Universal Newborn Screening Program Research Articles

The Sweat Metabolome of Screen-Positive Cystic Fibrosis Infants: Revealing Mechanisms beyond Impaired Chloride Transport.

The sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection–capillary electrophoresis–mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention.

Paper-Based Diagnostics: Rethinking Conventional Sickle Cell Screening to Improve Access to High-Quality Health Care in Resource-Limited Settings.

Every year, hundreds of thousands of children worldwide are born with sickle cell disease, a genetic disorder that impacts the hemoglobin molecules in blood. If left undiagnosed and untreated, most affected children will die before reaching the age of five. However, highly accurate diagnostic methods and effective treatment regimens for sickle cell disease have been known for many years, and children who receive early diagnosis and subsequent comprehensive care survive well into adulthood-as evidenced by the tremendous success of universal newborn screening programs in North America and Europe.

A Paper-Based Test for Screening Newborns for Sickle Cell Disease

The high cost, complexity and reliance on electricity, specialized equipment and supplies associated with conventional diagnostic methods limit the scope and sustainability of newborn screening for sickle cell disease (SCD) in sub-Saharan Africa and other resource-limited areas worldwide. Here we describe the development of a simple, low-cost, rapid, equipment- and electricity-free paper-based test capable of detecting sickle hemoglobin (HbS) in newborn blood samples with a limit of detection of 2% HbS. We validated this newborn paper-based test in a cohort of 159 newborns at an obstetric hospital in Cabinda, Angola. Newborn screening results using the paper-based test were compared to conventional isoelectric focusing (IEF). The test detected the presence of HbS with 81.8% sensitivity and 83.3% specificity, and identified SCD newborns with 100.0% sensitivity and 70.7% specificity. The use of the paper-based test in a two-stage newborn screening process could have excluded about 70% of all newborns from expensive confirmatory testing by IEF, without missing any of the SCD newborns in the studied cohort. This study demonstrates the potential utility of the newborn paper-based test for reducing the overall cost of screening newborns for SCD and thus increasing the practicality of universal newborn SCD screening programs in resource-limited settings.

Newborn Screening for Sickle Cell Disease in St. Vincent and the Grenadines: Results of a Pilot Newborn Screening Program.

Objective: To pilot a newborn screening program for sickle cell disease (SCD) in St. Vincent and the Grenadines using a novel partnership method to determine the feasibility of a universal newborn screening program in this country. Methods: A prospective study of mothers and their newborns was conducted between January 1, 2015, and November 1, 2015, at the country’s main hospital. Mothers of infants born at this hospital were offered screening for SCD for their infants. If accepted, the newborn’s heel-stick blood specimen was obtained and mailed to the South Carolina Department of Health and Environmental Control Newborn Screening Laboratory for testing. Samples were analyzed for variant hemoglobins using standard laboratory techniques and results were communicated to local physicians. Feasibility was determined by a benchmark of having >50% of SCD patients receive the diagnosis and initiate disease-specific care by 3 months of age. Descriptive statistics were completed using SAS 9.4. Results: There were 1147 newborn infants screened for SCD. Of these, 123 (10.7%) had results indicative of sickle trait and 3 patients (0.3%) were diagnosed with SCD: 1 with HbSS and 2 with HbSC. All 3 patients with SCD received treatment before 3 months of age. Conclusions: A newborn screening program is feasible in this population when partnered with an established newborn screening laboratory.

Cost-Effectiveness Analysis of a National Newborn Screening Program for Biotinidase Deficiency.

There are conflicting views as to whether testing for biotinidase deficiency (BD) ought to be incorporated into universal newborn screening (NBS) programs. The aim of this study was to evaluate the cost-effectiveness of adding BD to the panel of conditions currently screened under the national NBS program in Spain. We used information from the regional NBS program for BD that has been in place in the Spanish region of Galicia since 1987. These data, along with other sources, were used to develop a cost-effectiveness decision model that compared lifetime costs and health outcomes of a national birth cohort of newborns with and without an early detection program. The analysis took the perspective of the Spanish National Health Service. Effectiveness was measured in terms of quality-adjusted life years (QALYs). We undertook extensive sensitivity analyses around the main model assumptions, including a probabilistic sensitivity analysis. In the base case analysis, NBS for BD led to higher QALYs and higher health care costs, with an estimated incremental cost per QALY gained of $24,677. Lower costs per QALY gained were found when conservative assumptions were relaxed, yielding cost savings in some scenarios. The probability that BD screening was cost-effective was estimated to be >70% in the base case at a standard threshold value. This study indicates that NBS for BD is likely to be a cost-effective use of resources.

Sickle-cell disease: a call to action

Sickle-cell disease: a call to action

Use of ultrasonography in developmental dysplasia of the hip

PurposeUltrasonography has been used as a diagnostic tool in developmental dysplasia of the hip (DDH) during early infancy since the early 1980s. The aim of this review article is to summarise the technique, benefits and shortcomings of four infantile hip ultrasonography methods, focusing mainly on the Graf method, and to assess the effectiveness of ultrasonographic newborn hip screening programmes.MethodsSeveral infantile hip ultrasonography methods have been defined to assess the relationship between the femoral head and acetabulum. The Graf, Harcke, Terjesen and Suzuki methods are the universally known ones. The Graf method is composed of a quantitative classification system, while the Harcke and Suzuki methods have qualitative definitions and the Terjesen method contains both quantitative and qualitative descriptions.ResultsAlthough the results of several studies assessing the sensitivity and consistency of the ultrasonography methods have still not proven a clear dominance of one of these techniques, the primary advantage of the Graf method is that it has a standardised examination technique, as well as a very well defined numeric hip typing system. The importance of newborn hip screening has been universally accepted, but there is still no strong evidence regarding the superiority of either universal (screening of all newborns) or selective (screening of high-risk newborns) ultrasonographic newborn hip screening programmes.ConclusionsAn effective ultrasonographic method should include simple, precise, quantitative and consistent definitions for a proper examination and diagnosis. Both universal and selective ultrasonographic newborn hip screening programmes have significantly decreased the rate of late detected DDH and lessened the need for surgical treatment.

The Political History of PKU: Reflections on 50 Years of Newborn Screening

* Abbreviations: NBS — : newborn screening PKU — : phenylketonuria Just over 50 years ago, Dr Robert Guthrie developed a simple screening test for phenylketonuria (PKU) that became the prototype for universal newborn screening programs. Historians Jeffrey Brosco and Diane Paul explore why PKU screening marked a historical turning point in public health. It is a story that has left a far more complex legacy than most pediatricians recognize.—Jeffrey P. BakerSection Editor, Historical Perspectives Phenylketonuria, or PKU as it is more familiarly known, is a rare disorder, affecting only ∼1 in 15 000 people. In the United States, for example, ∼275 infants will be born with the disease each year.1 Thus in a lifetime of practice most pediatricians will not encounter a single case. Yet probably every pediatrician in the industrialized world has learned about PKU during medical school, many parents vividly remember the heel-stick test for their newborn, and scientists interested in genetics and metabolism say that they hope to “find another PKU.” Why has such a rare condition garnered so much attention? PKU is famous in part because it is widely seen as a victory for scientific medicine. If the condition is detected in the newborn period and a specialized diet is instituted, the profound cognitive impairment usually caused by PKU is averted. For the diet to be effective, however, the otherwise normal-appearing infant with PKU must be identified, among thousands of other nonaffected infants, in the first weeks of life. In the early 1960s, parents of children with intellectual disability began to advocate for state laws to test all newborns in the United States, and the first state laws for universal newborn screening (NBS) were implemented 50 years ago. By 1965, 32 American states had enacted screening laws, all but 5 making the test compulsory. By the mid-1970s, NBS for PKU had become routine in … Address correspondence to Jeffrey P. Brosco, MD, PhD, Department of Pediatrics, University of Miami Miller School of Medicine, PO Box 016820, Miami, FL 33101. E-mail: jbrosco{at}miami.edu

Cost effectiveness of newborn screening for cystic fibrosis: A simulation study

Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. To compare the cost effectiveness of various CF NBS options. A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

Universal newborn screening for haemoglobinopathies in Guadeloupe (French West Indies): A 27-year experience

In Guadeloupe, an island in the French West Indies, a universal newborn screening programme for sickle cell disease and other abnormal haemoglobins was initiated in 1984. In 1990, a comprehensive sickle cell centre was established to carry on the management programme. We here report the main results from the newborn screening programme from 1984 to 2010, and consider how the establishment of the sickle cell centre affected the programme. All blood samples were screened for the haemoglobinopathies using two reference methods in a single reference diagnosis laboratory. DNA analyses were also performed for confirmatory tests and analysis of the globin gene status. Between 1 January 1984 and 31 December 2010, 178,428 newborns were screened at birth, and 585 children were diagnosed with major sickle cell syndromes (ie. an overall incidence of 1 in 304 births). Sickle cell anaemia (haemoglobin SS disease) was the most frequently observed (1 in 575 births), followed by haemoglobin SC disease (1 in 771 births) and haemoglobin Sβ-thalassemia disease (1 in 4,243 births). Some other rare haemoglobin variants were also detected, the most common being HbD(Punjab). The establishment of a comprehensive sickle cell centre resulted in a significant improvement in the screening coverage (p < 0.001) and a significant reduction of the delay between diagnosis and the first medical visit (p < 0.001). The universal screening programme has made it possible to establish the incidence of the major sickle cell syndromes in Guadeloupe, and the management centre has improved its efficiency.

Newborn screening 50 years later: access issues faced by adults with PKU.

Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone. Moreover, a large percentage of adults with phenylketonuria are reported as lost to follow-up by metabolic clinics. While a group of experts identified by the National Institutes of Health convenes to update treatment guidelines for phenylketonuria, we explore individual patient, social, and economic factors preventing >70% of adult phenylketonuria patients in the United States from accessing treatment. As more conditions are identified through newborn screening, factors affecting access to treatment grow in importance, and we must continue to be vigilant in assessing and addressing factors that affect patient treatment outcomes and not just celebrate amelioration of the most severe manifestations of disease.Genet Med 2013:15(8):591–599

Advances in basic and clinical immunology in 2012

Basic and clinical immunology articles published in the Journal in 2012 were mostly related to the expanding area of primary immunodeficiencies (PIDs). Novel forms of PID were identified by using whole-exome sequencing or after careful examination of flow cytometric data, as in the reports of lymphocyte-specific protein tyrosine kinase, CD27, and CD21 deficiencies. Absent IgG and IgA memory B cells were described in patients with hyper-IgE syndrome, which is consistent with defective antibody response and suggests a potential benefit of immunoglobulin replacement. Impaired production of antibodies to polysaccharide antigens by the human B-cell subset analog to murine B-1 cells was reported in a child with selective polysaccharide antibody deficiency. Increased production of inflammatory cytokines by monocyte-derived cells on Toll-like receptor activation was reported in patients with X-linked agammaglobulinemia, underscoring the important role of Bruton tyrosine kinase in modulation of inflammation. The mechanisms explaining susceptibility to yeast infections and development of chronic mucocutaneous candidiasis were extensively studied. Universal newborn screening for T-cell deficiencies is being implemented in several states, resulting in the diagnosis of a higher number of immunodeficient newborns than previously estimated. The use of laboratory testing to distinguish PIDs from HIV infection was clarified. In the management of PIDs, refinement of indication and strategies to hematopoietic stem cell transplantation resulted in improved outcomes. The use of anti-IL-6 mAbs showed promise as an alternative treatment in patients with Schnitzler syndrome.

Feasibility and effectiveness of a population-based newborn hearing screening in an economically deprived region of Italy

AimTo describe the effectiveness of a population-based newborn hearing screening program in an economically deprived region of southern Italy. MethodsA screening protocol was proposed for all newborns of the Campania region, starting on January, 2007. For infants identified with hearing loss, information on degree and type of hearing loss and presence of risk factors was collected. ResultsThe infants born in the 3-year study period were 182,188. Among them, 146,026 (80%) were tested with OAE. Sensorineural hearing loss ≥40dBnHL was established for 159 infants (1.1×1000). Among the NICU and WIN infants, the rate of hearing loss was respectively 9×1000 and 0.67×1000. Follow-up information was available for 111 children (70%), as 48 (30%) got care in other regions or health facilities. Most infants were fitted hearing aids by 1 month after diagnosis and 15 children (13.5%) received a cochlear implant at a mean age of 25 months (SD 10). ConclusionsEven in a setting of population poverty, a universal newborn screening program can deliver satisfactory outcomes. The coverage and the tracking system of the program need to be improved, as well as the cooperation between public and private health services.

Sickle cell disease in pregnancy

Sickle cell disease (SCD) is an autosomal recessive condition, which leads to life-long haemolytic anaemia. Clinical features are intermittent episodes of severe pain and chronic complications including a high risk of stroke, renal dysfunction, retinopathy and cardiopulmonary disease. Advances in treatment have enabled affected women to live to childbearing age. Pregnancy and childbirth with SCD are considered high-risk, and are associated with increased maternal and fetal morbidity and mortality. A universal newborn screening programme provides for early identification of all affected newborns. The antenatal screening programme identifies women with haemoglobinopathies and offers them the option of fetal screening. Management of women with SCD begins with preconceptual care, which involves counselling, screening for end organ damage and a review of their medications. Multidisciplinary antenatal care is desirable. Contraception should be discussed post pregnancy. The only proven cure for this condition is correction of the genetic defect by haematopoietic stem cell transplantation.

Sickle Cell Disease: The Need for a Public Health Agenda

Sickle cell disease (SCD) is a collection of inherited blood disorders that affect a substantial number of people in the U.S., particularly African Americans. People with SCD have an abnormal type of hemoglobin, Hb S, which polymerizes when deoxygenated, causing the red blood cells to become misshapen and rigid. Individuals with SCD are at higher risk of morbidity and mortality from infections, vaso-occlusive pain crises, acute chest syndrome, and other complications. Addressing the public health needs related to SCD is an important step toward improving outcomes and maintaining health for those affected by the disorder. The objective of this study was to review public health activities focusing on SCD and define the need to address it more comprehensively from a public health perspective. We found that there has been some progress in the development of SCD-related public health activities. Such activities include establishing newborn screening (NBS) for SCD with all states currently having universal NBS programs. However, additional areas needing focus include strengthening surveillance and monitoring of disease occurrence and health outcomes, enhancing adherence to health maintenance guidelines, increasing knowledge and awareness among those affected, and improving healthcare access and utilization. These and other activities discussed in this paper can help strengthen public health efforts to address SCD.

Newborn screening for sickle cell disease: whose reproductive benefit?

Newborn screening for sickle cell disease: whose reproductive benefit?

Parental views on informed consent for expanded newborn screening

An increasing array of rare inherited conditions can be detected as part of the universal newborn screening programme. The introduction and evaluation of these service developments require consideration of the ethical issues involved and appropriate mechanisms for informing parents and gaining consent if required. Exploration of parental views is needed to inform the debate and specifically consider whether more flexible protocols are needed to fit with the public perception of new developments in this context. This study has been undertaken to explore perceptions and attitudes of parents and future parents to an expanded newborn screening programme in the United Kingdom and the necessary information provision and consent processes. A mixed methods study involving focus groups (n = 29) and a web-survey (n = 142) undertaken with parents and future parents. Parents want guaranteed information provision with clear decision-making powers and an awareness of the choices available to them. The difference between existing screening provision and expanded screening was not considered to be significant enough by participants to warrant formal written, informed consent for expanded screening. It is argued that the ethical review processes need to be more flexible towards the provision of information and consent processes for service developments in newborn screening.

Longitudinal Follow-up From Newborn Screening Reveals Deletional Hemoglobin H Disease and Hemoglobin H Constant Spring Disease Are Distinct Thalassemia Syndromes

AbstractAbstract 4260 Background:Alpha thalassemia disorders are rapidly increasing in North America. This has resulted in proposals for universal newborn screening (NBS) for hemoglobin H disease. However, the institution of routine newborn screening and construction of guidelines for early intervention requires longitudinal clinical data before setting national goals. Since 1995, California has performed universal screening for alpha thalassemia disorders. The longitudinal follow up of data from patients with hemoglobin H disorders diagnosed in the asymptomatic period provides essential information needed for formulating public health policy. Methods:Hemoglobin H disorders were diagnosed by high performance liquid chromatography with multiplex GAP-PCR assay to determine deletional hemoglobin H disease (deletion of 3 α globin genes, HbH) and the non-deletional hemoglobin H Constant Spring (α0 thalassemia with Constant Spring mutation, HCS). Longitudinal clinical data for all patients from the Northern California Thalassemia Center were analyzed. Ethnicity, growth data, clinic visits, hospitalizations, complications including splenectomy, transfusion, and iron overload were monitored. Quantitative liver iron concentration was determined by ferritometer. Results:86 patients predominantly diagnosed through NBS were longitudinally followed. Out of these, 60 (70%) had HbH, 23 (27%) had HCS and 3 (3%) had other forms of hemoglobin H disease. The parental ethnicity in HbH was 79% Asian, 6% Hispanic, and 15% African-American (in one or both parents). All patients with HCS were of Asian ethnicity. Longitudinal data for hemoglobin revealed that anemia was more severe in HCS at all ages (p<0.001). Mean hemoglobin in HbH increased from 8.8 g/dL (6.9-10.6 g/dL) at 6 months to 9.4 g/dL (7.9-11.5 g/dL) at 5 years (p<0.001). However, mean hemoglobin in HCS remained unchanged from 7.4 g/dL (5.8-9.9 g/dL) at 6 months to 7.2 g/dL (3.8-8.7 g/dL) at 5 years (p=ns). There was no hemoglobin value <6.7 g/dL in 237 patient-years of observation of 60 patients with HbH. Compared to HbH, red blood cells in HCS had higher mean corpuscular hemoglobin (18.6 versus 16.6 pg, p<0.001) and mean corpuscular volume (65.2 versus 54.0 fL, p<0.001). The mean absolute reticulocyte count was 88.2 ×103/μL in HbH versus 235.1 ×103/μL in HCS (p<0.001), while the mean serum bilirubin was 0.56 mg/dL and 2.60 mg/dL, respectively (p<0.001).Clinical severity and complications were markedly worse in HCS in contrast with HbH. Growth was delayed in HCS with mean weight-for-age Z-score -0.91 compared with -0.06 in HbH (p<0.001). The mean height-for-age Z-score was also lower in HCS (-1.29) compared with HbH (-0.43, p<0.001). The striking susceptibility to acute worsening of anemia with infections requiring urgent blood transfusion was observed in HCS, but not in HbH. The probability of receiving one or more blood transfusion by 20 years was 3% in HbH and 82% in HCS (p<0.001). Transfusions in HCS were required for 13% infants and median transfusion-free survival was 6 years. Splenectomy improved hemoglobin by 2.9 g/dL (0.4 to 4.0 g/dL, p=0.012) and reduced transfusions in HCS. Iron overload, measured by serum ferritin and liver iron concentration, developed during the first decade in HCS and increased during follow up. Median ferritin in HCS between 12 –17 years was 330 ng/mL (66-1420 ng/mL). Serum ferritin in HbH did not increase between 0–18 years (median 40 ng/mL, range 5–182 ng/mL), but older patients showed strong positive correlation between age and ferritin (p<0.001). In patients with HbH or HCS undergoing ferritometer examination, the degree of serum ferritin elevation underestimated the liver iron concentration. Conclusions:Our data support the utility of a universal NBS program, particularly in areas where αCS mutation is prevalent, since young infants with HCS can develop life-threatening anemia. HCS is a serious disease that needs close follow-up by a specialty thalassemia center to plan for emergency and elective transfusions, measure iron overload, monitor growth failure and evaluate the need for splenectomy. In contrast, HbH is asymptomatic during infancy and childhood; its complications are age-dependent, and monitoring for hemosiderosis and growth failure is more important in older children. In summary, HCS should be recognized as a thalassemia syndrome distinct from HbH with a different screening and treatment approach. Disclosures:No relevant conflicts of interest to declare.

Positive screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005–07

AimsThe overall aim of the new national newborn programme is to identify infants at risk of sickle cell disease to allow early detection and to minimise deaths and complications.MethodsUniversal screening...

Warning! Identification of significant hearing loss in a baby, following participation in the universal newborn screening programme, may seriously affect the extended family; a new case of Waardenburg's syndrome

Following the introduction of the Universal Newborn Hearing Screening Programme, the age of diagnosis of significant hearing loss has drastically decreased to the first few months of life. This presentation looks at an early diagnosis in the first born of a family pedigree previously undiagnosed with Waardenburg9s syndrome and the difficulties faced by both the family and the professionals involved and lessons that may be learnt for the future.