SARS-CoV-2 sero-immunity and quality of life in children and adolescents in relation to infections and vaccinations: the IMMUNEBRIDGE KIDS cross-sectional study, 2022.

PURPOSE: The study evaluates the effects on sero-immunity, health status and quality of life of children and adolescents after the upsurge of the Omicron variant in Germany. METHODS: This multicenter cross-sectional study (IMMUNEBRIDGE Kids) was conducted within the German Network University Medicine (NUM) from July to October 2022. SARS-CoV-2- antibodies were measured and data on SARS-CoV-2 infections, vaccinations, health and socioeconomic factors as well as caregiver-reported evaluation on their children's health and psychological status were assessed. RESULTS: 497 children aged 2-17 years were included. Three groups were analyzed: 183 pre-schoolchildren aged 2-4 years, 176 schoolchildren aged 5-11 years and 138 adolescents aged 12-18 years. Positive antibodies against the S- or N-antigen of SARS-CoV-2 were detected in 86.5% of all participants (70.0% [128/183] of pre-schoolchildren, 94.3% of schoolchildren [166/176] and 98.6% of adolescents [136/138]). Among all children, 40.4% (201/497) were vaccinated against COVID-19 (pre-schoolchildren 4.4% [8/183], schoolchildren 44.3% [78/176] and adolescents 83.3% [115/138]). SARS-CoV-2 seroprevalence was lowest in pre-school. Health status and quality of life reported by the parents were very positive at the time of the survey (Summer 2022). CONCLUSION: Age-related differences on SARS-CoV-2 sero-immunity could mainly be explained by differences in vaccination rates based on the official German vaccination recommendations as well as differences in SARS-CoV-2 infection rates in the different age groups. Health status and quality of life of almost all children were very good independent of SARS-CoV-2 infection and/or vaccination. TRIAL REGISTRATION: German Registry for Clinical Trials Identifier Würzburg: DRKS00025546 (registration: 11.09.2021), Bochum: DRKS00022434 (registration:07.08.2020), Dresden: DRKS 00022455 (registration: 23.07.2020).

Comparing SARS-CoV-2 variants among children and adolescents in Germany: relative risk of COVID-19-related hospitalization, ICU admission and mortality.

PURPOSE: SARS-CoV-2 infections cause COVID-19 and have a wide spectrum of morbidity. Severe disease courses among children are rare. To date, data on the variability of morbidity in relation to variant of concern (VOC) in children has been sparse and inconclusive. We compare the clinical severity of SARS-CoV-2 infection among children and adolescents in Germany during the Wildtype and Alpha combined, Delta and Omicron phases of the COVID-19 pandemic. METHODS: Comparing risk of COVID-19-related hospitalization, intensive care unit (ICU) admission and death due to COVID-19 in children and adolescents, we used: (1) a multi-center seroprevalence study (SARS-CoV-2-KIDS study); (2) a nationwide registry of pediatric patients hospitalized with SARS-CoV-2 infections; and (3) compulsory national reporting for RT-PCR-confirmed SARS-CoV-2 infections in Germany. RESULTS: During the Delta predominant phase, risk of COVID-19-related hospitalization among all SARS-CoV-2 seropositive children was 3.35, ICU admission 1.19 and fatality 0.09 per 10,000; hence about halved for hospitalization and ICU admission and unchanged for deaths as compared to the Wildtype- and Alpha-dominant period. The relative risk for COVID-19-related hospitalization and ICU admission compared to the alpha period decreased during Delta [0.60 (95% CI 0.54; 0.67) and 0.51 (95% CI 0.42; 0.61)] and Omicron [0.27 (95% CI 0.24; 0.30) and 0.06 (95% CI 0.05; 0.08)] period except for the < 5-year-olds. The rate of case fatalities decreased slightly during Delta, and substantially during Omicron phase. CONCLUSION: Morbidity caused by SARS-CoV-2 infections among children and adolescents in Germany decreased over the course of the COVID-19 pandemic, as different VOCs) emerged.

Test-Retest Reliability and Construct Validity of the German Translation of the Gait Outcome Assessment List (GOAL) Questionnaire for Children with Ambulatory Cerebral Palsy.

The Gait Outcome Assessment List (GOAL) is a patient or caregiver-reported assessment of gait-related function across different domains of the International Classification of Functioning, Disability, and Health (ICF) developed for ambulant children with cerebral palsy (CP). So far, the questionnaire is only available in English. The aim of this study was to translate the GOAL into German and to evaluate its reliability and validity by studying the association between GOAL scores and gross motor function as categorized by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The GOAL was administered to primary caregivers of n = 91 children and adolescents with CP (n = 32, GMFCS levels I; n = 27, GMFCS level II; and n = 32, GMFCS level III) and n = 15 patients were capable of independently completing the whole questionnaire (GMFCS level I). For assessing test-retest reliability, the questionnaire was completed for a second time 2 weeks after the first by the caregivers of n = 36 patients. Mean total GOAL scores decreased significantly with increasing GMFCS levels with scores of 71 (95% confidence interval [CI]: 66.90-74.77) for GMFCS level I, 56 (95% CI: 50.98-61.86) for GMFCS level II, and 45 (95% CI: 40.58-48.48) for GMFCS level III, respectively. In three out of seven domains, caregivers rated their children significantly lower than children rated themselves. The test-retest reliability was excellent as was internal consistency given the GOAL total score. The German GOAL may serve as a much needed patient-reported outcome measure of gait-related function in ambulant children and adolescents with CP.

Risk for severe outcomes of COVID-19 and PIMS-TS in children with SARS-CoV-2 infection in Germany.

Although children and adolescents have a lower burden of SARS-CoV-2-associated disease compared to adults, assessing the risk for severe outcomes among SARS-CoV-2-infected children remains difficult due to a high rate of undetected cases. We combine data from three data sources - a national seroprevalence study (the SARS-CoV-2 KIDS study), the nationwide, state-based reporting system for PCR-confirmed SARS-CoV-2 infections in Germany, and a nationwide registry on children and adolescents hospitalized with either SARS-CoV-2 or pediatric inflammatory multisystem syndrome (PIMS-TS, also known as MIS-C) - in order to provide estimates on the risk of hospitalization for COVID-19-related treatment, intensive care admission, and death due to COVID-19 and PIMS-TS in children. The rate of hospitalization for COVID-19-related treatment among all SARS-CoV-2 seropositive children was 7.13 per 10,000, ICU admission 2.21 per 10,000, and case fatality was 0.09 per 10,000. In children without comorbidities, the corresponding rates for severe or fatal disease courses were substantially lower. The lowest risk for the need of COVID-19-specific treatment was observed in children aged 5-11 without comorbidities. In this group, the ICU admission rate was 0.37 per 10,000, and case fatality could not be calculated due to the absence of cases. The overall PIMS-TS rate was 2.47 per 10,000 SARS-CoV-2 infections, the majority being children without comorbidities. CONCLUSION: Overall, the SARS-CoV-2-associated burden of a severe disease course or death in children and adolescents is low. This seems particularly the case for 5-11-year-old children without comorbidities. By contrast, PIMS-TS plays a major role in the overall disease burden among all pediatric age groups. WHAT IS KNOWN: • SARS-CoV-2-associated burden of disease in children is considered to be low, but accurate risk estimates accounting for clinically undiagnosed infections are lacking. • Asymptomatic SARS-CoV-2 infections are common in children. WHAT IS NEW: • We provide risk estimates for hospitalization for COVID-19-related treatment, ICU admission, death from COVID-19, and PIMS-TS for children with SARS-CoV-2 infections by pooling different data sources. • The risk for PIMS-TS exceeds the risk for severe COVID-19 in all age groups; the risk for severe COVID-19 is the lowest in 5-11 years old.

Impact of School Closures on the Proportion of Children in the COVID-19 Pandemic: An Example from the Winter Lockdown in Germany.

BACKGROUND: In addition to widely used basic hygiene measures in school, school closures are applied to contain SARS-CoV-2 spread, although the effect on the pandemic is unclear. We proposed a simple approach to disentangle the effect of school closures from other lockdown measures on the pandemic course based on publicly available data in Germany. METHODS: We used data on the number of SARS-CoV-2 cases from the onset of the pandemic to 14th April 2021. We compared the proportion of children (5-14 years old) in all cases prior to the lockdown measures, including school closure, to that during a ten-week lockdown in Germany. The total number of paediatric cases occurring during lockdown was compared to the number expected in absence of school closures. The latter was calculated based on the actual weekly number of all cases and the pre-lockdown proportion of paediatric cases. RESULTS: The proportion of children in all cases was 2.3 percentage points lower at the nadir than the proportion before the lockdown. The estimated total number of paediatric cases prevented by school closures was estimated at 13,246 amounting to 24% of the expected cases in absence of school closures. CONCLUSION: School closure during the winter lockdown reduced the number of expected SARS-CoV-2 cases in children in absence of school closures. The contribution of these prevented cases to the total population incidence is small. These data might provide the basis to model the effect of school closures in addition to basic hygiene measures on the course of the COVID-19 pandemic.

Migraine and the development of additional psychiatric and pain disorders in the transition from adolescence to adulthood.

INTRODUCTION: The transition from childhood to adolescence and from adolescence to adulthood are vulnerable phases in life. In these phases, late or insufficient treatment of diseases may lead to chronification and favor development of additional disorders. In adolescents, migraine often has a highly negative impact on school performance and everyday life. The hypothesis of the present study was that adolescents with migraine have a higher risk for developing additional disorders such as psychiatric disorders or other pain syndromes in the course of the disease. MATERIALS AND METHODS: In this study, we analyzed health insurance data of 56,597 German adolescents at the age of 15 years in the year 2006. By using the International Classification of Diseases (ICD 10), we determined a group with migraine diagnosis in the year 2006 and a control group without any headache diagnosis in 2006. We then compared both groups regarding the development of additional disorders (based on the ICD 10) during the following 10 years (2007 to 2016). RESULTS: Adolescents with migraine had a 2.1 fold higher risk than persons without migraine diagnosis to develop an additional affective or mood disorder, a 1.8 fold higher risk to obtain neurotic, stress-related and somatoform disorders, a 1.8 fold higher risk to subsequently suffer from behavioral syndromes, a 1.6 higher risk to get back pain and a 1.5 fold higher risk for irritable bowel syndrome during the next 10 years. CONCLUSION: Adolescents with migraine are at risk for developing additional disorders later. Considering and addressing the patient's risks and potential medical and psychosocial problems might improve the long-term outcome significantly.

Incidence and risk factors of cerebral sinovenous thrombosis in infants.

AIM: To describe the incidence of term and preterm neonatal cerebral sinovenous thrombosis (CSVT) and identify perinatal risk factors. METHOD: This was a national capture-recapture calculation-corrected surveillance and nested case-control study. Infants born preterm and at term with magnetic resonance imaging-confirmed neonatal CSVT were identified by surveillance in all paediatric hospitals in Germany (2015-2017). Incidence was corrected for underreporting using a capture-recapture method in one federal state and then extrapolated nationwide. We reviewed PubMed for comparisons with previously reported incidence estimators. We used a population-based perinatal database for quality assurance to select four controls per case and applied univariate and multivariable regression for risk factor analysis. RESULTS: Fifty-one newborn infants (34 males, 17 females; 14 born preterm) with neonatal CSVT were reported in the 3-year period. The incidence of term and preterm neonatal CSVT was 6.6 (95% confidence interval [CI] 4.4-8.7) per 100 000 live births. Median age at time of confirmation of the diagnosis was 9.95 days (range 0-39d). In the univariate analysis, male sex, preterm birth, hypoxia and related indicators (umbilical artery pH <7.1; 5-minute Apgar score <7; intubation/mask ventilation; perinatal asphyxia), operative vaginal delivery, emergency Caesarean section, and pathological fetal Doppler sonography were associated (p<0.05) with neonatal CSVT. Multivariable regression yielded hypoxia (odds ratio=20.3; 95% CI 8.1-50.8) as the independent risk factor. INTERPRETATION: Incidence of neonatal CSVT was within the range of other population-based studies. The results suggest that hypoxia is an important perinatal risk factor for the aetiology of neonatal CSVT.

[Decrease in Group B Streptococcal Infections in Neonates: Analysis of Health Insurance Data 2005 to 2017]. / Rückgang von Infektionen durch Streptokokken der Gruppe B bei Neugeborenen: Analyse von Krankenversicherungsdaten 2005 bis 2017.

BACKGROUND: In the German guidelines for prophylaxis of group B streptococcal (GBS) early onset sepsis in neonates (EOS), GBS screening of all pregnant women has been recommended, but is not yet included in the Maternity Directives. Aim of the study was to identify temporal trends in incidence of EOS and their association to GBS Screening. METHODS: The analysis based on health insurance data of the statutory health insurance provider Barmer from 2005 to 2017 of 313,385 mother-child pairs. Annual frequency of GBS infections in newborns was determined by ICD-10 P36.0. The frequency of maternal GBS colonization was indicated by ICD-10 B95.1, which was used as surrogate for GBS screening. Temporal trends of the risk of EOS in neonates were assessed in logistic regression models. Pearson's correlation coefficient of EOS incidence and the surrogate marker for maternal GBS colonization was calculated. RESULTS: The risk of EOS in neonates caused by GBS has decreased annually by 9.3%, resulting in an overall decrease in the observation period of 72.0%. There was no statistical significant change in the risk for LOS (Late Onset Sepsis). The decrease of EOS could not be explained by temporal changes in Caesarian section, risk factors or preterm delivery. The 3.5 fold increase in the proportion of mothers with documented positive GBS colonization in the same period correlated inversely with the incidence of EOS (r=- 0.75; p=0.002). CONCLUSION: The decrease of EOS in neonates caused by GBS in Germany and the unchanged risk of LOS in neonates may be explained by the increasing application of the GBS Screening in pregnant women.

Total health insurance costs in children with a migraine diagnosis compared to a control group.

BACKGROUND: Health care costs of migraine constitute a major issue in health economics. Several publications analyzed health care costs for adult migraine patients, based on questionnaires or secondary (health insurance) data. Although migraine often starts already in primary school age, data on migraine related costs in children is scarce. In this paper we aimed to assess the migraine-related health care costs in 6 to 11 year old children in Germany. METHODS: Using claims data of a large German health insurer (BARMER), overall annual health care costs of 6 to 11 year old children with a diagnosis of migraine in 2017 (n = 2597) were compared to a control group of 6 to 11 year old children without a headache diagnosis between 2013 and 2017 (n = 306,926). The association of migraine and costs was modeled by generalized linear regression (Gamma regression) with adjustment for sex, age and comorbidities. RESULTS: Children with migraine caused considerably higher annual per capita health care costs than children without a headache diagnosis (migraine group: € 1018, control group: € 618). Excess costs directly related to migraine amounted to € 115. The remaining excess costs were related to comorbidities, which were more frequent in the migraine group. Mental and behavioural disorders constituted the most expensive comorbidity, accounting for € 105 of the € 400 annual excess costs in the migraine group. CONCLUSION: 6 to 11 year old children with a migraine diagnosis cause significant direct and comorbidity related excess costs in the German health care system.

Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie.

PURPOSE: Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany. METHODS: The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID). RESULTS: Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening. CONCLUSIONS: SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.

Safety and effectiveness of acellular pertussis vaccination during pregnancy: a systematic review.

BACKGROUND: Infants < 3 months of age are at highest risk for developing severe complications after pertussis. The majority of pregnant women has low concentrations of pertussis-specific antibodies and thus newborns are insufficiently protected by maternally transferred antibodies. Acellular pertussis vaccination during pregnancy was recently implemented in various countries. Here, we assessed the evidence for safety and effectiveness of pertussis vaccination during pregnancy. METHODS: We searched Medline, Embase, and ClinicalTrials.gov from January 1st 2010 to January 10th 2019. We assessed risk of bias (ROB) using the Cochrane ROB tool and ROBINS-I. We evaluated the quality of evidence using the GRADE approach. RESULTS: We identified 1273 articles and included 22 studies (14 for safety; 8 for effectiveness), comprising 1.4 million pregnant women in safety studies and 855,546 mother-infant-pairs in effectiveness studies. No significant differences between vaccinated and unvaccinated women and their infants were observed for safety outcomes with the exception of fever and chorioamnionitis. Compared to no vaccination, three studies showed a significantly increased relative risk for the presence of the ICD-9 code for chorioamnionitis in electronic patient data after pertussis vaccination. However, no study reported an increased risk for clinical sequelae of chorioamnionitis after vaccination during pregnancy, such as preterm birth or neonatal intensive care unit admission. Vaccine effectiveness against pertussis in infants of immunized mothers ranged from 69 to 91% for pertussis prevention, from 91 to 94% for prevention of hospitalization and was 95% for prevention of death due to pertussis. Risk of bias was serious to critical for safety outcomes and moderate to serious for effectiveness outcomes. GRADE evidence quality was moderate to very low, depending on outcome. CONCLUSION: Although an increased risk for a diagnosis of fever and chorioamnionitis was detected in pregnant women after pertussis vaccination, there was no association with a higher frequency of clinically relevant sequelae. Vaccine effectiveness for prevention of infant pertussis, hospitalization and death is high. Pertussis vaccination during pregnancy has an overall positive benefit-risk ratio. In view of the overall quality of available evidence ongoing surveillance of chorioamnionitis and its potential sequelae is recommended when pertussis vaccination in pregnancy is implemented. TRIAL REGISTRATION: PROSPERO CRD42018087814, CRD42018090357.

Risk factors for perinatal arterial ischaemic stroke: a large case-control study.

AIM: To identify maternal, obstetric, and neonatal risk factors related to perinatal arterial ischaemic stroke (PAIS) diagnosed within 28 days after birth and to understand the underlying pathophysiology. METHOD: For case and control ascertainment, we used active surveillance in 345 paediatric hospitals and a population-based perinatal database for quality assurance of hospital care. We analysed complete cases of PAIS using logistic regression. Multivariate analysis was guided by a directed acyclic graph. RESULTS: After exclusion of records with missing data, we analysed 134 individuals with PAIS and 576 comparison individuals. In univariate analysis, male sex, preterm birth (<37wks gestational age), small for gestational age (SGA), low umbilical artery pH (<7.1), low 5-minute-Apgar score (<7), multiple pregnancies, hypoxia, intubation/mask ventilation, nulliparity, Caesarean section, vaginal-operative delivery, chorioamnionitis, and oligohydramnios were associated with an increased risk. Mutual adjustment yielded male sex (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.20-2.73), multiple birth (OR 3.22; 95% CI 1.21-8.58), chorioamnionitis (OR 9.89; 95% CI 2.88-33.94), preterm birth (OR 1.86; 95% CI 1.01-3.43), and SGA (OR 3.05; 95% CI 1.76-5.28) as independent risk factors. INTERPRETATION: We confirmed the increased risk in males and the role of chorioamnionitis and SGA for PAIS, pointing to the importance of inflammatory processes and fetal-placental insufficiency. Multiple birth and preterm birth were additional risk factors. WHAT THIS PAPER ADDS: Chorioamnionitis and small for gestational age (SGA) precede perinatal arterial ischaemic stroke (PAIS). Chorioamnionitis and SGA are independent risk factors for PAIS. Inflammatory processes and fetal-placental insufficiency are the likely underlying mechanisms. Multiple birth and preterm birth are additional risk factors.

Do pre-school episodic syndromes predict migraine in primary school children? A retrospective cohort study on health care data.

OBJECTIVE: To assess the relative risk, predictive value and population attributable risk fraction of pre-school episodic syndromes for later migraine in primary school age children. METHODS: This retrospective cohort study used health insurance data on 55,035 children born in 2006 with no diagnosis of migraine up to the age of 5 years. The relative risk, probability and population attributable risk fraction of migraine prompting a physician visit at the age of 6-10 years in children with episodic syndromes included in the International Classification of Headache Disorders (benign paroxysmal torticollis, benign paroxysmal vertigo, cyclic vomiting syndrome, recurrent abdominal symptoms and abdominal migraine) and those not included in the International Classification of Headache Disorders (pavor nocturnus, somnabulism and bruxism) diagnosed up to the age of 5 years were determined. RESULTS: The period prevalence of individual episodic syndromes ranged between 0.01% and 1.40%. For episodic syndromes included in the International Classification of Headache Disorders (recurrent abdominal symptoms and abdominal migraine) and for the episodic syndromes not included in the International Classification of Headache Disorders (somnambulism), the risk for later migraine was increased by factors of 2.08, 21.87 and 3.93, respectively. The proportion of risk for migraine in primary school children explained by any episodic syndromes included in the International Classification of Headache Disorders was 2.18% and for any episodic syndromes not included in the International Classification of Headache Disorders it was 0.59%. CONCLUSION: Several pre-school episodic syndromes are risk factors for migraine in primary school age children. The fraction of migraine in primary school age children explained by prior episodic syndromes, however, is below 3%. A probability to develop primary school age migraine above 50% was only observed for abdominal migraine.

Pediatric Chronic Inflammatory Bowel Disease in a German Statutory Health INSURANCE-Incidence Rates From 2009 to 2012.

OBJECTIVE: The incidence of pediatric inflammatory bowel disease (PIBD) varies over time and geographic region. We attempted to generate incidence rates form German health insurance data. METHODS: We used health care data for 2009-2015 provided by BARMER, a major statutory health insurance company in Germany, insuring approximately 8% of the pediatric population. We applied a Canadian case definition for PIBD based on International Classification of Diseases coding, documentation of (ileo)colonoscopy and the number of PIBD related visits, without external validation for Germany. An internal validation of the specificity of the diagnosis by checking whether the identified incident cases had also prescriptions of PIPD specific drugs was performed. RESULTS: In 2012, 187 pediatric patients were newly diagnosed, accounting for an overall PIBD incidence of 17.41 (95% CI 15.08-20.10) per 100,000 insured children and adolescents from 0 to 17.9 years per year compared with 13.65/100,000 (95% CI 11.63-16.01) in 2009. The age-specific incidence showed a steep increase as of the age of 7 years. The PIBD prevalence in 2012 was 66.29/100,000. CONCLUSIONS: In conclusion, the incidence of PIBD in 0 to 17.9-year-olds in Germany with health BARMER health insurance in 2012 is among the highest reported in the literature.

[The new standard operating procedure of the German standing committee on vaccination (STIKO): history, structure, and implementation]. / Die neue Standardvorgehensweise der Ständigen Impfkommission (STIKO): Entstehung, Struktur und Umsetzung.

In Germany, the Standing Committee on Vaccination (STIKO) develops recommendations on vaccinations and other measures of specific prophylaxis against communicable diseases. Myths, wrong assumptions, and conspiracy theories are able to disturb the implementation of vaccination recommendations. Evidence and transparency of recommendations are needed to rationalize the discussion.In November 2011, STIKO adopted a new standard operating procedure (SOP) for the development of evidence-based vaccination recommendations. Following guidance provided by the SOP, a number of new vaccination recommendations have been developed since 2011. Furthermore, existing recommendations were revised or extended accordingly. This article provides an overview on the methodology of the SOP, describes experiences made so far, and characterizes future challenges.

Late-pregnancy dysglycemia in obese pregnancies after negative testing for gestational diabetes and risk of future childhood overweight: An interim analysis from a longitudinal mother-child cohort study.

BACKGROUND: Maternal pre-conception obesity is a strong risk factor for childhood overweight. However, prenatal mechanisms and their effects in susceptible gestational periods that contribute to this risk are not well understood. We aimed to assess the impact of late-pregnancy dysglycemia in obese pregnancies with negative testing for gestational diabetes mellitus (GDM) on long-term mother-child outcomes. METHODS AND FINDINGS: The prospective cohort study Programming of Enhanced Adiposity Risk in Childhood-Early Screening (PEACHES) (n = 1,671) enrolled obese and normal weight mothers from August 2010 to December 2015 with trimester-specific data on glucose metabolism including GDM status at the end of the second trimester and maternal glycated hemoglobin (HbA1c) at delivery as a marker for late-pregnancy dysglycemia (HbA1c ≥ 5.7% [39 mmol/mol]). We assessed offspring short- and long-term outcomes up to 4 years, and maternal glucose metabolism 3.5 years postpartum. Multivariable linear and log-binomial regression with effects presented as mean increments (Δ) or relative risks (RRs) with 95% confidence intervals (CIs) were used to examine the association between late-pregnancy dysglycemia and outcomes. Linear mixed-effects models were used to study the longitudinal development of offspring body mass index (BMI) z-scores. The contribution of late-pregnancy dysglycemia to the association between maternal pre-conception obesity and offspring BMI was estimated using mediation analysis. In all, 898 mother-child pairs were included in this unplanned interim analysis. Among obese mothers with negative testing for GDM (n = 448), those with late-pregnancy dysglycemia (n = 135, 30.1%) had higher proportions of excessive total gestational weight gain (GWG), excessive third-trimester GWG, and offspring with large-for-gestational-age birth weight than those without. Besides higher birth weight (Δ 192 g, 95% CI 100-284) and cord-blood C-peptide concentration (Δ 0.10 ng/ml, 95% CI 0.02-0.17), offspring of these women had greater weight gain during early childhood (Δ BMI z-score per year 0.18, 95% CI 0.06-0.30, n = 262) and higher BMI z-score at 4 years (Δ 0.58, 95% CI 0.18-0.99, n = 43) than offspring of the obese, GDM-negative mothers with normal HbA1c values at delivery. Late-pregnancy dysglycemia in GDM-negative mothers accounted for about one-quarter of the association of maternal obesity with offspring BMI at age 4 years (n = 151). In contrast, childhood BMI z-scores were not affected by a diagnosis of GDM in obese pregnancies (GDM-positive: 0.58, 95% CI 0.36-0.79, versus GDM-negative: 0.62, 95% CI 0.44-0.79). One mechanism triggering late-pregnancy dysglycemia in obese, GDM-negative mothers was related to excessive third-trimester weight gain (RR 1.72, 95% CI 1.12-2.65). Furthermore, in the maternal population, we found a 4-fold (RR 4.01, 95% CI 1.97-8.17) increased risk of future prediabetes or diabetes if obese, GDM-negative women had a high versus normal HbA1c at delivery (absolute risk: 43.2% versus 10.5%). There is a potential for misclassification bias as the predominantly used GDM test procedure changed over the enrollment period. Further studies are required to validate the findings and elucidate the possible third-trimester factors contributing to future mother-child health status. CONCLUSIONS: Findings from this interim analysis suggest that offspring of obese mothers treated because of a diagnosis of GDM appeared to have a better BMI outcome in childhood than those of obese mothers who-following negative GDM testing-remained untreated in the last trimester and developed dysglycemia. Late-pregnancy dysglycemia related to uncontrolled weight gain may contribute to the development of child overweight and maternal diabetes. Our data suggest that negative GDM testing in obese pregnancies is not an "all-clear signal" and should not lead to reduced attention and risk awareness of physicians and obese women. Effective strategies are needed to maintain third-trimester glycemic and weight gain control among otherwise healthy obese pregnant women.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

Long-lasting cough in an adult German population: incidence, symptoms, and related pathogens.

Studies of the incidence of pertussis in adults have shown that it accounts for only 5-15% cases of prolonged coughing. We assessed the burden of suffering related to prolonged coughing and tried to identify further causative agents. Based on a sentinel study with 35 general practitioners in two German cities (Krefeld, Rostock), with 3,946 patients fulfilling the inclusion criteria, we estimated the incidence of prolonged coughing in adults. In 975 of these outpatients, PCR and/or serology for adenovirus, Bordetella pertussis and B. parapertussis, human metapneumovirus, influenza virus A and rhinovirus, parainfluenza virus, Mycoplasma pneumonia, and respiratory syncytial virus (RSV) were performed. Treatment data were extracted for a subgroup of 138 patients. Descriptive statistics, including Kaplan-Maier curves were generated. Yearly incidence ranged between 1.4 and 2.1% per population in the two cities. Adult patients sought medical attention only after a median of 3 weeks of coughing. Irrespective of smoking and unrelated to the identified pathogens, the median duration of coughing was 6 weeks, with an interquartile range of 4-11 weeks. In 48.3% of patients, possible pathogens were identified, among which adenovirus (15.1%), RSV (7.5%), B. pertussis (5.6%), and influenza viruses (4.0%) were most often found. Symptoms were not indicative of a specific agent and a total of 64% of patients received antibiotics. Prolonged adult coughing requiring medical attention prompts substantial healthcare use. Apart from B. pertussis, a broad range of pathogens was associated with the symptoms. However, patients sought medical attention too late to guide efficacious therapeutic interventions using the diagnostic tests.

Symptom patterns in childhood arterial ischemic stroke: Analysis of a population-based study in Germany.

HINTERGRUND: Die zeitliche Verzögerung zwischen Symptombeginn und Diagnose ist eine Herausforderung in der Behandlung von Kindern mit arteriell ischämischem Schlaganfall. Frühere Studien zur klinischen Präsentation beschäftigten sich v. a. mit kumulativen Symptomen. ZIELSETZUNG: Ziel dieser Studie ist es, mögliche Symptommuster aufzuzeigen. METHODEN: In einer aktiven Beobachtungsstudie zwischen 01/2015 und 12/2016 (ESPED-Studie) wurden Kinder mit Erstdiagnose eines arteriell ischämischen Schlaganfalls eingeschlossen. Isoliert auftretende Erstsymptome wurden verschiedenen Symptomkombinationen gegenübergestellt. Zudem wurde untersucht, inwieweit ein als "akut" oder "progredient" klassifiziertes Auftreten der Symptome Rückschlüsse auf die zugrundeliegende Ätiologie erlaubt. ERGEBNISSE: Es wurden 99 Kinder in die Studie eingeschlossen. Unabhängig vom Alter traten überwiegend fokale Symptome auf (86%). Krampfanfälle als Initialsymptom wurden insbesondere bei Säuglingen beschrieben (67%), wohin-gegen diffuse, unspezifische Symptome vor allem bei Vorschulkindern (38%) und älteren Kindern (59%) auftraten. Isoliert traten fokale Symptome bei 37 Kindern auf, 48 Kinder zeigten zusätzlich unspezifische Symptome, darunter auch 9 Kinder mit Krampfanfällen. Isolierte unspezifische Symptome zeigten sich lediglich bei 7 Kindern, 2 Kinder wurden nur mit Krampfanfällen symptomatisch. Die Akuität des Symptombeginns wurde bei 53/78 als "akut" und bei "25/78 Fällen als "progredient" klassifiziert, lieferte jedoch keinen Hinweis auf die zugrundeliegende Ätiologie. SCHLUSSFOLGERUNG: Jedes neue fokal neurologische Defizit sollte unabhängig vom Auftreten (isoliert oder kombiniert, akut oder progredient) an einen kindlichen Schlaganfall denken lassen. BACKGROUND: Time delay between onset of clinical symptoms and diagnosis is a challenge in childhood arterial ischemic stroke. Most previous studies reported cumulative symptoms. OBJECTIVE: We attempted to identify typical symptom patterns and assessed their emergence in childhood stroke. METHODS: Prospective active surveillance in ESPED, a hospital based Pediatric Surveillance Unit for rare diseases in Germany, between January 2015 and December 2016. Case definition: first diagnosis of a radiologically confirmed arterial ischemic stroke. Symptom patterns were identified as occurring in isolation or in combination. We distinguished acute vs. progressive onset. We ascertained risk factors to identify the possible etiology. RESULTS: 99 children with childhood arterial ischemic stroke were reported. Focal symptoms were the predominant presenting feature (86%), independent of age. Seizures were more often seen in infants < 1 year (67%), whereas diffuse symptoms were more present in pre-school children (38%) and older children (59%). 37 children had focal features alone and 48 additional non-specific features, including 9 with seizures. Isolated non-specific features accounted for 7 cases, and 2 children had (focal) seizures as the only symptom. In 77% of all cases at least one risk factor was identified. The emergence of symptoms was acute in 53/78 cases and progressive in 25/78 cases. The pattern of emergence was unrelated to the underlying etiology. CONCLUSIONS: Any new focal neurological deficit in isolation, or associated with seizures or further non-specific symptoms should alert to childhood stroke.

Health-Related Quality of Life of Children/Adolescents with Vertigo: Retrospective Study from the German Center of Vertigo and Balance Disorders.

Purpose To assess the impact of vertigo on health-related quality of life (HrQoL) of children/adolescents and to assess if the impact on HrQoL varies by age group, gender, and type of vertigo diagnoses. Methods A retrospective analysis was performed on the clinical and HrQoL data of children and adolescents referred to the German Center of Vertigo and Balance Disorders (n = 32; male = 17; female = 15; age range: 8-18 years), using the KIDSCREEN-52 questionnaire. For each scale, means of the Z-scores with 95% confidence intervals of the study and norm sample were compared. By nonparametric Kruskal-Wallis statistics differences between diagnostic groups were assessed. To assess the gender- and age-specific impact of vertigo on quality of life, Wilcoxon signed-rank test was used. Results The means of the physical well-being, psychological well-being, autonomy scale, and the general HrQoL index of patients were considerably lower than the means of the norm sample. The physical well-being seemed to be most affected by vertigo. The reduction of HrQoL was not related to gender and vertigo types but seemed to be higher in children suffering from vertigo aged 12 to 18 years than children aged 8 to 11 years. Conclusion These are the first data to demonstrate impaired HrQoL in children with chronic vertigo.