Int. J. Neonatal Screen., Volume 4, Issue 1 (March 2018) – 10 articles

This article reviews the development of the Ninth Clinical Consensus Statement by SIBEN (the Ibero-American of Neonatology) on “Early Detection with Pulse Oximetry (SpO₂) of Hypoxemic Neonatal Conditions”. It describes the process of the consensus, and the conclusions and recommendations for screening newborns with pulse oximetry. Full article

Fragile X syndrome (FXS) is the most prevalent heritable cause of cognitive impairment but is not yet included in a newborn screening (NBS) program within Australia. This paper aims to assess the feasibility and reliability of population screening for FXS using a pilot study in one hospital. A total of 1971 mothers consented for 2000 newborns to be tested using routine NBS dried blood spot samples. DNA was extracted and a modified PCR assay with a chimeric CGG primer was used to detect fragile X alleles in both males and females in the normal, premutation, and full mutation ranges. A routine PCR-based fragile X assay was run in parallel to validate the chimeric primer assay. Babies with CGG repeat number ≥59 were referred for family studies. One thousand nine hundred and ninety NBS samples had a CGG repeat number less than 55 (1986 < 50); 10 had premutation alleles >54 CGG repeats (1/123 females and 1/507 males). There was complete concordance between the two PCR-based assays. A recent review revealed no clinically identified cases in the cohort up to 5 years later. The cost per test was $AUD19. Fragile X status can be determined on routine NBS samples using the chimeric primer assay. However, whilst this assay may not be considered cost-effective for population screening, it could be considered as a second-tier assay to a developed immunoassay for fragile X mental retardation protein (FMRP). Full article

While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA) by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results. Full article

Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an “acute neonatal” and a “chronic intermittent” form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with l-carnitine and/or l-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required. Full article

Duchenne muscular dystrophy (DMD/Duchenne) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 5000 male births. While Duchenne is a 100% fatal disease, the clinical community has demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual’s life span. In anticipation of the changing therapeutic landscape for the Duchenne community, Parent Project Muscular Dystrophy established a newborn screening (NBS) initiative. This initiative included a Bioethics and Legal Issues Workgroup to consider the bioethics and legal issues of NBS for Duchenne. The workgroup’s discussion focused only on Duchenne NBS and met through conference calls over a one-year period of time seeking consensus on various identified issues. This article reports on the findings and recommendations from that workgroup. Full article

Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80% of them surpassed +3 SD (standard deviation), all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS. Full article

Pulse oximetry screening of the well newborn to assist in the diagnosis of critical congenital heart disease (CCHD) is increasingly being adopted. There are advantages to diagnosing CCHD prior to collapse, particularly if this occurs outside of the hospital setting. The current recommended approach links pulse oximetry screening with the assessment for CCHD. An alternative approach is to document the oxygen saturation as part of a routine set of vital signs in each newborn infant prior to discharge, delinking the measurement of oxygen saturation from assessment for CCHD. This approach, the way that many hospitals which contribute to the Australian New Zealand Neonatal Network (ANZNN) have introduced screening, has the potential benefits of decreasing parental anxiety and expectation, not requiring specific consent, changing the interpretation of false positives and therefore the timing of the test, and removing the pressure to perform an immediate echocardiogram if the test is positive. There are advantages of introducing a formal screening program, including the attainment of adequate funding and a universal approach, but the barriers noted above need to be dealt with and the process of acceptance by a national body as a screening test can take many years. Full article

Despite the progress in the fetal echocardiographic detection of congenital critical heart defects and neonatal physical examination, a significant number of newborn infants are discharged and readmitted to the hospital in severe condition due to cardiac failure or collapse. The aim of this study was to assess the incidence of undetected critical congenital heart disease (CCHD) by a pulse oximetry-screening program in the maternity wards of hospitals with Perinatal Services in a specific geographic area. This is a prospective observational study performed in in the health area corresponding to the city of Valencia. Eligible infants were consecutively admitted newborn infants in the maternities of the participating hospitals with negative fetal echocardiography after normal physical examination in the delivery room. All patients were screened following a specific pulse oximetry protocol before discharge. A total of 8856 newborn infants were screened. A total of three babies presented with severe congenital cardiac malformation and two babies presented with early onset sepsis. Sensitivity was 100% and specificity was 99.97%, with a positive predictive value of 60% and negative predictive value of 100%. Pulse oximetry screening programs in the early neonatal period constitute a valuable tool to avoid inadvertent hospital discharge of severe cardiac malformations and the subsequent life-threatening complications derived. Full article

A new and fully automated newborn screening method for mass spectrometry was introduced in this paper. Pathological relevant amino acids, acylcarnitines, and certain steroids are detected within 4 min per sample. Each sample is treated in an automated and standardized workflow, where a mixture of deuterated internal standards is sprayed onto the sample before extraction. All compounds showed good linearity, and intra- and inter-day variation lies within the acceptance criteria (except for aspartic acid). The described workflow decreases analysis cost and labor while improving the sample traceability towards good laboratory practice. Full article

As newborn screening (NBS) programs in the US implement expanded screening panels, utilize emerging technologies and identify areas for improvement, the need to establish and maintain a community engagement based national technical assistance center becomes apparent. The Newborn Screening Technical assistance and Evaluation Program (NewSTEPs)—a program of the Association of Public Health Laboratories (APHL) in partnership with the Colorado School of Public Health (ColoradoSPH), offers expertise in newborn screening program development, member connection, data analysis, and program evaluation. NewSTEPs provides a secure online data repository designed to collect comprehensive data on newborn screening programs in three strata: state profiles (description of each state program including program hours, fees, and disorders screened), quality indicators (metrics of program performance encompassing screening accuracy and timeliness) and NBS public health surveillance case definitions. NewSTEPs was created in 2012 under a cooperative agreement with the United States Department of Health and Human Services (HHS), Health Resources and Services Administration (HRSA), Maternal and Child Health Bureau (MCHB). Successful activities of NewSTEPs have resulted in the establishment of a technical assistance resource center and the organization of a network of newborn screening experts. In addition, NewSTEPs coordinates efforts with other federally funded programs in order to maximize resources and to ensure a unified approach to data collection and information sharing. Full article