Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since motor neuron injury is usually not reversible, early diagnosis and treatment are essential to prevent ...major disability. Our objective was to assess the impact of genetic newborn screening for SMA on outcome.
We provided clinical data from 43 SMA patients, identified via polymerase chain reaction of the SMN1 gene from dried blood spots between January 2018 and January 2020 in Germany. Follow-up included neurophysiological examinations and standardized physiotherapeutic testing.
Detection of SMA with newborn screening was consistent with known incidence in Germany. Birth prevalence was 1:6910; 39.5% had 2 SMN2 copies, 23% had 3 SMN2 copies, 32.5% had 4 copies, and 4.5% had 5 copies of the SMN2 gene. Treatment with SMA-specific medication could be started at the age of 14-39 days in 21 patients. Pre-symptomatically treated patients remained throughout asymptomatic within the observation period. 47% of patients with 2 SMN2 copies showed early, presumably intrauterine onset of disease. These patients reached motor milestones with delay; none of them developed respiratory symptoms. Untreated children with 2 SMN2 copies died. Untreated children with 3 SMN2 copies developed proximal weakness in their first year. In patients with ≥ 4 SMN2 copies, a follow-up strategy of "watchful waiting" was applied despite the fact that one of them was treated from the age of 6 months. Two infant siblings with 4 SMN2 copies were identified with a missed diagnosis of SMA type 3.
Identification of newborns with infantile SMA and prompt SMA-specific treatment substantially improves neurodevelopmental outcome, and we recommend implementation in the public newborn screening in countries where therapy is available. Electrophysiology is a relevant parameter to support the urgency of therapy. There has to be a short time interval between a positive screening result and referral to a therapy-ready specialized treatment center.
The efficacy of the BioNTech-Pfizer BNT162b2 vaccination in the elderly (greater than or equal to80 years) could not be fully assessed in the BioNTech-Pfizer trial due to low numbers in this age ...group. We aimed to evaluate the effectiveness of the BioNTech-Pfizer (BNT162b2) vaccine to prevent SARS-CoV-2 infection and severe outcomes in octo- and novo-generians in a German state setting. A prospective observational study of 708,187 persons aged greater than or equal to80 years living in Bavaria, Germany, was conducted between Jan 9 to Apr 11, 2021. We assessed the vaccine effectiveness (VE) for two doses of the BNT162b2 vaccine with respect to SARS-CoV-2 infection and related hospitalisations and mortality. Additionally, differences in VE by age groups greater than or equal to80 to less than or equal to89 years and greater than or equal to90 years were studied. Analyses were adjusted by sex. By the end of follow-up, 63.8% of the Bavarian population greater than or equal to80 years had received one dose, and 52.7% two doses, of the BNT162b2 vaccine. Two doses of the BNT162b2 vaccine lowered the proportion of SARS-CoV-2 infections and related outcomes, resulting in VE estimates of 68.3% (95% confidence interval (CI) 65.5%, 70.9%) for infection, 73.2% (95% CI 65.3%, 79.3%) for hospitalisation, and 85.1% (95% CI 80.0%, 89.0%) for mortality. Sex differences in the risk of COVID-19 outcomes observed among unvaccinated persons disappeared after two BNT162b2 vaccine doses. Overall, the BNT162b2 vaccine was equally effective in octo- and novo-genarians. Two doses of BioNTech-Pfizer's BNT162b2 vaccine is highly effective against COVID-19 outcomes in elderly persons.
Newborn screening for cystic fibrosis (CF-NBS) was introduced in Germany in 2016. Currently, systematic follow-up of positive CF-NBS results is not implemented or reimbursed in the NBS program. We ...investigated results of confirmatory testing over 24 months after implementation of CF-NBS for a large German NBS center before and after introduction of an active tracking system and performed a cost calculation for tracking. Results are compared with the federal state of Bavaria, where a centralized tracking system has been in place for many years. At the NBS center, 244 of 281,907 children had a positive CF-NBS result requiring diagnostic confirmation. Before implementation of a telephone tracking system, only 43% of confirmatory results were returned despite repeated written requests. The consecutive strategy including telephone tracking led to an increase of resolved cases to 84%. However, the centralized tracking system in Bavaria, assigning children with positive CF-NBS directly to a responsible CF-center, resolved 99% of cases. The calculated additional cost for a tracking system in Germany including telephone tracking is 1.20€ per newborn screened.
Conclusion
: The implementation of a tracking system achieves a distinct improvement in CF-NBS with justifiable costs. The effect can be limited by absence of centralized organization of confirmatory testing.
What is Known:
• Newborn screening for cystic fibrosis (CF-NBS) has been performed for many years in several countries worldwide
• While many studies have focused on different CF-NBS strategies, the organization of confirmatory testing and process quality concerning returned information to the NBS center has so far received less attention.
What is New:
• The implementation of an active tracking system achieves a distinct improvement of clarified cases after positive CF-NBS with justifiable costs.
• The effect of a tracking system can be limited by the absence of a centralized organization of confirmatory testing.
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial β-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.
What is Known:
• Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency identified by newborn screening has an excellent outcome.
• Fatal neonatal crises occur in the first days prior to screening.
What is New:
• Poor feeding, no monitoring of blood glucose, and homozygosity of the common gene variant (c.985A > G) are major risk factors for fatal neonatal crisis in MCAD deficiency.
• Post-mortem diagnostic protocols are indispensable for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.
Obesity in pregnancy and related early-life factors place the offspring at the highest risk of being overweight. Despite convincing evidence on these associations, there is an unmet public health ...need to identify "high-risk" offspring by predicting very early deviations in weight gain patterns as a subclinical stage towards overweight. However, data and methods for individual risk prediction are lacking. We aimed to identify those infants exposed to obesity in pregnancy at ages 3 months, 1 year, and 2 years who likely will follow a higher-than-normal body mass index (BMI) growth trajectory towards manifest overweight by developing an early-risk quantification system.
This study uses data from the prospective mother-child cohort study Programming of Enhanced Adiposity Risk in CHildhood-Early Screening (PEACHES) comprising 1671 mothers with pre-conception obesity and without (controls) and their offspring. Exposures were pre- and postnatal risks documented in patient-held maternal and child health records. The main outcome was a "higher-than-normal BMI growth pattern" preceding overweight, defined as BMI z-score >1 SD (i.e., World Health Organization WHO cut-off "at risk of overweight") at least twice during consecutive offspring growth periods between age 6 months and 5 years. The independent cohort PErinatal Prevention of Obesity (PEPO) comprising 11,730 mother-child pairs recruited close to school entry (around age 6 years) was available for data validation. Cluster analysis and sequential prediction modelling were performed.
Data of 1557 PEACHES mother-child pairs and the validation cohort were analyzed comprising more than 50,000 offspring BMI measurements. More than 1-in-5 offspring exposed to obesity in pregnancy belonged to an upper BMI z-score cluster as a distinct pattern of BMI development (above the cut-off of 1 SD) from the first months of life onwards resulting in preschool overweight/obesity (age 5 years: odds ratio OR 16.13; 95% confidence interval CI 9.98-26.05). Contributing early-life factors including excessive weight gain (OR 2.08; 95% CI 1.25-3.45) and smoking (OR 1.94; 95% CI 1.27-2.95) in pregnancy were instrumental in predicting a "higher-than-normal BMI growth pattern" at age 3 months and re-evaluating the risk at ages 1 year and 2 years (area under the receiver operating characteristic AUROC 0.69-0.79, sensitivity 70.7-76.0%, specificity 64.7-78.1%). External validation of prediction models demonstrated adequate predictive performances.
We devised a novel sequential strategy of individual prediction and re-evaluation of a higher-than-normal weight gain in "high-risk" infants well before developing overweight to guide decision-making. The strategy holds promise to elaborate interventions in an early preventive manner for integration in systems of well-child care.
Zusammenfassung
Hintergrund
Das Neugeborenen-Hörscreening (NHS) wurde 2009 durch den Gemeinsamen Bundesausschuss (G-BA) mit Aufnahme in die Kinder-Richtlinie bundesweit eingeführt. Dabei wurden in ...der Kinder-Richtlinie auch Qualitätsziele festgelegt. Um die Qualität des NHS in Deutschland zu überprüfen, hat der G‑BA eine Bietergemeinschaft mit einer ersten Evaluation für die Jahre 2011/2012 und einer Folge-Evaluation für 2017/2018 beauftragt.
Methoden
Grundlage der Evaluationen waren Sammelstatistiken, die von allen geburtshilflichen und neonatologischen Abteilungen, als Leistungserbringer des NHS, geführt werden müssen und ggf. in Kooperation mit Hörscreening-Zentralen (HSZ) erstellt werden. Zusätzliche Daten wurden durch Fragebögen und Interviews erhoben und durch Routinedaten ergänzt, um den vollständigen Screeningprozess zu evaluieren.
Ergebnisse
In 13 Bundesländern sind insgesamt 15 HSZ in den Screeningprozess eingebunden. Deutschlandweit wurde 2018 eine Screeningrate von 86,1 % (2012: 82,4 %) dokumentiert, die sich deutlich zwischen den Bundesländern unterschied. Die vorgegebenen Qualitätsziele konnten noch nicht überall umgesetzt werden. So erreichten nur knapp die Hälfte der Geburtsabteilungen die angestrebte Screeningrate von über 95 %. Beim Vergleich der Folge-Evaluation mit den Daten der ersten Evaluation konnte gezeigt werden, dass sich die Strukturqualität des NHS verbessert hatte, während die Prozessqualität eher gleich blieb oder schlechter geworden war, verdeutlicht insbesondere durch einen Anstieg der Refer-Rate (Kinder, die mit einem auffälligen Befund entlassen wurden) von 5,3 % auf 6,0 %.
Diskussion
Zur Verbesserung der Qualität des NHS sollten flächendeckend HSZ etabliert und – wie in der Richtlinie vorgesehen – bei auffälligem Erstscreening ein zweites Screening noch vor Entlassung konsequenter durchgeführt werden.
Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The study was conducted to assess the impact of early detection of SMA by newborn screening (NBS) on the ...clinical course of the disease.
Screening was performed in two federal states of Germany, Bavaria and North Rhine Westphalia, between January 2018 and February 2019. The incidence in the screening population was calculated as number of detected patients with a homozygous deletion in the SMN1-gene per number of screened patients. To get an idea about the incidence of newly diagnosed SMA in the year prior to screening a survey covering all neuropediatric centers in the state of Bavaria was conducted, identifying all SMA-cases in 2017 and 2018. Following positive NBS and confirmatory diagnostic test, treatment was advised according to the recommendations of the "American SMA NBS Multidisciplinary Working Group". Immediate treatment with Nusinersen was recommended in children with 2 and 3 SMN2 copies and a conservative strict follow-up strategy in children with ≥4 copies. All children underwent regular standardized neuropediatric examination, CHOP INTEND and HINE-2 testing as well as electrophysiological exams every 2-3 months.
165,525 children were screened. 22 cases of SMA were identified, meaning an incidence rate of 1:7524. SMN2 copy number analysis showed 2 SMN2 copies in 45% of patients, 3 SMN2 copies in 19 % and 4 SMN2 copies in 36%. These findings are confirmed in the most recent statistical data-cut from 31st August 2019 (incidence 1:7089, 2 SMN2 copies in 44%, 3 in 15% and 4 in 38%). Comparison with up-to-date German data on SMA incidence and the Bavarian survey give evidence that NBS did not lead to a relevant increase in incidence. 10 patients with 2 or 3 SMN2 copies were treated with Nusinersen, starting between 15- 39 days after birth, in 7/10 patients before onset of symptoms. Presymptomatically treated patients (age at last examination: 1- 12 months, median 8 months) showed no muscle weakness by the age of one month to one year. One child with 4 SMN2 copies became symptomatic at the age of 8 months.
Newborn screening, resulting in presymptomatic treatment, improves outcome in children with genetically proven SMA. Newborn screening for SMA should be introduced in all countries where therapy is available. An immediate therapy in cases with 4 SMN2 copies should be considered.
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.
Concerns about smoking displacement from public places to private amenities aroused following smoking ban implementation in Bavaria in 2008. We analysed children's exposure to second-hand smoke (SHS) ...before and after the ban, its effect on children's health and prevalence of active smoking in adults.
Six cross-sectional surveys (n = 32,443) on pre-school children in Bavaria were analysed, two surveys before the smoking ban in years 2004 and 2005 (S1 and S2) and four after the ban in 2008, 2012, 2014 and 2016 (S4, S6, S7 and S8). Using multivariable logistic regression, we analysed change in children's intra- and extrauterine SHS exposure and its adverse health effects (Asthma, wheezing, bronchitis and neurodermatitis) as well as change in parental active smoking.
The response rates were 78% for S1, 73% for S2, 61% for S4, 62% for S6, 56% for S7 and 54% for S8. Odds of parents never smoked at home in presence of children increased significantly from before to after the ban with odds ratios (OR) 1.17 (CI
1.01-1.35), 1.65 (CI
1.39-1.95), 2.85 (CI
2.32-3.51), 2.24 (CI
1.84-2.72) and 3.66 (CI
2.89-4.63) for S2, S4, S6, S7 and S8, respectively with S1 as reference. Compared to S4, odds of parents who were not actively smoking is significantly higher in S7 (OR = 1.13 (CI
1.03-1.24)) and S8 (OR = 1.24 (CI
1.13-1.36)). The odds of mothers who never smoked during pregnancy increased over time with OR = 1.22 (CI
1.06-1.40) for S2 and 1.57 (CI
1.33-1.86) for S8 compared to S1. Adverse health effects related to children's exposure to SHS are significantly less in S8 compared to S1.
After 11 years of smoking ban in Bavaria, smoking displacement to homes was disproved. Exposure of children to SHS intrauterine and at home is decreasing. Number of parents who are not actively smoking is increasing over time. Prevalence of health problems in children related to exposure to SHS is decreasing.
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