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Frontiers in Endocrinology 2023Neonatal hypoglycemia affects up to 15% of all newborns. Despite the high prevalence there is no uniform definition of neonatal hypoglycemia, and existing guidelines... (Review)
Review
Neonatal hypoglycemia affects up to 15% of all newborns. Despite the high prevalence there is no uniform definition of neonatal hypoglycemia, and existing guidelines differ significantly in terms of when and whom to screen for hypoglycemia, and where to set interventional thresholds and treatment goals. In this review, we discuss the difficulties to define hypoglycemia in neonates. Existing knowledge on different strategies to approach this problem will be reviewed with a focus on long-term neurodevelopmental outcome studies and results of interventional trials. Furthermore, we compare existing guidelines on the screening and management of neonatal hypoglycemia. We summarize that evidence-based knowledge about whom to screen, how to screen, and how to manage neonatal hypoglycemia is limited - particularly regarding operational thresholds (single values at which to intervene) and treatment goals (what blood glucose to aim for) to reliably prevent neurodevelopmental sequelae. These research gaps need to be addressed in future studies, systematically comparing different management strategies to progressively optimize the balance between prevention of neurodevelopmental sequelae and the burden of diagnostic or therapeutic procedures. Unfortunately, such studies are exceptionally challenging because they require large numbers of participants to be followed for years, as mild but relevant neurological consequences may not become apparent until mid-childhood or even later. Until there is clear, reproducible evidence on what blood glucose levels may be tolerated without negative impact, the operational threshold needs to include some safety margin to prevent potential long-term neurocognitive impairment from outweighing the short-term burden of hypoglycemia prevention during neonatal period.
Topics: Female; Infant, Newborn; Humans; Child; Blood Glucose; Hypoglycemia; Infant, Newborn, Diseases; Fetal Diseases; Disease Progression
PubMed: 37361517
DOI: 10.3389/fendo.2023.1179102 -
International Journal of Molecular... Jul 2023Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the... (Review)
Review
Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, , was identified. Genetic testing of has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, -deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.
Topics: Infant, Newborn; Humans; Muscular Atrophy, Spinal; Genetic Testing; Homozygote; Neonatal Screening; Inheritance Patterns
PubMed: 37569314
DOI: 10.3390/ijms241511939 -
Children (Basel, Switzerland) Jul 2023Hypoglycemia represents one of the most frequent metabolic disturbances of the neonate, associated with increased morbidity and mortality, especially if left untreated... (Review)
Review
Hypoglycemia represents one of the most frequent metabolic disturbances of the neonate, associated with increased morbidity and mortality, especially if left untreated or diagnosed after the establishment of brain damage. The aim of this study was to review and compare the recommendations from the most recently published influential guidelines on the diagnosis, screening, prevention and management of this common neonatal complication. Therefore, a descriptive review of the guidelines from the American Academy of Pediatrics (AAP), the British Association of Perinatal Medicine (BAPM), the European Foundation for the Care of the Newborn Infants (EFCNI), the Queensland Clinical Guidelines-Australia (AUS), the Canadian Pediatric Society (CPS) and the Pediatric Endocrine Society (PES) on neonatal hypoglycemia was carried out. There is a consensus among the reviewed guidelines on the risk factors, the clinical signs and symptoms of NH, and the main preventive strategies. Additionally, the importance of early recognition of at-risk infants, timely identification of NH and prompt initiation of treatment in optimizing the outcomes of hypoglycemic neonates are universally highlighted. All medical societies, except PES, recommend screening for NH in asymptomatic high-risk and symptomatic newborn infants, but they do not provide consistent screening approaches. Moreover, the reviewed guidelines point out that the diagnosis of NH should be confirmed by laboratory methods of BGL measurement, although treatment should not be delayed until the results become available. The definition of NH lacks uniformity and it is generally agreed that a single BG value cannot accurately define this clinical entity. Therefore, all medical societies support the use of operational thresholds for the management of NH, although discrepancies exist regarding the recommended cut-off values, the optimal treatment and surveillance strategies of both symptomatic and asymptomatic hypoglycemic neonates as well as the treatment targets. Over the past several decades, ΝH has remained an issue of keen debate as it is a preventable cause of brain injury and neurodevelopmental impairment; however, there is no clear definition or consistent treatment policies. Thus, the establishment of specific diagnostic criteria and uniform protocols for the management of this common biochemical disorder is of paramount importance as it will hopefully allow for the early identification of infants at risk, the establishment of efficient preventive measures, the optimal treatment in the first hours of a neonate's life and, subsequently, the improvement of neonatal outcomes.
PubMed: 37508719
DOI: 10.3390/children10071220 -
JAMA Jul 2023Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal... (Comparative Study)
Comparative Study
IMPORTANCE
Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results.
OBJECTIVE
To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test.
DESIGN, SETTING, AND PARTICIPANTS
The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021.
EXPOSURE
Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform.
MAIN OUTCOMES AND MEASURES
Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care).
RESULTS
A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis.
CONCLUSIONS AND RELEVANCE
The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.
Topics: Clinical Decision-Making; Genetic Profile; Genomics; Prospective Studies; Whole Genome Sequencing; Genetic Testing; Genetic Diseases, Inborn; Humans; Infant, Newborn; Neonatal Screening; Infant; Sequence Analysis, DNA; Mutation
PubMed: 37432431
DOI: 10.1001/jama.2023.9350 -
JAMA Network Open Sep 2023Newborn screening via biochemical tests is in use worldwide. The availability of genetic sequencing has allowed rapid screening for a substantial number of monogenic...
IMPORTANCE
Newborn screening via biochemical tests is in use worldwide. The availability of genetic sequencing has allowed rapid screening for a substantial number of monogenic disorders. However, the outcomes of this strategy have not been evaluated in a general newborn population.
OBJECTIVE
To evaluate the outcomes of applying gene panel sequencing as a first-tier newborn screening test.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included newborns who were prospectively recruited from 8 screening centers in China between February 21 and December 31, 2021. Neonates with positive results were followed up before July 5, 2022.
EXPOSURES
All participants were concurrently screened using dried blood spots. The screen consisted of biochemical screening tests and a targeted gene panel sequencing test for 128 conditions. The biochemical and genomic tests could both detect 43 of the conditions, whereas the other 85 conditions were screened solely by the gene panel.
MAIN OUTCOMES AND MEASURES
The primary outcomes were the number of patients detected by gene panel sequencing but undetected by the biochemical test.
RESULTS
This study prospectively recruited 29 601 newborns (15 357 [51.2%] male). The mean (SD) gestational age was 39.0 (1.5) weeks, and the mean (SD) birth weight was 3273 (457) g. The gene panel sequencing screened 813 infants (2.7%; 95% CI, 2.6%-2.9%) as positive. By the date of follow-up, 402 infants (1.4%; 95% CI, 1.2%-1.5%) had been diagnosed, indicating the positive predictive value was 50.4% (95% CI, 50.0%-53.9%). The gene panel sequencing identified 59 patients undetected by biochemical tests, including 20 patients affected by biochemically and genetically screened disorders and 39 patients affected by solely genetically screened disorders, which translates into 1 out of every 500 newborns (95% CI, 1/385-1/625) benefiting from the implementation of gene panels as a first-tier screening test.
CONCLUSIONS AND RELEVANCE
In this cohort study, the use of gene panel sequencing in a general newborn population as a first-tier screening test improved the detection capability of traditional screening, providing an evidence-based suggestion that it could be considered as a crucial method for first-tier screening.
Topics: Infant, Newborn; Infant; Humans; Male; Female; Cohort Studies; Neonatal Screening; Birth Weight; China; Genomics
PubMed: 37656460
DOI: 10.1001/jamanetworkopen.2023.31162 -
Cureus Aug 2023Developmental dysplasia of the hip (DDH) is a complex disorder that refers to different hip problems, ranging from neonatal instability to acetabular or femoral... (Review)
Review
Developmental dysplasia of the hip (DDH) is a complex disorder that refers to different hip problems, ranging from neonatal instability to acetabular or femoral dysplasia, hip subluxation, and hip dislocation. It may result in structural modifications, which may lead to early coxarthrosis. Despite identifying the risk factors, the exact aetiology and pathophysiology are still unclear. Neonatal screening, along with physical examination and ultrasound, is critical for the early diagnosis of DDH to prevent the occurrence of early coxarthrosis. This review summarizes the currently practised strategies for the detection and treatment of DDH, focusing particularly on current practices for managing residual acetabular dysplasia (AD). AD may persist even after a successful hip reduction. Pelvic osteotomy is required in cases of persistent AD. It could also be undertaken simultaneously with an open hip reduction. Evaluation of the residual dysplasia (RD) of the hip and its management is still a highly active area of discussion. Recent research has opened the door to discussion on this issue and suggested treatment options for AD. But there is still room for more research to assist in managing AD.
PubMed: 37692580
DOI: 10.7759/cureus.43207 -
BMJ Medicine 2024Low blood concentrations of glucose (hypoglycaemia) soon after birth are common because of the delayed metabolic transition from maternal to endogenous neonatal sources... (Review)
Review
Low blood concentrations of glucose (hypoglycaemia) soon after birth are common because of the delayed metabolic transition from maternal to endogenous neonatal sources of glucose. Because glucose is the main energy source for the brain, severe hypoglycaemia can cause neuroglycopenia (inadequate supply of glucose to the brain) and, if severe, permanent brain injury. Routine screening of infants at risk and treatment when hypoglycaemia is detected are therefore widely recommended. Robust evidence to support most aspects of management is lacking, however, including the appropriate threshold for diagnosis and optimal monitoring. Treatment is usually initially more feeding, with buccal dextrose gel, followed by intravenous dextrose. In infants at risk, developmental outcomes after mild hypoglycaemia seem to be worse than in those who do not develop hypoglycaemia, but the reasons for these observations are uncertain. Here, the current understanding of the pathophysiology of neonatal hypoglycaemia and recent evidence regarding its diagnosis, management, and outcomes are reviewed. Recommendations are made for further research priorities.
PubMed: 38618170
DOI: 10.1136/bmjmed-2023-000544