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Background Although immigrants are considered to be vulnerable to mental illness, there is limited knowledge regarding their suicide mortality. Aims To investigate standardised mortality ratios (SMR) for suicide among the largest immigrant populations in Germany before and after the refugee movement of 2015. Method Data on immigrants and the general population in Germany between 2000 and 2020 were provided by the scientific section of the Federal Statistical Office. SMR with 95% confidence intervals were calculated by indirect standardisation for gender, age and calendar year for the pre-2015 and post-2015 time interval, first for all the immigrant populations studied and second for the Syrian, Afghan and Iraqi populations separately. Results Immigrants from the countries studied showed a lower suicide risk compared with the German reference population (SMR = 0.38, 95% CI = 0.35–0.41). No differences in SMR were found between pre- and post-2015 time intervals, in either the aggregate data for all populations or the data for Syrian, Afghan and Iraqi populations. Post-2015, Afghan immigrants (SMR = 0.68, 95% CI = 0.54–0.83) showed a higher SMR than Syrians (SMR = 0.30, 95% CI = 0.25–0.36) or Iraqis (SMR = 0.37, 95% CI = 0.26–0.48). Conclusions Despite the many and varied stresses associated with flight, comparison of the pre- and post-2015 time intervals showed that the suicide risk of the populations studied did not change and was considerably lower than that of the German reference population. We attribute this to lower suicide rates in the countries of origin but also to flight-related selection processes that favour more resilient individuals.

ObjectiveTo evaluate the association between different types of human milk feeds and bronchopulmonary dysplasia (BPD) in preterm infants.MethodsData on dispensed mother’s own milk (MOM) and donor human milk (DHM) from Leipzig Milk Bank for hospitalized infants with a gestational age (GA) ≤32 weeks observed from birth to 36 weeks’ postmenstrual age or prior discharge were used. BPD was assessed based on documented International Statistical Classification of Diseases and Related Health Problems (ICD) diagnosis and on electronic hospital records (EHR) of data on ventilation and oxygen supplementation. Associations of dispensed milk feed variations with BPD were investigated using logistic regressions in crude and adjusted models.Results866 infants were included with a BPD prevalence of 15.4% (EHR) and 23.2% (ICD). The mean GA was 29.1 weeks. The majority (84.4%, n = 746) of infants were nurtured with a mix of MOM, DHM supplemented by formula or parenteral (other) nutrition during hospitalization. For which, MOM comprised the highest median [Q1–Q3] percentage proportion (53[31–81] %) of this mix. Exclusive fresh milk and exclusive MOM feeds were dispensed on a mean of 40 and 34% patient-days, respectively. Statistically significant associations with lower BPD incidence were only observed for 70–80% MOM vs. DHM, and 60% fresh vs. frozen milk, in crude and adjusted models.ConclusionOur findings suggest a protective association of MOM and fresh milk with lower odds of BPD, which may be dependent on the proportion of MOM or fresh milk administered. These results highlight the importance of MOM as an ideal source of nutrition during early infancy.

Abstract Background Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections. Methods A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the ‘exposed cohorts’ and ‘reference cohort’ was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC. Results Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final ‘matched’ analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3–120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9–21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts. Conclusions Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

Abstract Background Breastfeeding has long been associated with numerous benefits for both mothers and infants. While some observational studies have explored the relationship between breastfeeding and mental health outcomes in mothers and children, a systematic review of the available evidence is lacking. The purpose of this study is to systematically evaluate the association between breastfeeding and mental health disorders in mothers and children. Methods We systematically searched MEDLINE and EMBASE from inception to June 2, 2023. The inclusion criteria consisted of all studies evaluating links between breastfeeding and development of mental health disorders in children and mothers. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) while grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. A random-effects meta-analysis was used if possible, to estimate the odds ratio for the association between breastfeeding and mental health outcomes. The Mantel–Haenszel method was utilised for pooling ORs across studies. Study heterogeneity was assessed using the I 2 statistic. Results Our review identified twenty-one original study. Of these, 18 focused on the association between breastfeeding and child health, assessing depressive disorders, schizophrenia, anxiety disorders, eating disorders and borderline personality disorder. Three studies evaluated the associations between breastfeeding and maternal mental health disorders. Three studies looking at outcomes in children showed no significant association between breastfeeding and occurrence of schizophrenia later in life (OR 0.98; 95% CI 0.57–1.71; I 2 = 29%). For depressive disorders (5 studies) and anxiety disorders (3 studies), we found conflicting evidence with some studies showing a small protective effect while others found no effect. The GRADE certainty for all these findings was very low due to multiple limitations. Three studies looking at association between breastfeeding and maternal mental health, were too heterogeneous to draw any firm conclusions. Conclusions We found limited evidence to support a protective association between breastfeeding and the development of mental health disorders in children later in life. The data regarding the association between breastfeeding and maternal mental health beyond the postnatal period is also limited. The methodological limitations of the published literature prevent definitive conclusions, and further research is needed to better understand the relationship between breastfeeding and mental health in mothers and children.

Abstract Background Child overweight remains a prevalent public health concern, but the impact of maternal psychosocial stress and related constructs, the timing, and possible trajectories on child body mass index (BMI) is controversial. We aimed to investigate the association of maternal stress, depression and anxiety symptoms, and maternal hair cortisol concentrations (HCC) at delivery, 6, and 12 months postpartum with child BMI and age- and sex-standardized BMI (BMI-SDS) at age 3 years. Methods Data were derived from the Ulm SPATZ Health Study with a baseline examination between 04/2012 and 05/2013 at the University Medical Centre Ulm, Germany, the only maternity clinic in Ulm, with a good representation of the source population. Adjusted regression analyses based on BMI/BMI-SDS (dependent) and trajectories of stress, depression, and anxiety (independent variables) were investigated in 596 mothers and children. Multiple imputation of missing covariates was performed. Results Various trajectories in independent variables were identified, trajectories of maternal anxiety symptom differed between child sexes. We did not find an association between trajectories of maternal chronic stress, depression symptoms, or HCC and child BMI/BMI-SDS. However, trajectories of low-increasing maternal anxiety symptoms were linked to higher child BMI compared to a low-stable trajectory group (b = 0.58 kg/m2, 95% Confidence Interval: 0.11; 1.04) in girls. Conclusions Trajectories of maternal anxiety symptoms were associated with the child’s BMI/BMI-SDS in girls at age 3 years. However, further large scale studies should include variables to determine the causal pathway and enlighten sex-specific differences.

Abstract Background Many authors have described a significant mental health burden on children and adolescents during the COVID-19 pandemic, possibly moderated by social disparities. This analysis explores whether pre-pandemic family circumstances might be related to different aspects of child health during the pandemic. Methods We analyzed trajectories of health-related outcomes in children aged 5 to 9 years (T7 to T11) using the Ulm SPATZ Health study, a population based birth cohort study (baseline 04/2012–05/2013) conducted in the South of Germany. Outcomes were children’s mental health, quality of life, and lifestyle, such as screen time and physical activity. We conducted descriptive statistics of maternal and child characteristics before and throughout the pandemic. We defined three different groups of pre-pandemic family situations and used adjusted mixed models to estimate differences in means associated with the time during the pandemic vs. before the pandemic in (a) all children and in (b) children belonging to specific pre-pandemic family situations. Results We analyzed data from n = 588 children from whom at least one questionnaire was completed between T7 and T11. When not considering the pre-pandemic family situation, adjusted mixed models showed statistically significant lower mean scores of health-related quality of life among girls during vs. before the COVID-19 pandemic (difference in means (b): − 3.9 (95% confidence interval (CI): − 6.4, − 1.4). There were no substantial differences in mental health, screen time, or physical activity in boys or girls. When considering pre-pandemic family situations, boys with mothers having symptoms of depression or anxiety showed a substantial loss of health-related quality of life on the subscale of friends (b: − 10.5 (95% CI: − 19.7, − 1.4)). Among girls in this group, 60% of the 15 assessed outcomes were negatively associated with a remarkable loss in health-related quality of life (e.g., KINDL-physical well-being difference in means: − 12.2 (95% CI: − 18.9, − 5.4)). Furthermore, a substantial increase in screen time was found (+ 2.9 h (95% CI: 0.3, 5.6)). Conclusion Our results suggest that the health (and behavior) of primary school-aged children is possibly impacted by the COVID-19 pandemic, with adverse consequences differing by gender and very likely by the pre-pandemic family situation. Especially in girls having a mother with depression or anxiety symptoms, the adverse consequences of the pandemic on mental health seem to be aggregated. Boys showed fewer adverse trajectories, and it needs to be further assessed which factors exactly are behind the (socio-economic) factors, such as maternal working habits and limited living space, when analyzing the effect of the pandemic on children’s health.

BackgroundHuman milk banking has become an important aspect of Nutritional medicine. It is not just about the provision of mother’s own milk (MOM) or donor human milk (DHM) in the hospital, but also a strategy to encourage breastfeeding in the clinical setting and beyond.ObjectiveTo describe the feeding patterns of hospitalised infants including human milk dispensed by the Leipzig Donor Human Milk Bank (LMB).DesignA descriptive analysis of daily data on milk feeds dispensed by LMB for hospitalised infants distinguishing between MOM or DHM, either fresh or frozen, and raw/pasteurised milk from 2012–2019.ResultsWe included 2,562 infants with median hospitalisation of 23 days, for whom human milk was dispensed on median 76% of those days and other nutrition on the remaining days. Raw MOM and raw DHM comprised 52% and 8% of the dispensed milk, respectively. Dispensing exclusive DHM instead of MOM for at least one full day was required for 55% of the infants, mostly at the beginning but also later during hospitalisation. Exclusive raw DHM was dispensed on at least 1 day for 37% of the infants, in different birthweight strata 2,500 g: 3%. At discharge, MOM was dispensed for more than 60% of the infants.ConclusionDuring an infant’s hospital stay, LMB dispenses various human milk feeds with interspersed DHM resulting in complex intra-individual and time-variant feeding patterns. LMB dispenses raw MOM and especially raw DHM with the intention to retain the properties of human milk unlike a diet containing pasteurised DHM and/or formula. Although raw DHM comprises a small percentage of all dispensed milk, raw DHM is dispensed for a substantial portion of infants. Our results document that dispensing raw DHM, is possible in routine settings.

Sleep and emotions are closely associated; however, the methodological challenges in the examination of sleep and the processes of emotion regulation in children and adolescents have not been investigated so far. Additionally, there is the demand to identify the levels of emotion regulating processes in which problematic or restricted sleep causes effect. Experimental sleep deprivation as well as prevalent sleep problems have been found to have negative influence on mental health and regulating functions. This review focuses first on the methodological protocols of the included studies. Subsequently, the results are summarized in the context of a multilevel model of emotion regulation. Thereafter, suggestions for future directions are given. Sleep problems and sleep deprivation are associated with a decrease of functional emotion regulating behavior and impaired emotion generation, and prolonged sleep enhances better mood and affect states, positive emotion expression, and faster sensory processing in response to emotional stimuli. This literature review highlights the limitations in current research, focusing on types of measurements, task characteristics, and data analysis. At the conclusion, suggestions are given for the future research direction in the field of sleep and emotion regulation in children and adolescents.

Abstract Background Previous studies assessing the prevalence of COVID-19 sequelae in adults and children were performed in the absence of an agreed definition. We investigated prevalence of post-COVID-19 condition (PCC) (WHO definition), at 6- and 12-months follow-up, amongst previously hospitalised adults and children and assessed risk factors. Methods Prospective cohort study of children and adults with confirmed COVID-19 in Moscow, hospitalised between April and August, 2020. Two follow-up telephone interviews, using the International Severe Acute Respiratory and Emerging Infection Consortium survey, were performed at 6 and 12 months after discharge. Results One thousand thirteen of 2509 (40%) of adults and 360 of 849 (42%) of children discharged participated in both the 6- and 12-month follow-ups. PCC prevalence was 50% (95% CI 47–53) in adults and 20% (95% CI 16–24) in children at 6 months, with decline to 34% (95% CI 31–37) and 11% (95% CI 8–14), respectively, at 12 months. In adults, female sex was associated with PCC at 6- and 12-month follow-up (OR 2.04, 95% CI 1.57 to 2.65) and (OR 2.04, 1.54 to 2.69), respectively. Pre-existing hypertension (OR 1.42, 1.04 to 1.94) was associated with post-COVID-19 condition at 12 months. In children, neurological comorbidities were associated with PCC both at 6 months (OR 4.38, 1.36 to 15.67) and 12 months (OR 8.96, 2.55 to 34.82) while allergic respiratory diseases were associated at 12 months (OR 2.66, 1.04 to 6.47). Conclusions Although prevalence of PCC declined one year after discharge, one in three adults and one in ten children experienced ongoing sequelae. In adults, females and persons with pre-existing hypertension, and in children, persons with neurological comorbidities or allergic respiratory diseases are at higher risk of PCC.

Abstract Background The measures against the COVID-19 pandemic are challenging for children and parents, and detrimental effects on child health are suggested especially from lock-down measures and school closings. Methods We conducted a cross-sectional analysis using a population based longitudinal (birth-) cohort study (SPATZ study) conducted in the South of Germany. Data included all 6 or 7 year old children for whom a questionnaire was completed during first grade of school. Consequently, we were able to analyze children being in first grade before the first lockdown in Germany (≤ 15th March 2020), as well as children being in first grade during the pandemic (> 15th March 2020). We conducted descriptive statistics and estimated the associations between the two time periods, before and during the pandemic, and various outcomes of child health using multivariable adjusted linear or logistic regression modeling. The analysis was stratified by gender. Results Results among n = 362 children aged six or seven years showed substantially lower mean scores of health-related quality of life (difference in means: − 5.5, 95% confidence interval (CI) − 9.0, − 2.0), and higher mean scores in total emotional and behavioral difficulties (difference in means: 2.0, 95% CI 0.2, 3.8) in girls during vs. before the COVID-19 pandemic using multivariable linear regression modeling. In addition, weekly screen-time was increased in boys by 3.5 h (95% CI 0.6, 6.4). We did not find substantial differences in sleep quality, physical activity, and time spent with books, neither in boys nor in girls, however, the limited sample size has to be considered. Conclusion Child health (and behavior) of first grade school children is possibly impacted by the COVID-19 pandemic with adverse consequences possibly differing by gender.

Abstract Background A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. Main text While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. Conclusions A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.

Abstract Background Atopic diseases and behavioural difficulties in children have both been on the rise in recent decades. This study seeks to assess associations between atopic diseases and behavioural difficulties, examining the differences considering child age and how behavioural difficulties were reported (via self-report or parent-report). Methods Data on behavioural difficulties, assessed through the Strengths and Difficulties Questionnaire (SDQ), and on atopic diseases, assessed through the participant’s medical history, were available for 2701 study participants aged 3 to 18 years. Associations between atopic diseases and behavioural difficulties were evaluated using linear regression analyses. We split the study sample into two groups. I: 3-to 10-year-olds/parent-reported SDQ (n = 1764), II: 11- to 18-year-olds/parent-reported SDQ (n = 937) and self-reported SDQ (n = 915). All analyses were adjusted for age, gender, and socioeconomic status. Results In younger children, atopic dermatitis was strongly associated with higher total difficulties scores, more emotional problems and conduct problems, and more symptoms of hyperactivity/inattention. Parents reported higher total difficulties scores, more emotional problems, and more peer-relationship problems for adolescents with bronchial asthma and other allergies, whereas the adolescents themselves reported more peer relationship problems. Conclusion In younger children, atopic dermatitis is associated with internalizing and externalizing problems. In adolescents, bronchial asthma and other allergies are associated with a greater level of internalizing problems only. The findings further suggest that parents of adolescents are more likely to perceive associations between atopic diseases and behavioural difficulties than the adolescents themselves.

Abstract Background As sleep-related difficulties are a growing public health concern, it is important to gain an overview of the specific difficulty areas of the most vulnerable individuals: children. The current descriptive study presents the prevalence of sleep-related difficulties in two large samples of healthy children and adolescents and outlines the effects of age, gender, and socioeconomic status (SES) on various sleep-related difficulties. Methods Participants were 855 4–9 year-old children (child sample) and 1,047 10–17 year-old adolescents (adolescent sample) participating 2011–2015 in the LIFE Child study, a population-based cohort study in Germany. Parents of the child participants completed the Children’s Sleep Habits Questionnaire (CSHQ), whereas adolescents self-administered the Sleep Self Report (SSR). Familial SES was determined by a composite score considering parental education, occupational status, and income. Multiple regression analyses were carried out to address the research question. Results Among 4−9 year-old children, the mean bedtime was reported to be 8 p.m., the mean wake-up time 7 a.m., and sleep duration decreased by 14 min/year of age. 22.6 % of the children and 20.0 % of the adolescents showed problematic amounts of sleep-related difficulties. In the child sample, bedtime resistance, sleep onset delay, sleep-related anxiety, night waking, and parasomnia were more frequent in younger than older children. In the adolescent sample, difficulties at bedtime were more frequent among the younger adolescents, whereas daytime sleepiness was more prominent in the older than the younger adolescents. Considering gender differences, sleep-related difficulties were more frequent among boys in the child sample and among girls in the adolescent sample. Lower SES was associated with increased sleep-related difficulties in the adolescent, but not the child sample. Conclusions The present results report sleep-related difficulties throughout both childhood and adolescence. Gender differences can already be observed in early childhood, while effects of SES emerge only later in adolescence. The awareness for this circumstance is of great importance for pediatric clinicians who ought to early identify sleep-related difficulties in particularly vulnerable individuals.

Abstract Background Long-term effectiveness of asthma control medication has been shown in clinical trials but results from observational studies with children and adolescents are lacking. Marginal structural models estimated using targeted maximum likelihood methods are a novel statistiscal approach for such studies as it allows to account for time-varying confounders and time-varying treatment. Therefore, we aimed to calculate the long-term risk of reporting asthma symptoms in relation to control medication use in a real-life setting from childhood to adulthood applying targeted maximum likelihood estimation. Methods In the prospective cohort study SOLAR (Study on Occupational Allergy Risks) we followed a German subsample of 121 asthmatic children (9–11 years old) of the ISAAC II cohort (International Study of Asthma and Allergies in Childhood) until the age of 19 to 24. We obtained self-reported questionnaire data on asthma control medication use at baseline (1995–1996) and first follow-up (2002–2003) as well as self-reported asthma symptoms at baseline, first and second follow-up (2007–2009). Three hypothetical treatment scenarios were defined: early sustained intervention, early unsustained intervention and no treatment at all. We performed longitudinal targeted maximum likelihood estimation combined with Super Learner algorithm to estimate the relative risk (RR) to report asthma symptoms at SOLAR I and SOLAR II in relation to the different hypothetical scenarios. Results A hypothetical intervention of early sustained treatment was associated with a statistically significant risk increment of asthma symptoms at second follow-up when compared to no treatment at all (RR: 1.51, 95% CI: 1.19–1.83) or early unsustained intervention (RR:1.38, 95% CI: 1.11–1.65). Conclusions While we could confirm the tagerted maximum likelihood estimation to be a usable and robust statistical tool, we did not observe a beneficial effect of asthma control medication on asthma symptoms. Because of potential due to the small sample size, lack of data on disease severity and reverse causation our results should, however, be interpreted with caution.

The prospective Ulm-SPATZ study was investigated to assess the role of child sleeping quality between 4 to 6 years of age in affecting a partner’s sleeping and relationship satisfaction within a couple. The study was conducted using a triadic approach in which the child was included in the Actor-Partner-Interdependence Model (APIM). Sleeping quality of the child was determined by using the German version of the children’s sleep habits questionnaire, sleeping features of the parents were assessed by using the Munich chronotype questionnaire, and the partner relationship assessment was performed by employing the German version of the parenting stress index questionnaire. In 211 German triads, we observed that sleeping characteristics and partner relationship scores at different child ages are consistent for both men and women. Higher and statistically significant sleep duration, time spent in bed, the midpoint of sleep, time getting out of bed, and sleep onset in women compared to men during the working days were observed. The APIM analyses showed a significant direct effect of child sleep quality on the partner relationship satisfaction. In women, a mediated effect of child sleep quality acted through sleep duration and time spent in bed on the partner relationship satisfaction score during both free and working days. In men, low child sleep quality was found to be associated with increased sleep onset during both free and working days. Child sleep quality influences relationship satisfaction mostly in mothers, likely because of their higher involvement in childcare during working days. Distress in the couple could be counteracted by a major involvement of the fathers in child management.

Background: Human milk oligosaccharides (HMOs) support and concurrently shape the neonatal immune system through various mechanisms. Thereby, they may contribute to lower incidence of infections in infants. However, there is limited evidence on the role of individual HMOs in the risk of otitis media (OM), as well as lower and upper respiratory tract infections (LRTI and URTI, respectively) in children up to 2 years.Objective: To investigate whether individual HMO concentrations measured at 6 weeks of lactation were associated with risk of OM, LRTI or URTI up to 2 years in breastfed infants. Associations with OM, LRTI and URTI were determined for the most prominent human milk oligosaccharides including 13 neutral, partly isomeric structures (trioses up to hexaoses), two acidic trioses, and lactose.Design: HMO measurements and physician reported data on infections were available from human milk samples collected at 6 weeks postpartum (n = 667). Associations of HMOs with infections were assessed in crude and adjusted models using modified Poisson regression.Results: Absolute concentrations (median [min, max], in g/L) of 2′-fucosyllactose (2′-FL) tended (p = 0.04) to be lower, while lacto-N-tetraose (LNT) was higher in the milk for infants with OM in the 1st year of life (p = 0.0046). In the milk of secretor mothers, LNT was significantly higher in the milk for infants with OM (RR [95% CI]: 0.98 [0.15, 2.60]) compared to infants without OM (RR [95% CI]: 0.76 [0.14, 2.90]) at 1 year (p = 0.0019). No statistically significant milk group differences and associations were observed for OM, LRTI, and URTI (p > 0.0031).Conclusion: Our findings suggest that neither prominent neutral individual HMOs (ranging from 2′-FL to LNDFHs) nor acidic human milk sialyllactoses or lactose are significantly associated with a reduced or increased risk of infections in infants up to 2 years of age. Further research is needed to determine whether specific HMOs could potentially reduce the incidence or alleviate the course of distinct infections in early life.

Background: Research in early childhood allergy prevention (ECAP) is flourishing and new intervention strategies have proven to be promising. Due to the dynamic nature of ECAP, gaps between what is known and how guidelines inform practice are likely. A living systematic review (LSR) can narrow this gap by incorporating new evidence as it becomes available. No efficacy comparisons across various ECAP interventions for similar outcomes have been carried out. Networks of randomised clinical trials can be evaluated in the context of a network meta-analysis (NMA). We aim to establish a LSR on the efficacy and safety of any intervention investigated in randomised controlled trials (RCT) to prevent the occurrence of allergic sensitisation (AS), symptoms or diagnoses of allergic diseases in infancy and early childhood (0-3 years). Methods: A baseline SR will synthesise the evidence from existing SRs of RCTs as well as RCTs not yet considered in these. After completion of the baseline SR we propose to conduct a LSR. Using this methodology, we aim to undertake constant evidence surveillance, three-monthly search updates, and review updates every three months, should new evidence emerge. Conclusions: The ECAP evidence landscape has undergone dramatic transformations and this process is likely to continue. As a response to this, a LSR offers the potential to allow more timely synthesis of new evidence as it emerges. Long gaps between updates of SRs makes it harder for guidelines and recommendations to be up to date. Users of information, such as parents, may be confused if they encounter new evidence that is not part of a trusted guideline. A LSR approach allows us to continuously search the literature and update the evidence-base of existing ECAP interventions resulting in a decreased timespan from evidence accrual to informing clinical practice.

A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4th and 12th month of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52–28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2–56.1, p < 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.

Asthma and allergies are complex, chronic inflammatory diseases in which genetic and environmental factors are crucial. Protection against asthma and allergy development in the context of farming environment is established by early animal contact, unpasteurized milk consumption and gut microbiota maturation. The human β-defensin 2 (hBD-2) is a host defense peptide present almost exclusively in epithelial tissues, with pronounced immunomodulatory properties, which has recently been shown to ameliorate asthma and IBD in animal models. We hypothesized that adequate hBD-2 secretion plays a role in the protection against asthma and allergy development and that genetic variations in the complex gene locus coding for hBD-2 may be a risk factor for developing these diseases, if as a consequence, hBD-2 is insufficiently produced. We used MALDI-TOF MS genotyping, sequencing and a RFLP assay to study the genetic variation including mutations, polymorphisms and copy number variations in the locus harboring both genes coding for hBD-2 (DEFB4A and DEFB4B). We administered hBD-2 orally in a mouse model of house dust mite (HDM)-asthma before allergy challenge to explore its prophylactic potential, thereby mimicking a protective farm effect. Despite the high complexity of the region harboring DEFB4A and DEFB4B we identified numerous genetic variants to be associated with asthma and allergy in the GABRIELA Ulm population of 1,238 children living in rural areas, including rare mutations, polymorphisms and a lack of the DEFB4A. Furthermore, we found that prophylactic oral administration of hBD-2 significantly curbed lung resistance and pulmonary inflammation in our HDM mouse model. These data indicate that inadequate genetic capacity for hBD-2 is associated with increased asthma and allergy risk while adequate and early hBD-2 administration (in a mouse model) prevents atopic asthma. This suggests that hBD-2 could be involved in the protective farm effect and may be an excellent candidate to confer protection against asthma development.

Background Nickel allergy is the most prevalent contact allergy. It belongs to a different hypersensitivity type to asthma and rhinoconjunctivitis. The aim of this analysis was to assess whether self-reported nickel allergy is associated with incident wheezing, asthma and rhinoconjunctivitis in young German adults, taking into account potential effect modification by sex. Methods In total, 2051 (70.6%) participants aged 19–24 years took part in the second phase of SOLAR (Study on Occupational Allergy Risks), a follow-up study of ISAAC II (the second phase of the International Study of Asthma and Allergies in Childhood) in Germany. Self-reported nickel allergy, as well as having pierced ears, and the three outcomes incident wheezing, asthma and rhinoconjunctivitis, were analysed stratified for sex. Logistic regression adjusted for potential confounders was performed. Results An association between self-reported nickel allergy and incident wheezing was observed for men and women, while only in males did pierced ears show a significant association with the outcome (adjusted OR 2.26, 95% CI 1.10–4.62). Also only in males, self-reported nickel allergy was associated with elevated odds for incident asthma (adjusted OR 4.34, 95% CI 1.22–15.41). Neither in men nor in women was a significant association observed for incident rhinoconjunctivitis. Conclusion Our results suggest that self-reported nickel allergy is associated with incident wheezing. Whether this association is due to environmental or genetic predisposition, or due to an overlap of the mechanisms of type I and type IV hypersensitivity, needs to be elucidated.

Human milk oligosaccharides (HMOs) have specific dose-dependent effects on child health outcomes. The HMO profile differs across mothers and is largely dependent on gene expression of specific transferase enzymes in the lactocytes. This study investigated the trajectories of absolute HMO concentrations at three time points during lactation, using a more accurate, robust, and extensively validated method for HMO quantification. We analyzed human milk sampled at 6 weeks (n = 682), 6 months (n = 448), and 12 months (n = 73) of lactation in a birth cohort study conducted in south Germany, using label-free targeted liquid chromatography mass spectrometry (LC-MS2). We assessed trajectories of HMO concentrations over time and used linear mixed models to explore the effect of secretor status and milk group on these trajectories. Generalized linear model-based analysis was used to examine associations between HMOs measured at 6 weeks of lactation and maternal characteristics. Results: Overall, 74%, 18%, 7%, and 1% of human milk samples were attributed to milk groups I, II, III, and IV, respectively. Most HMO concentrations declined over lactation, but some increased. Cross-sectionally, HMOs presented high variations within milk groups and secretor groups. The trajectories of HMO concentrations during lactation were largely attributed to the milk group and secretor status. None of the other maternal characteristics were associated with the HMO concentrations. The observed changes in the HMO concentrations at different time points during lactation and variations of HMOs between milk groups warrant further investigation of their potential impact on child health outcomes. These results will aid in the evaluation and determination of adequate nutrient intakes, as well as further (or future) investigation of the dose-dependent impact of these biological components on infant and child health outcomes.

Free amino acids (FAAs) are important regulators of key pathways necessary for growth, development, and immunity. Data on FAAs in human milk (HM) and their roles in infant development are limited. We investigated the levels of FAAs and total amino acids (TAA, i.e., the sum of conjugated amino acids and FAAs) in HM in relation to infant and maternal characteristics and immunological conditions. FAA and TAA levels in HM sampled at 6 weeks (n = 671) and 6 months (n = 441) of lactation were determined using high-performance liquid chromatography. Child growth was ascertained at 4–5 weeks and at 6–7 months of age. Child allergy and lower respiratory tract infections were assessed in the first years of life. Associations of amino acid (AA) levels in HM with child growth and health outcomes were determined by Spearman correlation and modified Poisson regression, respectively. Free glutamine, glutamate, and serine in 6-week HM positively correlated with infant weight gain in the first 4–5 weeks of age. Maternal pre-pregnancy weight and body mass index (BMI) were negatively correlated with free glutamine and asparagine in 6-week and 6-month HM and positively correlated with the sum of TAAs in 6-month HM, but significance was lost following confounder adjustment. Free glutamine was lower in 6-month HM of mothers with an allergy (either active or non-active). No consistent associations were found between FAAs in HM and child health outcomes. However, potential negative associations were observed between specific FAAs and the risk of food allergy. These results suggest that specific FAAs play a role in infant growth. Moreover, these findings warrant further investigations into the relation of FAAs in HM with infant health outcomes and maternal allergy.

Abstract Background Recently, we have published an overview of systematic reviews in allergy epidemiology and identified asthma as the most commonly reviewed allergic disease. Building on this work, we aimed to investigate the quality of systematic reviews in asthma using the AMSTAR checklist and to provide a reference for future, more in-depth assessment of the extent of previous knowledge. Methods We included all 307 systematic reviews indexed with asthma, including occupational asthma, and/or wheeze from our previous search in PubMed and EMBASE up to December 2014 for systematic reviews on epidemiological research on allergic diseases. Topics of the included systematic reviews were indexed and we applied the AMSTAR checklist for methodological quality to all. Statistical analyses include description of lower and upper bounds of AMSTAR scores and variation across publication time and topics. Results Of 43 topics catalogued, family history, birth weight, and feeding of formula were only covered once in systematic reviews published from 2011 onwards. Overall, at least one meta-analysis was conducted for all topics except for “social determinants”, “perinatal”, “birth weight”, and “climate”. AMSTAR quality scores were significantly higher in more recently published systematic reviews, in those with meta-analysis, and in Cochrane reviews. There was evidence of variation of quality across topics even, after accounting for these characteristics. Genetic factors in asthma development were often covered by systematic reviews with some evidence of unsubstantiated updates or repetition. Conclusions We present a comprehensive overview with an indexed database of published systematic reviews in asthma epidemiology including quality scores. We highlight some topics including active smoking and pets, which should be considered for future systematic reviews. We propose that our search strategy and database could be a basis for topic-specific overviews of systematic reviews in asthma epidemiology.

PURPOSE:In utero exposure to cardiometabolic risk factors may determine health related outcomes at birth and in later life. The aim of this analysis was to describe the relationship of maternal serum uric acid (SUA) and cystatin C with maternal and neonatal cardiometabolic risk markers and with birth weight and risk of small-for-gestational age (SGA) as well as large-for gestational age (LGA). MATERIAL AND METHODS:In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm between 04/2012 and 05/2013 (overall response 49%). The association between SUA and cystatin C (both in quartiles and as continuous measures) with risk for SGA as well as with LGA was quantified by means of multivariable logistic regression. RESULTS:Overall, n = 885 mother-newborn pairs were included in the final analysis. Most of the mothers were of German nationality (85%) and were between 26 and 35 years of age at delivery (69%). Maternal SUA was associated with maternal age, body mass index, alcohol consumption and history of hypertension as well as with many other maternal and neonate cardiovascular risk markers. Cystatin C was associated with parity. No clear association of SUA with SGA and LGA was observed in fully adjusted models. However, cystatin C was negatively associated with SGA with an odds ratio (OR) of 0.35 (95% CI: 0.16-0.77; p for trend 0.04) comparing the top quartile vs. the bottom quartile and was positively associated with LGA with an OR of 5.92 (95% CI: 2.27-15.44; p for trend

The lipid fraction of human milk provides the infant with the fatty acids that are necessary for optimal growth and development. The aim of this study was to investigate the fatty acid composition of human milk at three time points during lactation and its change over time using appropriate statistical methods. Human milk samples from breastfeeding mothers at 6 weeks (n = 706), 6 months (n = 483), and 12 months (n = 81 with all three time points) were analyzed. Centered log-ratio (clr) transformation was applied to the fatty acid data. Principal component analysis (PCA) and generalized linear model-based repeated measure analysis were used to assess changes over time. The total lipid content was significantly higher at 6 months (β = 0.199, p < 0.029) and 12 months of lactation (β = 0.421, p < 0.001). The constituents of C20:3n-6 and C20:3n-3 were lower at 6 months (p < 0.001). Four distinct sub-compositional fatty acid groups were only identified at 12 months of lactation. The inclusion of small fatty acids of small constituent size in the analysis resulted in a shift in the balance between fatty acid constituents. Human milk fatty acid composition during prolonged lactation is different from that of human milk during a short duration of lactation. Our findings support the hypothesis that a combination of multiple fatty acids is important in fatty acid profiling beyond the presentation of individual fatty acids. Furthermore, the high variability of small fatty acids warrants attention because a compositional analysis may show more pronounced changes.

The objective of the study was to investigate the potential association of human milk leptin concentrations with child body mass index (BMI) and BMI trajectory patterns up to two years of age among children in the Ulm SPATZ Health Study. Leptin concentration was measured in skimmed human milk by ELISA (R&D System). Child BMI was determined at two to three days, three to four weeks, four to five months, one year, and two years of age. In SPATZ, leptin concentration at six weeks was inversely associated with child BMI at four to five weeks [beta −0.13, 95%CI −0.21;−0.05)] and at three to four months −0.12 −0.21;−0.03)]. Among infants of average BMI shortly after delivery, six week leptin was positively associated with greater increase in BMI from four to five weeks up to two years of age [0.16 (0.04;0.27)]. No associations were observed for six month leptin. Direction of association was the same in the Ulm Birth Cohort Study (UBCS), but statistically insignificant as the point estimate included the null effect value. Our results from SPATZ suggest human milk leptin may play a role in early infant growth. However, it is plausible that the lack of associations in UBCS suggest that these differences of human milk leptin composition between populations could have an impact in infant growth and development in a given population.

BACKGROUND:Numerous studies have reported associations between delivery mode and health outcomes in infancy and later life. Previous smaller studies indicated a relationship between delivery mode and newborn inflammation potentially constituting a mediating factor. We aimed to determine the influence of delivery mode and duration of labor on cord blood concentrations of adiponectin, leptin, and high-sensitivity C-reactive protein (hs-CRP). METHODS:In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm, Southern Germany, from 04/2012-05/2013. Inflammatory biomarkers were measured by ELISAs (n = 836). Delivery mode was analyzed categorically (elective cesarean (reference), active labor delivery: emergency cesarean, assisted vaginal, and spontaneous vaginal); duration of labor continuously. Following log-transformation, linear regression was used to estimate geometric means ratios (GMR) adjusted for potential confounders for the effects of delivery mode and duration of labor on each biomarker separately. Independent replication was sought in the similarly conducted Ulm Birth Cohort Study recruited from 11/2000-11/2001. RESULTS:Individually, active labor delivery modes as well as increasing duration of labor were associated with higher leptin and hs-CRP concentrations. After mutual adjustment, the associations with delivery modes were attenuated but those for duration of labor remained statistically significant (GMR (95%CI) 1.10 (1.00; 1.21) and 1.15 (1.04; 1.27) for leptin and hs-CRP per hour of labor, respectively). No significant adjusted associations were observed between delivery modes and adiponectin concentrations. These findings were replicated in an independent birth cohort study. CONCLUSIONS:Cord blood leptin and hs-CRP concentrations were associated with duration of labor rather than delivery mode. Further research is warranted to investigate these associations with additional cytokines involved in inflammatory response to delineate the inflammatory profile. Subsequently, research on determinants of these associations and their role in development of chronic disease is needed.

The increase in prevalence of asthma and atopic diseases in Western countries has been linked to aspects of microbial exposure patterns of people. It remains unclear which microbial aspects contribute to the protective farm effect.The objective of this study was to identify bacterial groups associated with prevalence of asthma and atopy, and to quantify indoor exposure to some of these bacterial groups.A DNA fingerprinting technique, denaturing gradient gel electrophoresis (DGGE), was applied to mattress dust samples of farm children and control children in the context of the GABRIEL Advanced study. Associations between signals in DGGE and atopy, asthma and other allergic health outcomes were analyzed. Quantitative DNA based assays (qPCR) for four bacterial groups were applied on the dust samples to seek quantitative confirmation of associations indicated in DNA fingerprinting.Several statistically significant associations between individual bacterial signals and also bacterial diversity in DGGE and health outcomes in children were observed. The majority of these associations showed inverse relationships with atopy, less so with asthma. Also, in a subsequent confirmation study using a quantitative method (qPCR), higher mattress levels of specifically targeted bacterial groups - Mycobacterium spp., Bifidobacteriaceae spp. and two different clusters of Clostridium spp. - were associated with a lower prevalence of atopy.DNA fingerprinting proved useful in identifying bacterial signals that were associated with atopy in particular. These findings were quantitatively confirmed for selected bacterial groups with a second method. High correlations between the different bacterial exposures impede a clear attribution of protective effects to one specific bacterial group. More diverse bacterial flora in mattress dust may link to microbial exposure patterns that protect against development of atopic diseases.

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values

Background: Research in early childhood allergy prevention (ECAP) is flourishing and new intervention strategies have proven to be promising. Due to the dynamic nature of ECAP, gaps between what is known and how guidelines inform practice are likely. A living systematic review (LSR) can narrow this gap by incorporating new evidence as it becomes available. No efficacy comparisons across various ECAP interventions for similar outcomes have been carried out. Networks of randomised clinical trials can be evaluated in the context of a network meta-analysis (NMA). We aim to establish a LSR on the efficacy and safety of any intervention investigated in randomised controlled trials (RCT) to prevent the occurrence of allergic sensitisation (AS), symptoms or diagnoses of allergic diseases in infancy and early childhood (0-3 years). Methods: A baseline SR will synthesise the evidence from existing SRs of RCTs as well as RCTs not yet considered in these. After completion of the baseline SR we propose to conduct a LSR. Using this methodology, we aim to undertake constant evidence surveillance, three-monthly search updates, and review updates every three months, should new evidence emerge. Conclusions: The ECAP evidence landscape has undergone dramatic transformations and this process is likely to continue. As a response to this, a LSR offers the potential to allow more timely synthesis of new evidence as it emerges. Long gaps between updates of SRs makes it harder for guidelines and recommendations to be up to date. Users of information, such as parents, may be confused if they encounter new evidence that is not part of a trusted guideline. A LSR approach allows us to continuously search the literature and update the evidence-base of existing ECAP interventions resulting in a decreased timespan from evidence accrual to informing clinical practice.

Background: Research in early childhood allergy prevention (ECAP) is flourishing and new intervention strategies have proven to be promising. Due to the dynamic nature of ECAP, gaps between what is known and how guidelines inform practice are likely. A living systematic review (LSR) can narrow this gap by incorporating new evidence as it becomes available. No efficacy comparisons across various ECAP interventions for similar outcomes have been carried out. Networks of randomised clinical trials can be evaluated in the context of a network meta-analysis (NMA). We aim to establish a LSR on the efficacy and safety of any intervention investigated in randomised controlled trials (RCT) to prevent the occurrence of allergic sensitisation (AS), symptoms or diagnoses of allergic diseases in infancy and early childhood (0-3 years). Methods: A baseline SR will synthesise the evidence from existing SRs of RCTs as well as RCTs not yet considered in these. After completion of the baseline SR we propose to conduct a LSR. Using this methodology, we aim to undertake constant evidence surveillance, three-monthly search updates, and review updates every three months, should new evidence emerge. Conclusions: The ECAP evidence landscape has undergone dramatic transformations and this process is likely to continue. As a response to this, a LSR offers the potential to allow more timely synthesis of new evidence as it emerges. Long gaps between updates of SRs makes it harder for guidelines and recommendations to be up to date. Users of information, such as parents, may be confused if they encounter new evidence that is not part of a trusted guideline. A LSR approach allows us to continuously search the literature and update the evidence-base of existing ECAP interventions resulting in a decreased timespan from evidence accrual to informing clinical practice.