcortical pathways or whether the visual cortex is functioning at birth. A critical test of cortical functioning is discrimination of orientation: orientation-selective neurons are found in the visual cortex but not in subcortical parts of the visual system. An experiment is described in which newborn infants were habituated to a square-wave grating oriented 45 degrees from vertical. After habituation, significant preferences for the novel, mirror-image, grating were found, a result which argues for some degree of visual cortical functioning at birth.