Newborn Bloodspot Screening Research Articles

The Cost-Effectiveness of Expanding the UK Newborn Bloodspot Screening Programme to Include Five Additional Inborn Errors of Metabolism.

Glutaric aciduria type 1, homocystinuria, isovaleric acidaemia, long-chain hydroxyacyl CoA dehydrogenase deficiency and maple syrup urine disease are all inborn errors of metabolism that can be detected through newborn bloodspot screening. This evaluation was undertaken in 2013 to provide evidence to the UK National Screening Committee for the cost-effectiveness of including these five conditions in the UK Newborn Bloodspot Screening Programme. A decision-tree model with lifetable estimates of outcomes was built with the model structure and parameterisation informed by a systematic review and expert clinical judgment. A National Health Service/Personal Social Services perspective was used, and lifetime costs and quality-adjusted life years (QALYs) were discounted at 1.5%. Uncertainty in the results was explored using expected value of perfect information analysis methods together with a sensitivity analysis using the screened incidence rate in the UK from 2014 to 2018. The model estimates that screening for all the conditions is more effective and cost saving when compared to not screening for each of the conditions, and the results were robust to the updated incidence rates. The key uncertainties included the sensitivity and specificity of the screening test and the estimated costs and QALYs.

Instability of Acylcarnitines in Stored Dried Blood Spots: The Impact on Retrospective Analysis of Biomarkers for Inborn Errors of Metabolism.

Stored dried blood spots (DBS) can provide valuable samples for the retrospective diagnosis of inborn errors of metabolism, and for validation studies for newborn blood spot screening programs. Acylcarnitine species are subject to degradation upon long-term storage at room temperature, but limited data are available on the stability in original samples and the impact on acylcarnitine ratios. We analysed complete acylcarnitine profiles by flow-injection tandem mass spectrometry in 598 anonymous DBS stored from 2013 to 2017, at +4 °C during the first year and thereafter at room temperature. The concentrations of C2-, C3-, C4-, C5-, C6-, C8-, C10:1-, C10-, C12:1-, C12-, C14:1-, C14-, C16:1-, C16-, C18:2-, C18:1-, C18-, C5OH+C4DC-, C18:1OH-, and C16DC-carnitine decreased significantly, whereas a positive trend was found for free carnitine. Only the C4/C8-, C8/C10-, C14:1/C10- and C14:1/C16-carnitine ratios appeared robust for the metabolite instability. The metabolite instability may provoke the wrong interpretation of test results in the case of retrospective studies and risk the inaccurate estimation of cut-off targets in validation studies when only stored control DBS are used. We recommend including control DBS in diagnostic, retrospective cohort studies, and, for validation studies, we recommend using fresh samples and repeatedly re-evaluating cut-off targets.

Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study

Neonatal diabetes presents <6 months of life but delays in recognition result in presentation with life-threatening hyperglycaemia/diabetic ketoacidosis. Early identification and rapid genetic diagnosis is crucial and ensures correct treatment/management....

Newborn Screening Knowledge and Attitudes Among Midwives and Out-of-Hospital-Birth Parents.

Midwifery and nursing are collaborative partners in both education and practice. Understanding needs and barriers to clinical services such as newborn screening is essential. This study examined knowledge and attitudes of midwives and out-of-hospital-birth parents about newborn blood spot screening (NBS). Descriptive and cross-sectional surveys were distributed to midwives and out-of-hospital-birth parents from birth center registries and the Utah Health Department of Vital Records. Seventeen midwife surveys (response rate: 17%) and 113 parent surveys (response rate: 31%) were returned. Most midwives and out-of-hospital-birth parents reported satisfactory knowledge scores about NBS. Only 5% of parents (n = 6) did not participate in NBS. Most midwives reported that NBS is important and encouraged patients to consider undergoing NBS. Some concerns included the lack of education for both midwives and out-of-hospital patients and the trauma and accuracy of the heel prick soon after birth. Both midwives and out-of-hospital-birth parents expressed a need for improved NBS education. Additional studies are needed to ascertain whether this trend is seen with similar populations throughout the United States, to further elucidate the factors that drive NBS nonparticipation, and to develop educational resources for midwives and their patients.

Qualitative exploration of health professionals’ experiences of communicating positive newborn bloodspot screening results for nine conditions in England

ObjectiveTo explore health professionals’ experiences of communicating positive newborn bloodspot screening (NBS) results, highlight differences, share good practice and make recommendations for future research.DesignQualitative exploratory design was employed using semi-structured...

Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme.

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.

Constructing a Bioethical Framework to Evaluate and Optimise Newborn Bloodspot Screening for Cystic Fibrosis.

Newborn bloodspot screening for cystic fibrosis is a valid public health strategy for populations with a high incidence of this inherited condition. There are a wide variety of approaches to screening and in this paper, we propose that a bioethical framework is required to determine the most appropriate screening protocol for a population. This framework depends on the detailed evaluation of the ethical consequences of all screening outcomes and placing these in the context of the genetic profile of the population screened, the geography of the region and the healthcare resources available.

Processing Newborn Bloodspot Screening Results for CF.

Every newborn bloodspot screening (NBS) result for cystic fibrosis (CF) consists of two parts: a screening part in the laboratory and a clinical part in a CF centre. When introducing an NBS programme, more attention is usually paid to the laboratory part, especially which algorithm is most suitable for the region or the country. However, the clinical part, how a positive screening result is processed, is often underestimated and can have great consequences for the affected child and their parents. A clear algorithm for the diagnostic part in CF centres is also important and influences the performance of a CF NBS programme. The processing of a positive screening result includes the initial information given to the parents, the invitation to the sweat test, what to do if a sweat test fails, information about the results of the sweat test, the inconclusive diagnosis and the carrier status, which is handled differently from country to country. The time until the definitive diagnosis and adequate information is given, is considered by the parents and the CF team as the most important factor. The communication of a positive NBS result is crucial. It is not a singular event but rather a process that includes ensuring the appropriate clinicians are aware of the result and that families are informed in the most efficient and effective manner to facilitate consistent and timely follow-up.

Health-care providers’ perspectives on uncertainty generated by variant forms of newborn screening targets

PurposeDespite the public health successes of newborn bloodspot screening, uncertainty associated with variant forms of primary screening targets has led to discrepancies in medical management. This study explored health-care providers’ approaches to managing atypical forms of inherited metabolic diseases (IMDs) in the absence of evidence-based guidelines. MethodsSemistructured telephone interviews were conducted with metabolic specialists. 3-Methylcrotonyl CoA deficiency and variant forms of phenylketonuria, biotinidase deficiency, and fatty acid oxidation disorders were considered. Data were analyzed inductively and deductively using a novel taxonomy of uncertainty. ResultsHealth-care providers (n = 12) navigate diagnostic, prognostic, and therapeutic challenges of uncertainty while interpreting patient and family attitudes, preferences, and ideas in the care of children with these result types. Participants explained the limits of classifying mild and atypical metabolic phenotypes. Participants also described the challenge of finding balance between cautious care and overmedicalization. Developing consistent care plans and honest communication with families were perceived as effective strategies when navigating uncertainty. ConclusionProviders’ experiences suggest a need for transparent and accessible guidelines that account for challenges associated with uncertainty generated by screening. Timely consideration of this challenge is warranted with increasing emergence of genotype-first approaches to screening.

Consent for newborn screening: screening professionals' and parents’ views

ObjectivesExpansion of newborn bloodspot screening (NBS) within England, which practices an informed consent model, justified examining acceptability and effectiveness of alternative consent models. Study designQualitative focus groups. MethodsForty-five parents and 37 screening professionals (SPs) participated. Data were analysed using thematic analysis. ResultsParents and SPs initially appeared to have differing views about appropriate consent models. Most parents accepted assumed consent, if adequately informed; however, once aware of bloodspot storage, informed consent was wanted. SPs valued informed consent, but acknowledged it was difficult to obtain. Both samples wanted parents to be informed but were unclear how this could be achieved. Most parents felt NBS was not presented as optional. ConclusionThe simultaneous exploration of parents and SPs views, in real time is original. This rigour avoided the reliance on retrospective accounts which make it difficult to establish how decisions were made at the time. It is also unique in providing pre-interview consent models to drive the depth of data. It was rigorous in member checking. Findings suggested a preference for full disclosure of all information with some parents valuing this more than choice. Both samples queried whether current consent was sufficiently informed and voluntary. Results suggest differing tolerances of consent type if screening is solely for diagnostic purposes vs bloodspot storage. Results highlight the need for caution when examining consent model preferences without also checking knowledge, as opinions may be based on incomplete knowledge. Future research is needed to examine efficacy of proposed changes. FundingNational Institute for Health Research Health Technology Assessment HTAProgramme (11/62/02). Trial registrationISRCTN70227207.

Lessons learnt from implementing change in newborn bloodspot screening processes over more than a decade: Midwives, genetics and education

ObjectiveTo explore midwives’ roles and education requirements in newborn bloodspot screening (NBS) for genetic conditions, as programs and supporting education evolve over time. BackgroundNBS processes are evolving and will continue to evolve with new genetic and genomic technologies. Midwives have a critical role in facilitating NBS, as they are the primary healthcare professional to interact with parents at the time of collecting the bloodspot. As new consent processes and genomic technologies are incorporated into NBS, midwives need to stay up-to-date with these changes, so that parents can make an informed decision about having the test and future use of the DNA sample. Research design/settingWe used a cross-sectional approach to analyse midwives’ knowledge and behaviour in 2005/6 and 2016, with changes in NBS processes and education introduced in 2011. FindingsWe found midwives’ NBS knowledge improved in 8/18 areas after a 10-year period, mostly related to process changes, but there was also an increase in misconceptions regarding which conditions are screened. Areas of significant improvement were not consistently explained by participation in continuing professional development (CPD). We found midwives used official brochures and NBS collection cards to guide discussions with families. Changes to the NBS collection cards, together with the content of CPD materials, aligned with the significant improvements and deficits we observed. When considering potential changes to future maternity care that incorporates emerging genomic technologies, midwives indicated the main barrier was their lack of knowledge; the majority (60.3%) reported supervision support to attend genomics CPD. Key conclusionsChanges in NBS practice should be implemented through multifaceted programs that include education sessions and procedural prompts. The NBS collection card should be seen not just as a legal consent document but also as an educational tool. Implications for practiceAs NBS programs evolve through the addition of conditions screened for or changes to technology or consent processes, multiple strategies should be applied to upskill midwives to ensure they can best support parents to make informed choices.

A Cost-Effectiveness Analysis of Newborn Screening for Severe Combined Immunodeficiency in the UK.

Severe combined immunodeficiency (SCID) can be detected through newborn bloodspot screening. In the UK, the National Screening Committee (NSC) requires screening programmes to be cost-effective at standard UK thresholds. To assess the cost-effectiveness of SCID screening for the NSC, a decision-tree model with lifetable estimates of outcomes was built. Model structure and parameterisation were informed by systematic review and expert clinical judgment. A public service perspective was used and lifetime costs and quality-adjusted life years (QALYs) were discounted at 3.5%. Probabilistic, one-way sensitivity analyses and an exploratory disbenefit analysis for the identification of non-SCID patients were conducted. Screening for SCID was estimated to result in an incremental cost-effectiveness ratio (ICER) of £18,222 with a reduction in SCID mortality from 8.1 (5–12) to 1.7 (0.6–4.0) cases per year of screening. Results were sensitive to a number of parameters, including the cost of the screening test, the incidence of SCID and the disbenefit to the healthy at birth and false-positive cases. Screening for SCID is likely to be cost-effective at £20,000 per QALY, key uncertainties relate to the impact on false positives and the impact on the identification of children with non-SCID T Cell lymphopenia.

Management of sickle cell disease: outpatient and community aspects

<h2>Abstract</h2> Sickle cell disease (SCD) is the commonest inherited disorder in England, affecting 1 in 2000 births, the majority born in London and of Black African family origins. Newborn bloodspot screening for SCD has now been implemented across the whole of England and this review considers the neonatal screening pathway and aspects of outpatient and community care which should be delivered within the comprehensive care networks. Morbidity and mortality during childhood has declined due to implementation of effective care programmes, which include infection and stroke prophylaxis. Children still suffer from complications of SCD affecting long-term health, quality of life, self esteem, school performance and attainment. Treatment options for long-term control of the disease include hydroxycarbamide, regular transfusion and sibling allogeneic bone marrow transplantation. The indications, evidence of efficacy and adverse effects of these treatments are discussed.

Impact of Cystic Fibrosis on Unaffected Siblings: A Systematic Review

To conduct a systematic review of the evidence to determine the impact of cystic fibrosis (CF) on unaffected siblings. We searched MEDLINE (Ovid interface, from 1946); EMBASE (Ovid interface, from 1946); CINAHL (EBSCO interface); Academic Search Complete (EBSCO interface); Psych Info (EBSCO interface); ProQuest Theses' and Dissertation's (ProQuest); British Index of Nursing (ProQuest); Web of Science (ISI, Web of Knowledge portal); PubMed (PubMed NCBI); BASE (Bielefeld Academic Research Engine); Scopus; EThOS (e-theses online service); Open Grey; and Cochrane Library. Contents pages of the Journal of Cystic Fibrosis, June 2002-April 2017 were hand searched to identify further eligible studies. Reference lists of eligible articles and relevant review papers were screened. Inclusion criteria were full studies published after 1989 in English focusing on the impact of cystic fibrosis on unaffected siblings. In total, 13 papers, 4 PhD theses and 1 MSc thesis were included in the review. Four themes were identified; family functioning, psychosocial impact, knowledge of CF, and condition-specific differences. Most studies are old and may not accurately represent the impact of CF on unaffected siblings following changes to health care provision including newborn bloodspot screening and the advent of CF transmembrane regulator modulator therapies. Further work is needed directly with siblings rather than using mothers as proxies to determine effect of age, sex, and disease trajectory on unaffected siblings' experiences.

Psychological Impact on Parents of an Inconclusive Diagnosis Following Newborn Bloodspot Screening for Cystic Fibrosis: A Qualitative Study.

Genetic results of uncertain clinical significance are being returned to parents following newborn screening, representing a paradigm change in how society considers health and illness. ‘Cystic Fibrosis screen positive, inconclusive diagnosis’ (CFSPID) is a designation given to newborns with a positive screening result for, but not a definitive diagnosis of, cystic fibrosis. We explored the psychological impact of receiving a CFSPID result on parents. Five semi-structured interviews were conducted with eight parents whose children have CFSPID. Interpretative phenomenological analysis identified these themes: “The way we were told”: ‘diagnosis as a traumatic event’ focused on how parents were distressed and dissatisfied by the initial screening result communication, ‘Facing and challenging traditional ideas about health and illness’ explored the emerging problem of how CFSPID does not fit the commonly accepted medical model, and ‘Making certainty out of uncertainty’ explored the varying strategies parents developed to adapt to the uncertainty regarding their child’s prognosis. Findings suggest that CFSPID results caused parents’ distress, initiated with the first communication of the result and persisting thereafter. Our data suggests approaches to the delivery of CFSPID results that may reduce the impact. Work is needed to close the gap between healthcare advances and societies commonly held medical model.

P054 Parents' experience of receiving a diagnosis of cystic fibrosis through the UK Newborn Blood Spot Screening programme

P054 Parents' experience of receiving a diagnosis of cystic fibrosis through the UK Newborn Blood Spot Screening programme

P048 An audit of the timeliness of processing newborn bloodspot screening results in a regional UK cystic fibrosis centre

P048 An audit of the timeliness of processing newborn bloodspot screening results in a regional UK cystic fibrosis centre

WS20-2 Parents' psychological adaptation to an unclear diagnosis after positive newborn bloodspot screening for cystic fibrosis: a qualitative study

WS20-2 Parents' psychological adaptation to an unclear diagnosis after positive newborn bloodspot screening for cystic fibrosis: a qualitative study

WS20-1 An international survey to determine understanding of the designation of infants with an inconclusive diagnosis after newborn bloodspot screening for cystic fibrosis

WS20-1 An international survey to determine understanding of the designation of infants with an inconclusive diagnosis after newborn bloodspot screening for cystic fibrosis

The utility of post-test newborn blood spot screening cards for epigenetic association analyses: association between HIF3A methylation and birth weight-for-gestational age

Identification of disease-associated epigenetic markers in early life might be useful for pre-emptive intervention to prevent diseases. Epigenome-wide association analyses using newborn blood spot screening cards are an anticipated field of research in Japan. Here, in this study, post-test dried blood spot (DBS) samples were anonymized, with only three attributes of gender, gestational age, and birth weight identified. We isolated DNA from DBS (n = 300) archived for more than 3 years. The median DNA yield (ng) per individual was 429 (interquartile range 300–565). In a model epigenetic analysis, we conducted a confirmative study on the known association between birth weight and hypoxia-inducible factor 3A (HIF3A) gene methylation. DNA methylation levels and cis-acting SNP genotypes (rs8102595 and rs3826795) were measured using EpiTYPER and Taqman assays, respectively. HIF3A methylation was positively associated with birth weight-for-gestational age centile (p = 0.021). While HIF3A methylation was associated with cis-genotypes (rs8102595, p = 2.08E−13; rs3826795, p = 3.63E−09), the association with birth weight centile was retained after adjusting for cis-genotypes (p = 0.029). Thus, we successfully reproduced the results reported previously by others, and demonstrated the usefulness of archived DBS in secondary use for epigenetic association analyses.