[Newborn blood spot screening (NBS) in Germany : Status quo and presentation of a concept for further development]. / Neugeborenen-Screening aus Trockenblut (NBS) in Deutschland : Status quo und Vorstellung eines Konzeptes zur Weiterentwicklung.

Newborn screening from dried blood spots (NBS) is a highly effective secondary prevention measure that has been established for many years. Against the background of the inclusion of "new diseases" that meet the screening criteria, a concept for the further advancement of NBS was developed on behalf of the GKV-Spitzenverband. This was based on a systematic literature review and a survey of the status quo of NBS in Germany using quantitative and qualitative methods.It is essential for the success of NBS that all newborns affected by a target disease are diagnosed and treated at an early stage and that the harm to be expected with each screening (e.g., due to false positive findings) is kept as low as possible. This requires the organisation of screening in the sense of an integrated programme through central coordination with standardised structures, continuous quality management and digitalisation in line with data protection requirements.Although in general NBS is being implemented successfully in Germany, the research project presented here also reveals weaknesses and a need for action. Proposals and recommendations were compiled in a concept paper, which shows approaches for further development of NBS in line with the current state of research in consideration of changing demands on the infrastructure and processes in the health system. This review article summarises the challenges, current status and possible solutions for the central topics of the concept paper.

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples.

Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.

Is Our Newborn Screening Working Well? A Literature Review of Quality Requirements for Newborn Blood Spot Screening (NBS) Infrastructure and Procedures.

Newborn screening using dried blood spots (NBS) is widely acknowledged as a highly successful procedure in secondary prevention. For a number of congenital disorders, severe disability or death are impressively prevented by early detection and early treatment through NBS. However, as with any other screening, NBS can also cause harm, and the principle that "the overall benefits of screening should outweigh the harms" must be considered when introducing and implementing NBS programmes. This publication compiles the results of a systematic literature research on requirements for NBS infrastructure and procedures which was conducted as part of a research project on the quality and shortcomings of the NBS pathway in Germany. The compilation contains the requirements and recommendations for realising the principle of "maximise benefits and minimise harms" in relevant NBS pathway components such as parental education and information, coverage, timeliness, laboratory quality assurance, follow-up of abnormal results, confirmatory diagnostics, documentation, and evaluation. The results reflect the complexity of NBS infrastructure, and thus, they illustrate the importance of considering and implementing NBS as a well-coordinated public health programme with continuous quality management. Special attention should be paid to the perspectives of parents and families. Some NBS issues can substantially benefit from digital instruments or international cooperation. The literature review presented here has contributed to a concept of proposals for the advancement of NBS in Germany, and despite different settings, it may as well be of interest for other countries to achieve the best possible course and outcome of NBS for each child.

Caring for a Child with Congenital Adrenal Hyperplasia Diagnosed by Newborn Screening: Parental Health-Related Quality of Life, Coping Patterns, and Needs.

Diagnosing a child by newborn screening with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) causes multiple challenges for the affected parents and the whole family. We aimed to examine the health-related Quality of Life (HrQoL), coping, and needs of parents caring for a child with CAH to develop demand-responsive interventions for improving the psychosocial situation of affected families. In a retrospective cross-sectional design, we assessed HrQoL, coping patterns, and the needs of parents caring for a CAH-diagnosed child using specific questionnaires. Data of 59 families with at least one child diagnosed with CAH were analyzed. The results show that mothers and fathers in this study reached significantly higher HrQoL scores compared to reference cohorts. Decisive for the above-average parental HrQoL were effective coping behaviors and the parental needs being met. These findings verify the importance of helpful coping patterns and rapid fulfillment of parental needs for maintaining a good and stable HrQoL of parents with a child diagnosed with CAH. It is crucial to strengthen the parental HrQoL to build a reasonable basis for a healthy upbringing and improve the medical care of CAH-diagnosed children.

Sudden neonatal death in individuals with medium-chain acyl-coenzyme A dehydrogenase deficiency: limit of newborn screening.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial ß-oxidation of fatty acids resulting in hypoketotic hypoglycemia, hepatopathy, and often fatal outcome in undiagnosed children. Introduction of tandem mass spectrometry-based newborn screening programs in the late 1990s has significantly reduced morbidity and mortality in MCAD deficiency; however, neonatal death in individuals with early disease manifestation and severe hypoglycemia may still occur. We describe the fatal disease course in eight newborns with MCAD deficiency, aiming to raise awareness for early clinical symptoms and the life-saving treatment, and promote systematic post-mortem protocols for biochemical and genetic testing, necessary for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.Conclusion: Early newborn screening and awareness for clinical symptoms is lifesaving in MCAD deficiency, which may present with fatal neonatal crisis. Systematic post-mortem diagnostic protocols are needed for sudden neonatal deaths.

Long-Term Course of Hypothyroidism Detected through Neonatal TSH Screening in a Population-Based Cohort of Very Preterm Infants Born at Less than 32 Weeks of Gestation.

After several decades of successful newborn screening (NBS) for congenital hypothyroidism, the optimal hypothyroidism NBS algorithm for very preterm infants is still controversial. Due to concerns about an elevated risk of a false-negative initial thyroid-stimulation hormone (TSH) screening, repeat NBS has been implemented for this group. While transient hypothyroidism is known to be more frequent among very preterm infants, the prevalence of permanent hypothyroidism is generally assumed to be the same as in more mature newborns. This study analyses screening and long-term follow-up data from the population-based cohort of 51 infants born from 1999-2017 at less than 32 weeks of gestation and diagnosed with hypothyroidism after NBS in the German Federal State of Bavaria (total number of infants screened 2,107,864). Severe permanent hypothyroidism was always detected at initial TSH screening unless there was a known confounding factor. Cases detected by repeat screening after a negative initial screen most frequently proved to be transient, less frequently mild permanent, or a definitive diagnosis was not possible because of inadequate re-evaluation of the thyroid axis. The prevalence of both permanent and transient hypothyroidism was elevated compared to a cohort of children from the same region born at a higher gestational age. The results seem to support the need for the repeated NBS of very preterm infants. However, as the recommendation to treat mild hypothyroidism is not based on high quality evidence, important issues for future research include treatment outcome studies or even a general review of whether this diagnosis meets the screening criteria. Meanwhile, involving a paediatric endocrinologist in treatment decisions is crucial for optimising the benefit of hypothyroidism screening for this particularly vulnerable group.

Newborn screening for carnitine transporter defect in Bavaria and the long-term follow-up of the identified newborns and mothers: Assessing the benefit and possible harm based on 19 ½ years of experience.

Carnitine transporter defect (CTD) is a potentially life-threatening disorder causing acute metabolic decompensation, cardiac arrhythmia, and cardiac and skeletal myopathies. CTD is included in many newborn screening (NBS) programs. The screening parameter free carnitine, however, is influenced by maternal conditions due to placental transfer. This study reviewed the NBS results for CTD as part of a pilot study in Bavaria, Germany, and the long-term follow-up of the identified patients treated in our center between January 1999 and June 2018. Among 1,816,000 Bavarian NBS samples, six newborns were diagnosed with CTD (incidence of 1:302,667; positive predictive value (PPV) of 1.63% from 2008 to 2018). In the 24 newborns presented to our center for confirmatory testing, we detected four newborns and six mothers with CTD, one newborn and three mothers in whom CTD was presumed but not genetically confirmed, and one mother with glutaric aciduria type I. In 11 newborns, no indication for an inborn error of metabolism was found. The newborns and mothers with CTD had no serious cardiac adverse events or relevant muscular symptoms at diagnosis and during treatment for up to 14 years. Three mothers were lost to follow-up. Revealing a lower incidence than expected, our data confirm that NBS for CTD most likely misses newborns with CTD. It rather produces high numbers of false-positives and a low PPV picking up asymptomatic mothers with a diagnosis of uncertain clinical significance. Our data add to the growing evidence that argues against an implementation of CTD in NBS programs.