Metabolic Disorders In Newborns Research Articles

Analysis of Imprecision for Internal Quality Control of Newborn Screening by Tandem Mass Spectrometry in China, 2015 - 2021.

This study aimed to assess the performance of the newborn screening laboratories in China through retrospective analysis of the coefficient of variation (CV) of the internal quality control (IQC) data in the national tandem mass spectrometry screening for inherited metabolic disorders in newborns. From 2015 to 2021, the IQC data of amino acid and acylcarnitine test were collected twice each year. CVmonthly in-control was calculated by excluding outliers for the current month and its discrete distribution and changes in trend were comprehensively evaluated for both normal and high concentration levels. The proportion of laboratories meeting both 1/3 and 1/4 quality criteria of the total error allowable (TEa), based on the CVmonthly in-control for each testing item, was calculated. The analysis of CVmonthly in-control for the two concentration levels for the amino acids and acylcarnitine parameters showed that CVmonthly in-control for the normal concentration levels were more discrete before 2018, while CVmonthly in-control for the high concentration levels were less discrete than the normal concentration levels, but there were relatively more outliers. More than 80% of laboratories were able to meet the 1/3 TEa standard for each test at the high concentration level, while the pass rate for the 1/4 TEa standard was significantly lower than 80% (except for C2). According to the current status of testing in China, it is recommended to use 1/3TEa as the imprecision level standard; for laboratories with relatively high precision, the 1/4TEa standard can be used.

Application of machine learning tools and integrated OMICS for screening and diagnosis of inborn errors of metabolism

Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility. TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling. This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00). Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates.

SAFETY AND QUALITY OF INTRAVENOUS LIPIDS FOR NEWBORNS: EFFECTS ON CRITICAL DISEASES AND METABOLIC DISORDERS (PART II)

Premature birth and its complications cause stress in newborns, which restrains their physical growth for several weeks after birth and is associated with chronic morbidity and neurological disability in the future. Preterm infants face such difficulties as respiratory distress, cardiovascular disease, gastrointestinal dysfunction and very low birth weight. Most complications in newborns are associated with oxidative stress that develops during the early period of growth. The formation of free radicals entails oxidative damage to many organs and systems of the body and is the main factor responsible for the development of typical diseases of preterm infants, such as bronchopulmonary dysplasia, patent ductus arteriosus, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, and respiratory distress syndrome.
 Premature infants depend on adequate early parenteral nutrition, which not only guarantees they will survive but also ensures positive health outcomes later in life. Early use of intravenous lipids helps to prevent essential fatty acid deficiencies, provides energy and substrates for cell membrane synthesis, which are important for the growth and development of infants with very low and extremely low birth weight. This publication represents data on the effect of intravenous lipids on critical conditions and metabolic disorders in newborns. Literature sources are analyzed and the existing evidence of the possible influence of lipid emulsions on critical diseases in newborns is presented: intraventricular hemorrhage; necrotizing enterocolitis, patent ductus arteriosus and thrombocytopenia; glucose metabolism (hypo- and hyperglycemia); hyperbilirubinemia and chronic liver damage. The literature review is aimed at finding optimal strategies for the use of lipid emulsions in intensive care of newborns to improve the quality of care for premature infants. The purpose of this work is to analyze the results of published studies and systematize data on the feasibility and safety of lipid emulsions used in newborns with critical diseases of the perinatal period.

Elevated maternal androgen is associated with dysfunctional placenta and lipid disorder in newborns of mothers with polycystic ovary syndrome

To investigate the placental morphology alterations and identify the clinical characteristics of women with polycystic ovary syndrome (PCOS) and their newborns. Pregnant women with PCOS (n = 12) and pregnant women without PCOS (n = 11) were recruited. Then, the placenta, maternal blood and cord blood were collected after delivery. Clinical observational study. Not applicable. In the present study, pregnant women with PCOS and healthy pregnant women were recruited from the clinic of the Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, China, between February 2015 and October2015. None. A proteomic analysis was performed on the placenta in women with PCOS and healthy women. The maternal testosterone, androstenedione, dehydroepiandrosterone sulfate, free androgen index, cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I levels were significantly higher in the PCOS group than in the control group, and the offspring in the PCOS group had higher dehydroepiandrosterone sulfate, high-density lipoprotein, and cholesterol levels, when compared with the control group. The placenta in the PCOS group demonstrated infarction, calcification, and a greater intervillous space, when compared with the control group. A higher level of estrogen receptor-β protein was observed in the placenta of women with PCOS, when compared with women without PCOS. A total of 258 proteins in the placenta were identified to be significantly different, when the PCOS and control groups were compared, and fibronectin 1 exhibited the closest relationship with other differential proteins. The overexposure to hyperandrogenism and hyperlipidemia affects the functions of the placenta, which are associated with the development of metabolic disorders in newborns.

Fatty acid metabolism in newborns with sepsis; Report 1 — New clinical outcome prediction scale

The aim of our study was to develop a new scale for predicting clinical outcome in newborns with sepsis, taking into account the information about depth of metabolic disorders.Methods. Design of study — retrospective observational single-center study. Medical cards data of 163 newborns with sepsis were included in analysis. To measure the predictive value of the analyzed clinical and laboratory signs we used the Kullback measure. The clinical outcome of the disease was determined as the response function: survived or died.Results. An analysis of the predictive value of the clinical and laboratory parameters of in newborns with sepsis was made, the threshold values of the most informative indicators were developed, which were: the number of blood platelets, the level of total blood protein, body weight and the number of blood neutrophils. The Clinical and Laboratory Condition Index for Newborns scale has been developed, which takes into account the depth of metabolic disorders. ROC analysis (Area Under Curve — 0,723) and the information method (information coefficient 0.992) showed that the Clinical and Laboratory Condition Index score can be used in the intensive care unit to predict the risk negative clinical outcome and evaluate the effectiveness of treatment in infants with organ dysfunction caused by systemic infection.Conclusion. New Clinical and Laboratory Condition Index score scale allows to predict the development of negative outcome of sepsis in newborns taking into account the depth of metabolic disorders in newborns with sepsis.

Метаболизм жирных кислот у новорожденных с сепсисом; Сообщение 2 — Нарушение метаболизма жирных кислот

The aim of our study was to develop a new scale for predicting clinical outcome in newborns with sepsis, taking into account the information about depth of metabolic disorders.Methods. Design of study — retrospective observational single-center study. Medical cards data of 163 newborns with sepsis were included in analysis. To measure the predictive value of the analyzed clinical and laboratory signs we used the Kullback measure. The clinical outcome of the disease was determined as the response function: survived or died.Results. An analysis of the predictive value of the clinical and laboratory parameters of in newborns with sepsis was made, the threshold values of the most informative indicators were developed, which were: the number of blood platelets, the level of total blood protein, body weight and the number of blood neutrophils. The Clinical and Laboratory Condition Index for Newborns scale has been developed, which takes into account the depth of metabolic disorders. ROC analysis (Area Under Curve — 0,723) and the information method (information coefficient 0.992) showed that the Clinical and Laboratory Condition Index score can be used in the intensive care unit to predict the risk negative clinical outcome and evaluate the effectiveness of treatment in infants with organ dysfunction caused by systemic infection.Conclusion. New Clinical and Laboratory Condition Index score scale allows to predict the development of negative outcome of sepsis in newborns taking into account the depth of metabolic disorders in newborns with sepsis.

Experts Brainstorm How to Expand Clozapine Use

Back to table of contents Previous article Next article Clinical & ResearchFull AccessExperts Brainstorm How to Expand Clozapine UseNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:2 Aug 2019https://doi.org/10.1176/appi.pn.2019.7a5AbstractMonthly blood tests are not the only hurdle keeping some psychiatrists from prescribing this proven treatment for treatment-resistant schizophrenia.The availability of quick, easy-to-use, point-of-care blood tests should help increase the use of clozapine, said a panel of experts at APA’s Annual Meeting in May. However, the rigorous blood monitoring required to check for clozapine-associated neutropenia is not the only reason this proven treatment for treatment-resistant schizophrenia remains underused, they noted. Psychiatrists’ hesitancy and lack of experience using clozapine are even greater barriers.iStock/angelpSpeaking to a packed house, investigators Dan Siskind, Ph.D., M.B.B.S., of the University of Queensland in Australia; Dan Cohen, M.D., Ph.D., of Mental Health Care North-Holland in the Netherlands; Henry Nasrallah, M.D., of St. Louis University School of Medicine; and Jonathan Meyer, M.D., of the University of California, San Diego, shared their experiences prescribing clozapine and discussed available resources for psychiatrists interested in learning more about the medication.Cohen touched on an issue that concerns many psychiatrists: Physicians who prescribe clozapine are expected to regularly monitor these patients’ blood to ensure they do not exhibit a rapid loss of white blood cells (neutropenia), which can endanger their health. Many clinics may be hesitant to prescribe clozapine because of costs and time involved in blood monitoring.There are blood tests that can simplify the collection process, Cohen explained. One option might be tabletop, point-of-care blood tests that use a finger prick to collect capillary blood (as opposed to venous blood draws) to quickly assess samples. Cohen conducted a survey study of 70 patients who reported that capillary blood drawing was more convenient and tolerable than traditional blood drawing. It’s also more cost effective, he noted. (His study involved a device developed by the Swedish company Hemocue, and the panel pointed out that U.S. company Athelas received FDA approval last year for a point-of-care, white blood cell test.)Another approach might be to use dried blood spot sampling, as is done to test for metabolic disorders in newborns. While dried blood spot sampling can assess clozapine drug levels only to determine whether the patient is in a therapeutic range, the test involves a pinprick and some filter paper to collect blood, which can then be sent to a laboratory for analysis.While the panelists noted that there are other rare side effects associated with clozapine, including myocarditis (inflammation of the heart muscle), constipation, and excess drooling, physicians’ limited experience with clozapine remains a key contributor to underuse.Siskind encouraged psychiatrists with clozapine experience to share their knowledge with others whenever possible and to get others—including nurses, other clinical staff, even patients—involved in the process as well. “If we can get current users to discuss their experiences, the good and the bad, it could help convince many others,” he said.As one example of a clozapine-users network, Nasrallah talked about the CURESZ (Comprehensive Understanding via Research and Education into Schizophrenia) Foundation. He established CURESZ in 2016 along with Bethany Yeiser, a patient of Nasrallah’s with schizophrenia who made a full recovery with the help of clozapine. In addition to providing educational lectures about schizophrenia to young adults across the nation, CURESZ has established an international panel of clozapine experts to help guide physicians and their patients. Any physician can access the CURESZ website to find the nearest expert for assistance and potential referral.Meyer then highlighted a book he recently co-authored that serves as a comprehensive clozapine therapy resource for physicians. “I felt the field needed this more than anything. For all the years clozapine has been used, there has only been one previous textbook on the subject,” he said. And, unfortunately, that previous book quickly became outdated as the clozapine blood-monitoring guidelines were changed right after it was published.“The clinical evidence is there,” Siskind said in conclusion of his talk. “Clozapine reduces hospitalizations, it reduces mortality, patients like to take it, and it saves hospitals money. We just need to convince providers to overcome their worries about lack of experience and give clozapine a shot.” ■CURESZ is posted here. ISSUES NewArchived

Fully automated determination of nicotine and its major metabolites in whole blood by means of a DBS online-SPE LC-HR-MS/MS approach for sports drug testing

Dried blood spots (DBS) represent a sample matrix collected under minimal-invasive, straightforward and robust conditions. DBS specimens have been shown to provide appropriate test material for different analytical disciplines, e.g., preclinical drug development, therapeutic drug monitoring, forensic toxicology and diagnostic analysis of metabolic disorders in newborns. However, the sample preparation has occasionally been reported as laborious and time consuming. In order to minimize the manual workload and to substantiate the suitability of DBS for high sample-throughput, the automation of sample preparation processes is of paramount interest. In the current study, the development and validation of a fully automated DBS extraction method coupled to online solid-phase extraction using the example of nicotine, its major metabolites nornicotine, cotinine and trans-3′-hydroxycotinine and the tobacco alkaloids anabasine and anatabine is presented, based on the rationale that the use of nicotine-containing products for performance-enhancing purposes has been monitored by the World Anti-Doping Agency (WADA) for several years. Automation-derived DBS sample extracts were directed online to liquid chromatography high resolution/high mass accuracy tandem mass spectrometry, and target analytes were determined with support of four deuterated internal standards. Validation of the method yielded precise (CV <7.5% for intraday and <12.3% for interday measurements) and linear (r2>0.998) results. The limit of detection was established at 5ngmL−1 for all studied compounds, the extraction recovery ranged from 25 to 44%, and no matrix effects were observed. To exemplify the applicability of the DBS online-SPE LC–MS/MS approach for sports drug testing purposes, the method was applied to authentic DBS samples obtained from smokers, snus users, and e-cigarette users. Statistical evaluation of the obtained results indicated differences in metabolic behavior depending on the route of administration (inhalative versus buccal absorption) in terms of the ratio of nicotine and nornicotine.

Determination of Synacthen(®) in dried blood spots for doping control analysis using liquid chromatography tandem mass spectrometry.

Dried blood spot (DBS) sampling, a technique used for taking whole blood samples dried on a filter paper, was initially reported in 1963 by Robert Guthrie. While the diagnostic analysis of metabolic disorders in newborns was the focus of investigations at that time, the number of established applications for preclinical drug development, toxicological studies, and therapeutic drug monitoring increased enormously in the last decades. As a consequence of speed, simplicity, and minimal invasiveness, DBS recommends itself as the preferential technique in sports drug testing. The present approach highlights for the first time the development of a screening assay for the analysis of the synthetic human adrenocorticotropic hormone tetracosactide hexaacetate (Synacthen(®)) in DBS using liquid chromatography tandem mass spectrometry. Highly purified sample extracts were obtained by an advanced sample preparation procedure including the addition of an internal standard (d8-tetracosactide) and immunoaffinity purification. The method's overall recovery was 27.6 %, and the assay's imprecision was calculated between 8.1 and 17.9 % for intraday and 12.9 to 20.5 % for interday measurements. Stability of the synthetic peptide in DBS was shown for at least 10 days at room temperature and presents a major benefit, since a rapid degradation in conventionally applied matrices such as urine or plasma is well known. With a limit of detection of 50 pg/mL, a detection window of several hours is expected considering reported steady-state plasma levels of 300 pg/mL after intramuscular application of Synacthen(®) Depot (1 mg). The analysis of authentic DBS samples within the scope of an administration study with 250 μg Synacthen(®) (short stimulation test) demonstrated the great potential of the developed assay to simplify the analysis of Synacthen(®) for doping control purposes.

DİYABETİK ANNE BEBEKLERİNİN YENİDOĞAN DÖNEMİ SORUNLARI

Objectives: Diabetes is a disease that effects fetal development during pregnancy and leads metabolic disorders in newborns. In this study, we aimed to evaluate the problems of infants of diabetic mothers and to determine risk factors of mothers during pregnancy. Material and Methods: The morbidity rates of 31 infants of diabetic mothers who were born and followed in neonatal intensive unit between January 2013 and December 2013 at Gaziosmanpasa University and demographic properties of mothers were retrospectively evaluated. Results: A total of 31 infants were included. The incidence of insulin dependent diabetes mellitus was %22,6 and the incidence of gestational diabetes was 77,4%. Mothers’ mean age was 32,6±7,9 years and HbA1c level was 5,4±1 (4,2-10,2). The mean gestational age of infants was 37,5±1,5 weeks and the mean birth weight of infants was 3322,5± 695,8 g. Macrosomia was present in 32.2% of infants. Hypoglycemia was present in 9,7% of infants, hypocalcemia was seen 3.2%, polycytemia was seen 6.5%, anemia was seen 6.5%, thrombocytopenia was seen 9.2%, hyperbilirubinemia was seen 41.9%, respiratory distress syndrome was seen 12.9%, congenital anomaly was seen 3.7% of all infants. There was no correlation between HbA1c levels of mothers and hypoglycemia, hypocalcemia, anemia and respiratory distress syndrome. Conclusion: Many complications may be prevented with appropriate management, obstetric care and neonatal management in infants of diabetic mother. It is possible to reduce morbidities with the identification of gestational diabetes and metabolic control of hyperglycemia, the determination of risk factors, the close contact between the diabetic mother and her infant in the first hours of delivery and the close follow-up of infants of diabetic mothers with rooming-in who do not need neonatal intensive care unit care.

Asymptomatic maternal 3-methylcrotonylglycinuria detected by her unaffected baby's neonatal screening test.

3-methylcrotonyl-coenzyme A carboxylase (3MCC) deficiency is an autosomal recessive disorder in which leucine catabolism is hampered, leading to increased urinary excretion of 3-methylcrotonylglycine. In addition, 3-hydroxyisovalerylcarnitine levels increase in the blood, and the elevated levels form the basis of neonatal screening. 3MCC deficiency symptoms are variable, ranging from neonatal onset with severe neurological abnormality to a normal, asymptomatic phenotype. Although 3MCC deficiency was previously considered to be rare, it has been found to be one of the most common metabolic disorders in newborns after the neonatal screening test using tandem mass spectrometry was introduced. Additionally, asymptomatic 3MCC deficient mothers have been identified due to abnormal results of unaffected baby's neonatal screening test. Some of the 3MCC-deficient mothers show symptoms such as fatigue, myopathy, or metabolic crisis with febrile illnesses. In the current study, we identified an asymptomatic 3MCC deficient mother when she showed abnormal results during a neonatal screening test of a healthy infant.

Prevención de la transmisión vertical y efectos secundarios de la terapia anti-retroviral en hijos nacidos de madres seropositivas para VIH en el área Sur-Oriente de Santiago, Chile: perspectiva de 15 años

Antiretroviral therapy (ART) has shown to be an effective measure in decreasing HIV vertical transmission (VT). Nevertheless, it is not free from adverse effects in the newborn: risk of prematurity, low birth weight, metabolic disorders, among others. Despite the importance of the subject, there are few national data that analyze the problem. We performed a retrospective analysis of a cohort of HIV positive mother/child binomial, followed between 1995 and 2010. Ninety-four pregnancies and 96 children (2 twin pregnancies) were analyzed. The rate of VT was 2.1%. Adverse effects attributed to ART were found on 85.4% of the newborn; highlighting the presence of anemia (70.8%) and several metabolic disorders [elevated lactate without acidosis (29.2%), lactic acidosis (12.5%), hyperkalemia (14.6%), metabolic acidosis (9.4%)]. Maternal exposure to protease inhibitors proved to be an independent risk factor for the development of metabolic disorders in newborns (OR 0.15 [0.04-0.48], p < 0.01). In our series, ART was effective in reducing the VT, however exposed newborns showed a high frequency of adverse effects, so it is advisable to implement programs for monitoring these patients to prevent sequelae.

Impact of premature birth and critical illness on neonatal range of plasma amino acid concentrations determined by LC-MS/MS

BackgroundThe number of newborns and the number of disorders detected by large-scale screening programs has increased dramatically in the last decade. Newborn screening is a multi-step process requiring confirmatory testing to establish and refine a diagnosis. Whereas screening cutoffs are established to detect all cases of a specific disease, confirmatory testing is performed against a backdrop of many co-morbid conditions and interpretation of results is often not straightforward. The goal of the current study was to define the range of amino acid concentrations encountered in normal, premature, and acutely ill newborns as an aid to the interpretation of follow-up testing for suspicious newborn screens. Materials and methodsResidual plasma samples from 354 neonates (age 1–10days) were utilized. 206 samples were from neonates with uncomplicated birth histories and prompt hospital discharge. 98 specimens were derived from a population of children receiving intensive care with diagnoses that included sepsis, respiratory insufficiency, cardiac malfunction/malformation and gastrointestinal complications. 50 samples were from infants born after 32 but before 37 full weeks gestation that were discharged following uneventful hospital courses. 25 amino acids were quantitated by LC-MS/MS and reference intervals determined by non-parametric statistical methods. Distributions were compared using Kruskal–Wallis analyses for independent samples. ResultsThe distributions of multiple amino acids in premature and critically ill infants were significantly different than those observed in healthy newborns. Differing distributions were found for phenylalanine, the branched chain amino acids, methionine, glutamine, glutamate, arginine, lysine, α-aminoadipic acid, and β-aminoisobutyric acid. In most cases median values were increased and distributions more positively skewed in premature or ill newborns compared to healthy newborns. In addition, we report neonatal homocitrulline reference intervals for these newborn populations determined by an LC-MS/MS technique that is not confounded by methionine interference. ConclusionThese data provide a basis for improved detection of genetic metabolic disorders in newborns, particularly those born prematurely or with a variety of critical co-morbid conditions.

Capillary electrophoresis and mass spectrometry for screening of metabolic disorders in newborns.

Clinical analyses always represent a challenge for the sensitivity and selectivity of the analytical techniques. Of the most critical are the techniques required for the quick determination of the disease state and application of the proper treatment in newborns. This short critical review overviews the present state of the art of the use of mass spectrometry and capillary electrophoresis for screening of metabolic disorders in newborns.

Anwendungsgebiete der Massenspektrometrie in der Klinischen Chemie und Laboratoriumsmedizin / Application of mass spectrometry in clinical chemistry and laboratory medicine

The use of mass spectrometry (MS) as an analytical tool becomes increasingly important in clinical laboratory diagnostics. In the last decade there has been an exponential growth in clinical laboratory, pharmacology, and toxicology applications. At present, the spectrum of MS applications ranges from the measurement of single analytes to qualitative and quantitative multiparametric analyses. Combining tandem mass spectrometry with atmospheric pressure ionization techniques offers high analytic sensitivity and specificity, robustness, and the option for high throughput analyses at low running costs. Today, this analytical platform is already used in routine clinical laboratory to screen for inherited metabolic disorders in newborns, for therapeutic drug monitoring, and for hormone profiling. In addition, SELDI-TOF and MALDI-TOF techniques are used for clinical proteomic pattern diagnostics. This short review will give an overview of the current status of mass spectrometry techniques, established applications in clinical laboratory diagnostics, and the perspectives for future developments in laboratory medicine.

Confidence limits for the incidence of metabolic disorders screened in Switzerland

The incidence of rare disorders in the population is usually indicated in the literature by a rate, without any confidence limits added. Using data of the Swiss screening program for metabolic disorders in newborns (provided by R.Gitzelmann and R.Bütler) we found that the occurence of elevated phenylalanine is compatible with a POISSON distribution (Chi square test, Kolmogorov-Smirnov test). Thus confidence limits can be established. Comparisons between different populations are easily tested statistically. The 95% confidence limits for the incidence of metabolic disorders screened in Switzerland are as follows: The incidence of hypothyroidism found in Switzerland by TSH-assay is significantly higher (p<0.025) than that found in Quebec (16.6-25.3/100'000)by T4 screening.