UK Newborn Screening Programme 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.

Improving how positive newborn screening results are communicated to parents of children with sickle cell disease.

Sickle cell disease, the most common inherited disorder at birth in the UK, has been included in the UK newborn screening programme since 2006. For parents, receiving the news that their newborn has a serious long-term condition can trigger reactions such as shock, disbelief and guilt. Guidelines on sickle cell disease provide clear screening pathways, but there is variation in how and by whom positive results are communicated to parents. The way in which this is done is crucial, not only for parents' acceptance of the diagnosis but also for their future therapeutic relationships with healthcare professionals and therefore for their child's future health outcomes. Being given reliable and relevant information by confident and knowledgeable staff gives parents hope that their child will achieve a good quality of life. Based on the literature and on the author's experience as a haemoglobinopathy nurse specialist, this article discusses how to improve the communication of positive newborn screening results to parents of children with sickle cell disease.

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.

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

Provision of information about newborn screening antenatally: a sequential exploratory mixed-methods project.

Participation in the UK Newborn Bloodspot Screening Programme (NBSP) requires parental consent but concerns exist about whether or not this happens in practice and the best methods and timing to obtain consent at reasonable cost. To collate all possible modes of prescreening communication and consent for newborn (neonatal) screening (NBS); examine midwives', screening professionals' and users' views about the feasibility, efficiency and impact on understanding of each; measure midwives' and parents' preferences for information provision; and identify key drivers of cost-effectiveness for alternative modes of information provision. Six study designs were used: (1) realist review - to generate alternative communication and consent models; (2) qualitative interviews with parents and health professionals - to examine the implications of current practice for understanding and views on alternative models; (3) survey and observation of midwives - to establish current costs; (4) stated preference surveys with midwives, parents and potential future parents - to establish preferences for information provision; (5) economic analysis - to identify cost-effectiveness drivers of alternative models; and (6) stakeholder validation focus groups and interviews - to examine the acceptability, views and broader impact of alternative communication and consent models. Providers and users of NBS in England. Study 2: 45 parents and 37 health professionals; study 3: 22 midwives and eight observations; study 4: 705 adults aged 18-45 years and 134 midwives; and study 6: 12 health-care professionals and five parents. The realist review identified low parental knowledge and evidence of coercive consent practices. Interview, focus group and stated preference data suggested a preference for full information, with some valuing this more than choice. Health professionals preferred informed choice models but parents and health professionals queried whether or not current consent was fully informed. Barriers to using leaflets effectively were highlighted. All studies indicated that a 'personalised' approach to NBS communication, allowing parents to select the mode and level of information suited to their learning needs, could have added value. A personalised approach should rely on midwife communication and should occur in the third trimester. Overall awareness was identified as requiring improvement. Starting NBS communication by alerting parents that they have a choice to make and telling them that samples could be stored are both likely to enhance engagement. The methods of information provision and maternal anxiety causing additional visits to health-care professionals were the drivers of relative cost-effectiveness. Lack of data to populate an economic analysis, confirmed by value of information analysis, indicated a need for further research. There are some limitations with regard to the range of participants used in studies 2 and 3 and so caution should be exercised when interpreting some of the results. This project highlighted the importance of focusing on information receipt and identified key communication barriers. Health professionals strongly preferred informed consent, which parents endorsed if they were made aware of sample storage. Uniform models of information provision were perceived as ineffective. A choice of information provision was supported by health professionals and parents, which both enhances cost-effectiveness and improves engagement, understanding and the validity of consent. Remaining uncertainties suggest that more research is needed before new communication modes are introduced into practice. Future research should measure the impact of the suggested practice changes (informing in third trimester, information toolkits, changed role of midwife). Current Controlled Trials ISRCTN70227207. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 55. See the NIHR Journals Library website for further project information.

Newborn screening to identify cystic fibrosis.

Background Newborn screening (NBS) identifies pre-symptomatic babies who are at risk of carrying or being affected by genetic or congenital conditions (UK Newborn Screening Programme Centre 2012). Screening for cystic fibrosis (CF) is not diagnostic and, once a positive screening result has been obtained, further testing is required to determine whether the child is affected by CF.

Sickle cell and cystic fibrosis carrier results.

Background Newborn screening (NBS) is used to identify pre-symptomatic babies who carry, or are affected by, genetic or congenital conditions ( UK Newborn Screening Programme Centre 2012 ). In England, parents are required to provide informed consent before their babies are screened.

Inherited genetic conditions.

Background While it is known that early diagnosis leads to better health outcomes for children with inherited genetic conditions (IGCs) ( UK Newborn Screening Programme Centre 2012 , Bush 2008 ), families affected by IGCs face difficulties, including those associated with complex treatment regimens.

Evidence or enthusiasm? Why yields from UK newborn screening programmes for congenital hypothyroidism are increasing

Newborn screening for congenital hypothyroidism (CHT) is generally regarded as a highly successful public health measure. It was officially added to the UK newborn screening programme for phenylketonuria in 19811...

Newborn screening blood spot analysis in the UK: influence of spot size, punch location and haematocrit.

In dried blood spot analysis, punch location and variations in applied sample volume and haematocrit can produce different measured concentrations of analytes. We investigated the magnitude of these effects in newborn screening in the UK. Heparinized blood spiked with thyroid stimulating hormone (TSH), phenylalanine, tyrosine, leucine, methionine, octanoyl carnitine (C8), and immunoreactive trypsinogen (IRT) was spotted onto filter paper: (i) at a constant haematocrit of 50% at various volumes, and (ii) at a range of haematocrits using a constant volume. Subpunches (3.2 mm) of the dried blood spots were then analysed. Compared with a central punch from a 50 µL blood spot with 50% haematocrit, 10 µL spots can have significantly lower measured concentrations of all analytes, with decreases of 15% or more observed for leucine, methionine, phenylalanine, and tyrosine. Punching at the edge of a spot can increase measured concentrations up to 35%. Higher haematocrit decreased measured TSH and C8 yet increased amino acids and IRT by 15% compared with 50% haematocrit. Lower haematocrits had the opposite effect, but only with higher concentrations of some analytes. Differences in blood spot size, haematocrit and punch location substantially affect measured concentrations for analytes used in the UK newborn screening programme, and this could affect false positive and negative rates. To minimize analytical bias, these variables should be controlled or adjusted for where possible.

No evidence of an increase in early infant mortality from congenital adrenal hyperplasia in the absence of screening

ObjectiveCongenital adrenal hyperplasia (CAH) is not currently included in the UK newborn screening programme. We investigated the hypothesis that, owing to non-specificity of symptoms, a proportion of males affected by...

Neonatal blood spot testing for genetic conditions

Neonatal blood spot testing is offered to all babies in the first week of life as part of the UK Newborn Screening Programme. A blood sample is taken from the heel and used to screen for phenylketonuria, congenital hypothyroidism, cystic fibrosis, sickle cell diseases and medium-chain acyl-CoA dehydrogenase deficiency. This article aims to discuss the principles of screening as applied to neonatal blood spot testing, the blood spot test and the conditions which screening aims to detect.

Data: ‘Initial Clinical Referral Standards after Newborn Screening for Congenital Hypothyroidism: Final Report of the UK Newborn Screening Programme Centre Expert Working Group and Systematic Evidence Review 2010-2011’.

The multidisciplinary Expert Working Group was tasked with revising the existing standards of the UK NHS National Screening Programme for diagnosis and management of babies in whom congenital hypothyroidism (CHT) is suspected after newborn bloodspot screening. This report includes a systematic evidence review and account of the proceedings of the working group in key areas: screening test performance, referral pathways, diagnostic investigations, treatment and communication with parents. After public consultation, the recommendations were adopted as policy. This final report provides an evidence base for reviewing newborn screening for CHT in other populations and outlines a transparent consensus-based process for agreeing changes to screening standards and policy.

Screening for Congenital Hypothyroidism: Comparison of Borderline Screening Cut-Off Points and the Effect on the Number of Children Treated with Levothyroxine

Background: The newborn screening programme for congenital hypothyroidism (CH) has led to the prevention of severe developmental delay associated with this condition. In the UK, thyroid-stimulating hormone (TSH) screening cut-off points have changed over time, in some instances prompted by changing methodological platforms. The use of borderline cut-off points varies throughout the country. Objective: To use discordance in cut-off points to assess the performance of the UK Newborn Screening Programme Centre (UKNSPC) definitions. Methods: Between January 2006 and December 2007, 223,658 newborn infants were screened by the Great Ormond Street Hospital (GOSH) for CH. All children with positive results and those with blood-spot TSH concentrations >6 mU/l on repeat screening were referred to GOSH. We compared the numbers of children detected and treated for CH using the GOSH cut-off points (>6 mU/l) and those of the national screening programme (>10 mU/l). Children were defined as transient CH if levothyroxine treatment had been discontinued by 3 years. Results: Of the children screened between January 2006 and December 2007, 167 out of 223,658 fulfilled the GOSH screening criteria; 136 of these required levothyroxine treatment, but 29 (21%) of the children treated would not have been detected by the current UKNSPC guidelines. Transient CH was found in 17/47 (36%) of the treated children detected with a cut-off point >6 mU/l. Raising the cut-off point to >10 mU/l reduced the number of children treated for transient CH to 4/18 (22%). Conclusion: A significant number of children with true and transient CH are missed with a screening cut-off point of >10 mU/l. Our data suggests that a cut-off point of 6 mU/l is appropriate.

Hypothyroidism in preterm infants following normal screening

Congenital hypothyroidism is screened for in the UK using blood spot thyroid-stimulating hormone (TSH) screening at 5-8 d of age. Although standards are set by the UK Newborn Screening Programme Centre, there are variations in TSH cut-offs used. The introduction of repeat screening of preterm babies at 36 weeks' gestational age in 2005 was controversial in its utility and timing. Two cases of preterm babies are presented, who had normal blood spot TSH values on the first test and who became screen positive when re-tested at term. The first with Trisomy 21 was born at 29 + 6 weeks with an initial blood spot TSH of 3.3 mU/L rising to 263 mU/L at term-corrected gestational age (plasma TSH 476.5 mU/L). The second was born at 24 + 6 weeks' gestational age and on day 7, the heel prick blood spot TSH was <2 mU/L, rising to 6.4 mU/L at 36 weeks corrected gestational age. After a barium enema, the plasma TSH increased to 66.6 mU/L with a free thyroxine of 7.6 pmol/L at day 101. Both cases were treated with thyroxine until death due to complications of prematurity. These cases illustrate the difficulties in screening for congenital hypothyroidism in preterm infants, due to the immaturity of the hypothalamo-pituitary-thyroid axis, and the effect of intercurrent illness and drugs on thyroid function. Despite a reassuring published review of 2200 preterm infants, these cases suggest that it may be unwise not to re-screen ex-preterm infants for congenital hypothyroidism at term.

Congenital Hypothyroidism—Monitoring Thyroid Function in Infants

Guidelines for monitoring thyroid function in congenital hypothyroidism (CH) are published by the American Academy of Pediatrics, the European Society for Paediatric Endocrinology, and the UK Newborn Screening Programme Centre. The fact that the recommendations are not uniform reflects management uncertainty. In addition, clinical care may not always be informed by these guidelines. Recent studies suggest that more frequent monitoring is indicated in some infants. Monitoring to identify delayed thyroid stimulating hormone (TSH) rise is indicated in pre-term, low birth weight, and sick full-term newborns. Monitoring thyroid function in infants with CH monthly after normalization of TSH until six months of age, and every one to two months between six and 12 months of age, will decrease exposure to suboptimal thyroid hormone levels. Assessment for permanency of hypothyroidism should be done only in children in which there is likelihood of resolution and not earlier than three years of age. In some instances when TSH elevations persist after normalization of the free thyroxine, it may be reasonable to try combined therapy with triiodothyronine.

Elevated phenylalanine on newborn screening: follow-up testing may reveal undiagnosed galactosaemia

Introduction Newborn screening for phenylketonuria (PKU) can reveal other conditions which lead to an increased blood spot phenylalanine (Phe) concentration. We have investigated the proportion of blood spot samples that gave a positive screen due to clinically significant conditions other than PKU, compared the positive predictive value (PPV) of our referral Phe cut-off with that recommended by the UK Newborn Screening Programme Centre (UKNSPC) (>210 and >240 μmol/L, respectively) and evaluated the effectiveness of reflex testing for galactosaemia using a lower blood spot Phe cut-off concentration of 130 μmol/L. All blood spot samples that screened positive, for an increased Phe concentration, between April 2001 and March 2008, were identified from the records of the Sheffield Newborn Screening Laboratory and the diagnoses noted. In addition, all cases of galactosaemia detected in or notified to our screening laboratory within this time were also examined and the screened Phe concentrations compared. Out of 438,674 babies who were screened, 67 had Phe concentration >210 μmol/L (15 per 100,000). Of these, 40 had PKU or persistent hyperphenylalaninaemia with a Phe concentration identified by screening between 270 and 2350 μmol/L. A further 11 were diagnosed with another clinically significant disorder: galactosaemia (n = 8), biopterin defects (n = 2), tyrosinaemia Type 1 (n = 1). In addition, 16 had transient elevations in Phe. In total, nine cases of galactosaemia were identified, of whom, three had Phe concentrations <240 μmol/L with one asymptomatic individual having a concentration <210 μmol/L. Adoption of the UKNSPC recommended cut-off (>240 μmol/L) will not affect the detection rate of classical PKU, but will improve the PPV from 76% to 80%. The use of a lower cut-off (130 μmol/L) for reflex galactosaemia testing enables the timely identification of asymptomatic cases that benefit particularly from early treatment, without prompting any unnecessary clinical referrals or delaying any referrals. This intervention may reduce mortality in this vulnerable group.

Improvements to the newborn bloodspot screening service are required to meet national standards

The UK Newborn Screening Programme has standards to facilitate the early identification and treatment of five specific diseases to prevent lifelong impairment or death. This audit aimed to assess the newborn bloodspot screening programme in an inner London borough and to make recommendations for service improvement. Data on babies registered with a general practitioner in the borough between April 2008 and March 2009 were obtained from the borough's health database and the laboratory result systems and compared with national screening standards. Interviews were conducted with the leads of each service providing components of newborn screening. A total of 292 (8%) out of 3636 babies registered within the audit period had no result on the database (average 1 in 13). Regional reports revealed that over the previous three years the borough, like many others, had consistently failed to achieve the core standards for newborn bloodspot screening. Major areas of concern identified by this audit pertained to the quality of the bloodspot sample, response to requests for repeat samples, timely identification of untested babies and communication of results to parents. The audit revealed that for the majority of children registered in the borough, screening was successfully carried out. However, gaps in the service meant that with current practice one affected child could be missed every seven years. Recommendations include staff training, frequent data reviews, and providing a coordinating officer to oversee the programme and follow up missing results.

Difficulties in selecting an appropriate neonatal thyroid stimulating hormone (TSH) screening threshold

BackgroundThe UK Newborn Screening Programme Centre recommends that a blood spot thyroid stimulating hormone (TSH) cut-off of 10 mU/l is used to detect congenital hypothyroidism (CHT). As the value used...

Is the current threshold level for screening for congenital hypothyroidism too high? An audit of the clinical evaluation, confirmatory diagnostic tests and treatment of infants with increased blood spot thyroid-stimulating hormone concentrations identified on newborn blood spot screening in Wales

The UK Newborn Screening Programme has set standards for the identification, investigation and early management of children with congenital hypothyroidism. (1)