[Impact of the COVID-19 pandemic on Neonatal Screening for Congenital Hypothyroidism.] / Impacto de la pandemia por COVID-19 en el cribado neonatal de hipotirodismo congénito.

OBJECTIVE: The purpose of this paper was to describe the diagnosis, treatment and follow-up of patients diagnosed with congenital hypothyroidism (CH) by the Neonatal Screening Program in the Autonomous Community of Madrid during the state of alarm due to the COVID-19 health crisis. METHODS: The data were extracted from the retrospective analysis of patients diagnosed with CH and treated at the Clinical Diagnosis and Follow-up Center of CH located in the Pediatric Endocrinology Unit of the General University Hospital Gregorio Marañon. RESULTS: During the period between March 14 and June 21, 2020, 7 neonates were diagnosed with congenital hypothyroidism. The Screening Center contacted the Clinical Diagnosis and Follow-up Center urgently, with the location and clinical assessment of the patient on the same day, performing the usual complementary examinations in all of them according to clinical pathway. The median age of diagnosis was 15.5 days (range 7.00-24.00). The subsequent clinical and analytical follow-up was carried out in all cases according to the recommended times. All patients presented normalization of the thyroid function after two weeks of treatment. CONCLUSIONS: All patients seen at the Congenital Hypothyroidism Clinical Diagnosis and Follow-up Center during the alarm state period were diagnosed, treated and reevaluated following the usual clinical pathways without incidents. The current epidemiological situation of the COVID-19 pandemic has revealed the correct functioning of the circuit of the Congenital Hypothyroidism Screening Program in less favorable circumstances.

OBJETIVO: El objetivo de este trabajo fue mostrar el diagnóstico, tratamiento y seguimiento de los pacientes diagnosticados de hipotiroidismo congénito (HC) mediante el Programa de Cribado Neonatal en la Comunidad Autó-noma de Madrid durante el estado de alarma debido a la crisis sanitaria por la COVID-19. METODOS: Los datos fueron extraídos del análisis retrospectivo de pacientes diagnosticados de HC en el Centro de Diagnóstico y Seguimiento Clínico de HC, ubicado en la Unidad de Endocrinología Pediátrica del Hospital General Universitario Gregorio Marañón. RESULTADOS: Durante el período comprendido entre el 14 de marzo y el 21 de junio de 2020, siete neonatos fueron diagnosticados de HC. Desde el Centro de Cribado se contactó de forma urgente con el Centro Clínico de Diagnóstico y Seguimiento, con localización y valoración clínica del paciente el mismo día, realizándose las exploraciones complementarias habituales en todos ellos según la vía clínica. La edad mediana del diagnóstico fue de 15,5 días (rango 7,00-24,00). El seguimiento clínico y analítico posterior se realizó en todos los casos acorde a los tiempos recomendados. Todos los pacientes presentaron normalización de la función tiroidea a las dos semanas de tratamiento. CONCLUSIONES: Todos los pacientes atendidos en el Centro Clínico de Diagnóstico y Seguimiento de Hipotiroidismo Congénito durante el período de estado de alarma son diagnosticados, tratados y reevaluados siguiendo la vía clínica habitual, sin incidencias. La situación epidemiológica actual de la pandemia por la COVID-19 pone de manifiesto el correcto funcionamiento del circuito del Programa de Cribado de Hipotiroidismo Congénito en circunstancias menos favorables.

Fifteen years of newborn sickle cell disease screening in Madrid, Spain: an emerging disease in a European country.

Sickle cell disease (SCD) describes a set of chronic inherited anemias characterized by hemolysis, episodes of vaso-occlusion, and high infectious risk, with high morbidity and mortality. Newborn screening (NBS) for SCD allows family health education and early start of infectious prophylaxis. In the Community of Madrid, a pilot universal NBS study found that the SCA birth prevalence was 1/5851 in newborns, higher than expected, confirming the need to include early detection in the NBS program. The aim of the present prospective single-center study is to analyze the results of newborn SCD screening in Madrid in terms of epidemiological data and its inclusion in a comprehensive care program during the last 15 years, between 1st of May 2003 and 1st of May 2018. During the study period, 1,048,222 dried bloodspots were analyzed. One hundred ninety-seven patients were diagnosed with possible SCD (HPLC phenotype of FS, FSA, FSC, FSE, FSDPunjab, FSOArab), with 187 patients finally confirmed (birth prevalence 1/5552 newborns, 0.18 per 1000 live births), and 1 out of 213 infants carried Hb S. All of them were seen by a specialist clinician; median age at the first visit consultation was 35 days and median age at the beginning of penicillin treatment was 66 days. The Madrid SCD NBS program achieved high rates of sensitivity and specificity and good quality of care assistance. Establishing a good relationship with the family, a strong education program, and a multidisciplinary team that includes social workers and a psychologist are needed to ensure the success of early intervention.

A Novel Icterometer for Hyperbilirubinemia Screening in Low-Resource Settings.

BACKGROUND: Severe neonatal hyperbilirubinemia (>20 mg/dL) affects ∼1 million infants annually. Improved jaundice screening in low-income countries is needed to prevent bilirubin encephalopathy and mortality. METHODS: The Bili-ruler is an icterometer for the assessment of neonatal jaundice that was designed by using advanced digital color processing. A total of 790 newborns were enrolled in a validation study at Brigham and Women's Hospital (Boston) and Sylhet Osmani Medical College Hospital (Sylhet, Bangladesh). Independent Bili-ruler measurements were made and compared with reference standard transcutaneous bilirubin (TcB) and total serum bilirubin (TSB) concentrations. RESULTS: Bili-ruler scores on the nose were correlated with TcB and TSB levels (r = 0.76 and 0.78, respectively). The Bili-ruler distinguished different clinical thresholds of hyperbilirubinemia, defined by TcB, with high sensitivity and specificity (score ≥3.5: 90.1% [95% confidence interval (CI): 84.8%-95.4%] and 85.9% [95% CI: 83.2%-88.6%], respectively, for TcB ≥13 mg/dL). The Bili-ruler also performed reasonably well compared to TSB (score ≥3.5: sensitivity 84.5% [95% CI: 79.1%-90.3%] and specificity 83.2% [95% CI: 76.1%-90.3%] for TSB ≥11 mg/dL). Areas under the receiver operating characteristic curve for identifying TcB ≥11, ≥13, and ≥15 were 0.92, 0.93, and 0.94, respectively, and 0.90, 0.87, and 0.86 for identifying TSB ≥11, ≥13, and ≥15. Interrater reliability was high; 97% of scores by independent readers fell within 1 score of one another (N = 88). CONCLUSIONS: The Bili-ruler is a low-cost, noninvasive tool with high diagnostic accuracy for neonatal jaundice screening. This device may be used to improve referrals from community or peripheral health centers to higher-level facilities with capacity for bilirubin testing and/or phototherapy.

The role of the clinician in the multi-omics era: are you ready?

Since Garrod's first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team's plan to his/her and the family's wishes most certainly is the capstone. Are you ready?

The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.

BACKGROUND: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. METHODS: A retrospective review of governmental databanks, the national CF registry and CF centers. RESULTS: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. CONCLUSIONS: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

Universal bilirubin screening and health care utilization.

OBJECTIVE: To evaluate the impact of the implementation of universal bilirubin screening on neonatal health care use in the context of a large jurisdiction with universal health insurance. METHODS: We conducted a population-based retrospective cohort study of all newborns discharged after birth between April 2003 and February 2011 from 42 hospitals that implemented universal bilirubin screening between July 2007 and June 2010 in Ontario, Canada. We surveyed hospitals to determine their screening implementation date. We used multiple linked administrative health data sets to measure phototherapy use, length of stay (LOS), jaundice-related emergency department visits, and jaundice-related readmissions. We modeled the relationship between universal bilirubin screening and outcomes using generalized estimating equations to account for clustering by hospital, underlying temporal trends, and important covariates. RESULTS: Screening was associated with an increase in phototherapy during hospitalization at birth (relative risk, 1.32; 95% confidence interval, 1.09-1.59) and a decrease in jaundice-related emergency department visits (relative risk, 0.79; 95% confidence interval, 0.64-0.96) but no statistically significant difference in phototherapy after discharge, LOS, or jaundice-related readmissions after accounting for preexisting temporal trends in health care service use and other patient sociodemographic and hospital characteristics. CONCLUSIONS: Universal bilirubin screening may not be associated with increased neonatal LOS or increased subsequent hospital use. Our findings are relevant for determining the resource implications of universal bilirubin screening in Ontario. They highlight the limitations in generalizability of previous research on health care utilization associated with similar programs and underline the importance of context-specific local evaluation of guideline implementation.

Longitudinal cystic fibrosis care.

Cystic fibrosis is a complex disease entity that presents considerable lifelong challenges. Implementation of medical and surgical treatment options involves multisystem interventions to prevent and treat lung and gastrointestinal manifestations of cystic fibrosis and associated comorbidities. From birth through adulthood, cystic fibrosis care entails a longitudinal regimen aimed at achieving relief of disease symptoms and enhanced life expectancy. With increased knowledge of the molecular behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) in health and disease, clinical practice has been enriched by the prospect of novel strategies, including mutation-specific drug and gene therapy targeting restoration of corrupted transepithelial ion transport. Emerging paradigms of comprehensive care increasingly enable personalized solutions to address the root cause of disease-transforming management options for individuals with cystic fibrosis.

Effect of universal neonatal transcutaneous bilirubin screening on blood draws for bilirubin analysis and phototherapy usage.

OBJECTIVE: To determine the effect of universal transcutaneous bilirubin (TcB) screening on total serum bilirubin (TSB) blood draws and phototherapy usage. STUDY DESIGN: The subjects were infants ≥ 36 weeks gestation. In period 1, TSB was ordered based on clinical factors. In period 2, all infants underwent predischarge TcB measurement; infants with adjusted TcB values in the high-intermediate or high-risk zones had TSB ordered. Data were extracted through chart review. RESULT: TSB measurements per 1000 infants decreased from 717 to 713 (P=0.008) between period 1 and 2, with more outpatient and less inpatient blood draws in period 2. Between periods 1 and 2, total phototherapy decreased from 59 to 39 per 1000 infants (P<0.0001), with less inpatient and more readmission phototherapy. CONCLUSION: Universal TcB screening was implemented without increasing total blood draws or phototherapy treatment; however, it was associated with a shift in blood draws and phototherapy usage from inpatients to outpatients.

Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use.

OBJECTIVE: The goal was to assess the impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. METHODS: In this retrospective cohort study of 358086 infants of > or =35 weeks and > or =2000 g born between January 1, 1995, and June 30, 2007, we obtained demographic data, bilirubin levels, and codes for inpatient phototherapy from existing databases. We compared the incidence of high total serum bilirubin (TSB) levels and phototherapy before and after implementation of universal screening and examined risk factors for high TSB levels. RESULTS: A total of 38182 infants (10.6%) were born at facilities that had implemented universal bilirubin screening. Compared with infants born at facilities that were not screening, these infants had a 62% lower incidence of TSB levels exceeding the American Academy of Pediatrics exchange guideline (0.17% vs 0.45%; P < .001), received twice the inpatient phototherapy (9.1% vs 4.2%; P < .001), and had slightly longer birth hospitalization lengths of stay (50.9 vs 48.7 hours; P < .001). Of those receiving phototherapy, 56% after initiation of universal screening had TSB levels at which phototherapy was recommended by the guideline, compared with 70% before screening. The adjusted odds ratio for developing TSB levels exceeding the guideline value was 0.28 (95% confidence interval: 0.20-0.40) for those born at a facility using TSB screening and 0.28 (95% confidence interval: 0.19-0.42) for those born at a facility using transcutaneous bilirubin screening. CONCLUSIONS: Universal bilirubin screening was associated with a significantly lower incidence of severe hyperbilirubinemia but also with increased phototherapy use.

Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues.

Technology will make it possible to screen for fragile X syndrome and other conditions that do not meet current guidelines for routine newborn screening. This possibility evokes at least 8 broad ethical, legal, and social concerns: (1) early identification of fragile X syndrome, an "untreatable" condition, could lead to heightened anxiety about parenting, oversensitivity to development, alterations in parenting, or disrupted bonding; (2) because fragile X syndrome screening should be voluntary, informed consent could overwhelm parents with information, significantly burden hospitals, and reduce participation in the core screening program; (3) screening will identify some children who are or appear to be phenotypically normal; (4) screening might identify children with other conditions not originally targeted for screening; (5) screening could overwhelm an already limited capacity for genetic counseling and comprehensive care; (6) screening for fragile X syndrome, especially if carrier status is disclosed, increases the likelihood of negative self-concept, societal stigmatization, and insurance or employment discrimination; (7) screening will suggest risk in extended family members, raising ethical and legal issues (because they never consented to screening) and creating a communication burden for parents or expanding the scope of physician responsibility; and (8) screening for fragile X syndrome could heighten discrepancies in how men and women experience genetic risk or decide about testing. To address these concerns we recommend a national newborn screening research network; the development of models for informed decision-making; materials and approaches for helping families understand genetic information and communicating it to others; a national forum to address carrier testing and the disclosure of secondary or incidental findings; and public engagement of scientists, policy makers, ethicists, practitioners, and other citizens to discuss the desired aims of newborn screening and the characteristics of a system needed to achieve those aims.

[Neonatal screening: trends, debates and consensus]. / Dépister les nouveau-nés: évolutions, débats et consensus.

This study focuses on the social and political implications of the substantial expansion of genetic tests and neonatal screening. The introduction of neonatal screening for cystic fibrosis is one of the significant developments that have fuelled debate on their appropriateness. It has raised a series of questions on the pros and cons, the role of evidence in biomedicine, and the articulation between the therapeutic approach and foetal selection. In this respect France provides an ideal research field as it was one of the first countries to generalize this screening, launched in January 2002. Several questions arise: What were the terms of the debate in France and their underlying logics? How was consensus reached? More generally, what does this screening tell us about policies on life forms today?

[Public Health Genomics. The integration of genome-based knowledge into public health research, policies and health services]. / Public Health Genomics: Die Integration genombasierten Wissens in die Public-Health-Forschung, Politik und Gesundheitsversorgung.

Which consequences can be drawn from genome-based knowledge and how can it be responsibly and timely translated into policies and practice? What are recent developments in genetics and molecular biology, what are the challenges, what are the risks of these developments? Which policies can provide an acceptable balance between providing strong protection of individuals'interests and needs while enabling society to benefit from the genomic advances and empowering individuals? How can molecular medicine contribute to more effective and efficient health care services, and what infrastructures and policies can already now be implemented to assure a benefit for population health? Thus, Public Health Genomics (PHG) tries to answer these challenging questions. This integration of genomics into the aims of public health is called Public Health Genomics (PHG) and is defined as "the responsible and effective translation of genome-based knowledge and technologies into public policy and health services for the benefit of population health".

Evaluating the accuracy of Malformations Surveillance Program in detecting virilization due to congenital adrenal hyperplasia.

Malformations surveillance programs of newborn infants have been developed as a method for identifying serious and relatively common birth defects. The virilization of newborn infants with the classic 21-hydroxylase form of congenital adrenal hyperplasia must be identified early if the associated metabolic crisis in the perinatal period is to be prevented. We compared the detection of virilization associated with 21-hydroxylase congenital adrenal hyperplasia in infants by three methods: an 'active' malformations surveillance of medical records at a large urban hospital; routine medical care by examining physicians; and newborn biochemical screening of blood samples. The experience at a large maternity center in Boston, since 1972, showed that pediatricians often recognized affected females (6/6), but not males (0/2); the state newborn screening program, begun in 1990, identified correctly all affected males and females. The Active Malformations Surveillance Program was the least effective screening method, identifying four of six affected females and neither of the affected males. The low rate of detecting affected females by the Surveillance Program was attributed to a failure to sensitize the research assistants to the importance of physicians' notations regarding the signs and symptoms of virilization. The failure of examining physicians, and thereby, the malformations surveillance program, to detect virilized newborn males was due to the lack of consistent associated physical features. These comparisons between these three methods of detection can be used to design and improve malformations surveillance programs.

Newborn screening in Indonesia.

In Indonesia, newborn screening is not yet a policy, and the incidence of preventable causes of mental retardation detected by newborn screening is not known. Congenital hypothyroidism (CH) is not infrequent. Without a screening program, unrecognized CH patients were neglected for years. Since May 1999, the International Atomic Energy Agency (IAEA) has assisted in starting a CH Newborn Screening Project to estimate the local incidence of CH and to evaluate the problems associated with the screening. In June 2000, a pilot study was conducted using primary TSH measurement, supplemented by T4 in infants with elevated TSH. The target was to screen 12,000 newborn infants, using cord blood serum taken at birth, or a heel prick between 2 to 6 days of age. Between June 2000 and February 2001, 3,534 neonates born in 4 hospitals were screened using cord blood serum taken at birth (recall rate 3.3%). From March 2001 onwards, the heel prick method was used and participating hospitals increased from 4 to 7. Using this approach, until August 2001, 3,309 samples were analysed and the recall rate was much lower (0.64%). The number of unsatisfactory samples was relatively high due to an unstable process of blood collection. Parental refusal and low acceptance of screening among policy makers resulted from lack of awareness of the dangers of CH, and the screening program was not considered a health priority. Recall of patients after screening was a major barrier, with problems in tracking patients arising from urbanization and a high rate of relocation. To advance the CH screening program nationwide, infrastructure must be improved along with the recall system, and education as well as information campaigns for parents and medical professionals must be intensified. The Department of Health must be persuaded to give a national mandate.

U.S. newborn screening policy dilemmas for the twenty-first century.

Newborn screening has traditionally referred to biochemical testing for inherited disorders, generally metabolic in origin, that are usually correctable by dietary or drug interventions. As new tests have been developed, state public health newborn screening systems have slowly evolved without the benefit of national policies. Thus, newborn screening program changes, when viewed nationally, have been uncoordinated. The net result has been unequally applied mandated screening and, consequently, unequal availability of related public health disease prevention services. Technological advances in laboratory testing over the past 10 years have resulted in limited program changes in some state newborn screening systems, and even greater program disparities. A recent Newborn Screening Task Force identified numerous issues of concern and proposed elements for a plan of action involving public health programs, healthcare providers, and consumers. This minireview details past policy history in newborn screening and identifies some of the current issues confronting programs as they seek to move ahead with the technologies and medical treatments for the twenty-first century.

Evaluating newborn screening programmes based on dried blood spots: future challenges.

A UK national programme to screen all newborn infants for phenylketonuria was introduced in 1969, followed in 1981 by a similar programme for congenital hypothyroidism. Decisions to start these national programmes were informed by evidence from observational studies rather than randomised controlled trials. Subsequently, outcome for affected children has been assessed through national disease registers, from which inferences about the effectiveness of screening have been made. Both programmes are based on a single blood specimen, collected from each infant at the end of the first week of life, and stored as dried spots on a filter paper or 'Guthrie' card. This infrastructure has made it relatively easy for routine screening for other conditions to be introduced at a district or regional level, resulting in inconsistent policies and inequitable access to effective screening services. This variation in screening practices reflects uncertainty and the lack of a national framework to guide the introduction and evaluation of new screening initiatives, rather than geographical variations in disease prevalence or severity. More recently, developments in tandem mass spectrometry have made it technically possible to screen for several inborn errors of metabolism in a single analytical step. However, for each of these conditions, evidence is required that the benefits of screening outweigh the harms. How should that evidence be obtained? Ideally policy decisions about new screening initiatives should be informed by evidence from randomised controlled trials but for most of the conditions for which newborn screening is proposed, large trials would be needed. Prioritising which conditions should be formally evaluated, and developing a framework to support their evaluation, poses an important challenge to the public health, clinical and scientific community. In this chapter, issues underlying the evaluation of newborn screening programmes will be discussed in relation to medium chain acyl CoA dehydrogenase deficiency, a recessively inherited disorder of fatty acid oxidation.