Scientific Citizenship’s Youngest Domain: Function Creep in Norway’s Newborn Screening Programme

Newborn screening (NBS) for inborn errors of metabolism and other serious conditions with onset during infancy is a widespread public health initiative. Like other screening programmes, it aims to discover and treat a disease before effects manifest themselves. Recently, there have been two prominent changes in NBS: a substantial increase in the number of conditions screened for and growing attention to secondary use of residual newborn blood spots. Here, we analyse how this latter change has transpired in Norway. In 2018, Norway’s parliament sanctioned the secondary use of NBS samples for epidemiological research unrelated to NBS. This broadened the programme’s scope, co-opting it for research purposes, making samples available for inclusion in Norway’s biobanking strategy. We argue that this transformation is a case of function creep, whereby the function of screening samples is expanded to serve purposes other than helping newborns. The process provided only minimal involvement from ordinary citizens, but it transformed screened infants into potential scientific citizens. Henceforth, all future generations of Norwegians must choose to stay in or opt out of biobank research when they turn sixteen. Additionally, consenting to this research may occasion a second form of function creep, as ‘actionable findings’ are fed back to participants.

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.

Developmental dysplasia of the hip

Developmental dysplasia of the hip encompasses a range of hip abnormalities in which the femoral head and acetabulum fail to develop and articulate anatomically. Developmental dysplasia of the hip is a clinically important condition, with a prevalence of 1–2/1000 in unscreened populations and 5–30/1000 in clinically screened populations. The pathology is incongruence between the femoral head and the acetabulum, which can be caused by an abnormally shaped femoral head, acetabulum, or both. This results in a spectrum of different hip abnormalities. The precise aetiology behind developmental dysplasia of the hip is unclear, but there are a number of established risk factors. In the UK, universal clinical examination of newborns and 6–8-week-old babies is performed under the national UK newborn screening programme for developmental dysplasia of the hip (part of the Newborn and Infant Physical Examination). The physical examination of the newborn hip involves initial inspection of the infant for any of the clinical features of developmental dysplasia of the hip, followed by hip stability tests (Barlow's and Ortolani's tests). Hip ultrasound is the gold standard diagnostic and monitoring tool for developmental dysplasia of the hip in newborns and infants under 6 months of age, or until ossification of the femoral head. Some mild cases of developmental dysplasia of the hip (and the immature hip) resolve without requiring intervention; however, there are a number of treatments, both non-operative and operative, that may be used at various stages of this condition.

Pancreatitis-Associated Protein in Neonatal Screening for Cystic Fibrosis: Strengths and Weaknesses

There are currently four countries and one local region in Europe that use PAP in their newborn screening programme. The first country to employ PAP at a national level was the Netherlands, which started using IRT/PAP/DNA/EGA in 2011. Germany followed in 2016 with a slightly different IRT/PAP/DNA strategy. Portugal also started in 2016, but with an IRT/PAP/IRT programme, and in 2017, Austria changed its IRT/IRT protocol to an IRT/PAP/IRT program. In 2018, Catalonia started to use an IRT/PAP/IRT/DNA strategy. The strengths of PAP are the avoidance of carrier detection and a lower detection rate of CFSPID. PAP seems to have advantages in detecting CF in ethnically-diverse populations, as it is a biochemical approach to screening, which looks for pancreatic injury. Compared to an IRT/IRT protocol, an IRT/PAP protocol leads to earlier diagnoses. While PAP can be assessed with the same screening card as the first IRT, the second IRT in an IRT/IRT protocol requires a second heel prick around the 21st day of the patient’s life. However, IRT/PAP has two main weaknesses. First, an IRT/PAP protocol seems to have a lower sensitivity compared to a well-functioning IRT/DNA protocol, and second, IRT/PAP that is performed as a purely biochemical protocol has a very low positive predictive value. However, if the advantages of PAP are to be exploited, a combination of IRT/PAP with genetic screening or a second IRT as a third tier could be an alternative for a sufficiently performing CF-NBS protocol.

Surveillance of transient congenital hypothyroidism using the French newborn screening programme

Introduction Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. Untreated CH results in severe mental impairment. An increased incidence of CH has been reported in France and worldwide that could be explained by an increase in transient forms of CH (TCH). We aimed to estimate the proportion of transient eutopic gland based on the characteristics of children at birth. Methods A probabilistic matching data from French CH neonatal screening program and French national health data system (SNDS) of children born between 2006 and 2012 (1, 763 with CH) allowed to linking 484 (68.8%) among 703 children with eutopic gland. Infants with six months or greater discontinuation of levothyroxine (LT4) treatment before the 31th December 2017 were classified transient CH. We used the Cox model to examine the predictors of TCH. Results Among infants with eutopic gland, 52.9% were female, 14.9% were preterm and 14, 1 % had low birth weight, 11.8 % had a first degree family history of thyroid diseases, 48.1% of mild CH (TSH<50mU/L) at diagnosis and 30,0μg/j median dose of LT4 treatment. The probability of transient CH at five years of follow-up was 25.3% [IC95%:21.6% -29.4%] and 36.7% [31.7% -42.2%] after ten years. In a cox multivariable analysis, neonates with a TSH<50mU/L (adjusted Hazard Ratio=4.1 [2.8-6.2]) and preterm 1.9 [1.1-3.4] had more risk to be transient. Conclusions Prematurity and TSH level were predictors of transient CH. Additional analyses are ongoing to determine whether the occurrence of transient forms of TCH is increasing over the study period. Key messages Transient congenital hypothyroidism represent a significant part of HC at 10 years of follow-up. This finding has important implication on medical practices and should trigger research on the etiology of these transient forms.

Medium-chain acyl-CoA dehydrogenase deficiency: Two novel ACADM mutations identified in a retrospective screening

Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible β-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients. Conclusions An expanded newborn screening programme would be beneficial because it would have detected MCAD deficiency in both patients before the development of clinical signs. Our study also provides one of the first descriptions of ACADM mutations in Southeast Europe.