Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Prediction of pregnancy-related complications in women undergoing assisted reproduction, using machine learning methods.

OBJECTIVE: To use machine learning methods to develop prediction models of pregnancy complications in women who conceived with assisted reproductive techniques (ART). DESIGN: A nation-wide register-based cohort study with prospectively collected data. SETTING: Swedish national registers and nationwide quality IVF register. PATIENT(S): all nulliparous women who achieved birth within the first 3 ART treatment cycles between 2008 and 2016 in Sweden. INTERVENTION(S): Characteristics before the use of ART, such as demographics and medical history, were considered potential predictors in the development of before treatment prediction models. ART treatment details were further included in after treatment prediction models. MAIN OUTCOME MEASURE(S): Potential diagnoses of preeclampsia, placental complications (previa, accreta, and abruption), and postpartum hemorrhage were identified using the International Classification of Diseases recorded in the Swedish Medical Birth and Patient registers, respectively. Multiple prediction model algorithms were performed and compared for each outcome and treatment cycle, including logistic regression, decision tree model, naïve Bayes classification, support vector machine, random forest, and gradient boosting. The performance of each model was assessed with C statistic, and nested cross-validation was used to aid model selection and hyperparameter tuning. RESULT(S): A total of 14,732 women gave birth after the first (N = 7,302), second (N = 4,688), or third (N = 2,742) ART cycle, representing birth rates of 24.1%, 23.8%, and 22.0%. Overall prediction performance did not vary much across the different methods used. In the first cycle, the before treatment prediction performance was at best 66%, 66%, and 60% for preeclampsia, placental complications, and postpartum hemorrhage, respectively. Inclusion of after treatment characteristics conferred slight improvement (approximately 1%-5%), as did prediction in later cycles (approximately 1%-5%). The top influential and consistent predictors included age, region of residence, infertility diagnosis, and type of embryo transfer (fresh or frozen) in the later (2nd and 3rd) cycles. Body mass index was a top predictor of preeclampsia and was also influential for placental complications but not for postpartum hemorrhage. CONCLUSION(S): The combined use of demographics, medical history, and ART treatment information was not enough to confidently predict serious pregnancy complications in women who conceived with ART. Future studies are needed to assess if additional longitudinal follow-up during pregnancy can improve the prediction to allow clinical protocol development.

Comorbidity Between Inflammatory Bowel Disease and Asthma and Allergic Diseases: A Genetically Informed Study.

BACKGROUND: Little is known about shared origins between inflammatory bowel disease (IBD) and allergic diseases (asthma, allergic rhinitis, and eczema). We aimed to expand current knowledge on the etiological sources of comorbidities between these disorders using a range of genetically informed methods. METHODS: Within-individual and familial co-aggregation analysis was applied to 2 873 445 individuals born in Sweden from 1987 to 2014 and their first- and second-degree relatives. Quantitative genetic modeling was applied to 38 723 twin pairs to decompose the genetic and environmental sources for comorbidity. Polygenic risk score analysis between IBD and allergic diseases was conducted in 48 186 genotyped twins, and linkage disequilibrium score regression was applied using publicly available data to explore the genetic overlap. RESULTS: IBD was associated with asthma (adjusted odds ratio [aOR], 1.35; 95% confidence interval [CI], 1.30 to 1.40), allergic rhinitis (aOR, 1.27; 95% CI, 1.20 to 1.34), and eczema (aOR, 1.47; 95% CI, 1.38 to 1.56), with similar estimates for ulcerative colitis or Crohn's disease. The ORs for familial co-aggregation decreased with decreasing genetic relatedness. Quantitative genetic modeling revealed little evidence of common genetic factors between IBD and allergic diseases (eg, IBD and allergic rhinitis; genetic correlation ra = 0.06; 95% CI, -0.03 to 0.15) but did reveal some evidence of unique environmental factors between IBD and eczema (re = 0.16; 95% CI, 0.00 to 0.32). Molecular genetic analyses were similarly null for IBD and allergic diseases, except for a slight association between Crohn's disease polygenic risk score and eczema (OR, 1.09; 95% CI, 1.06 to 1.12). CONCLUSIONS: We found little evidence to support a shared origin between IBD and any allergic disease but weak evidence for shared genetic and unique environmental components for IBD and eczema.

Comorbidities between inflammatory bowel disease (IBD) with asthma and allergic diseases have been documented, but shared origin remains unknown. Using multiple genetically informed approaches, we found little evidence of a shared origin explaining the comorbidities of IBD with asthma and allergic rhinitis but weak evidence for IBD and eczema.

Maternal mental health disorders and offspring asthma and allergic diseases: The role of child mental health.

BACKGROUND: Maternal psychological stress during pregnancy and postnatally has been shown to be associated with offspring atopic diseases (asthma, atopic dermatitis and allergic rhinitis). The aim of this study was to assess whether this association may be attributable to the child's own mental health disorders. METHOD: The study population included 15,092 twin children born 2002-2010 in Sweden. Questionnaire data at age 9 years was linked to national patient- and prescription registers. Maternal mental health during pregnancy and 3 years postnatally were identified from diagnosis and medication data (depression, anxiety and stress disorders). Atopic diseases in children were identified from questionnaires, diagnosis and medication data. Child mental health status (depression and anxiety) was identified from questionnaires. Three-way decomposition methods tested for mediation or interaction by child mental health disorders. RESULTS: Maternal mental health disorders were associated with most child atopic diseases including asthma aRR1.36 (95% CI 1.12, 1.60), and child mental health disorders, aRR1.73 (95% CI 1.56, 1.92). Children with mental health disorders were comorbid for atopic diseases with only asthma reaching statistical significance, aRR1.29 (95% CI 1.14, 1.47). Three-way decomposition found that mediation or interaction by child mental health disorders did not account for the mother mental health and child atopy associations except in parent-report asthma, where child mental health disorders mediated 13.4% (95% CI 2.1, 24.7) of the effect, but not for objectively defined (diagnosis and medication) asthma. CONCLUSION: The associations between maternal mental health and child asthma and allergic diseases do not appear to be attributable to child mental health disorders.

Use of inhaled corticosteroids and the risk of hospitalisation for pneumonia in children with asthma: a nationwide cohort study.

BACKGROUND: The potential association between the use of inhaled corticosteroids (ICS) and the risk of pneumonia among adults is disputed and paediatric-specific evidence is scarce. AIM: To assess the potential association between ICS, use and the risk of hospitalisation for pneumonia among children (age 2-17 years) with asthma. METHODS: This was a cohort study based on nationwide data from routine clinical practice in Sweden (January 2007 to November 2021). From 425 965 children with confirmed asthma, episodes of new ICS use and no use were identified using records of dispensed drugs. We adjusted for potential confounders with propensity score overlap weighting and the risk of a hospitalisation with pneumonia as primary diagnosis was estimated. Multiple subgroup and sensitivity analyses were also performed. RESULTS: We identified 249 351 ICS (mean follow-up of 0.9 years) and 214 840 no-use (mean follow-up of 0.7 years) episodes. During follow-up, 369 and 181 events of hospitalisation for pneumonia were observed in the ICS and no-use episodes, respectively. The weighted incidence rates of hospitalisation for pneumonia was 14.5 per 10 000 patient-years for ICS use episodes and 14.6 for no-use episodes. The weighted HR for hospitalisation for pneumonia associated with ICS use was 1.06 (95% CI 0.88 to 1.28) and the absolute rate difference was -0.06 (95% CI -2.83 to 2.72) events per 10 000 patient-years, compared with no use. CONCLUSIONS: In this nationwide cohort study, we found no evidence of an association between ICS use and the risk of hospitalisation for pneumonia among children with asthma, as compared with no use.

Bidirectional association between autoimmune disease and perinatal depression: a nationwide study with sibling comparison.

Although major depression, characterized by a pro-inflammatory profile, genetically overlap with autoimmune disease (AD) and the perinatal period involve immune system adaptations and AD symptom alterations, the bidirectional link between perinatal depression (PND) and AD is largely unexplored. Hence, the objective of this study was to investigate the bidirectional association between PND and AD. Using nationwide Swedish population and health registers, we conducted a nested case-control study and a matched cohort study. From 1,347,901 pregnancies during 2001-2013, we included 55,299 incident PND, their unaffected full sisters, and 10 unaffected matched women per PND case. We identified 41 subtypes of AD diagnoses recorded in the registers and compared PND with unaffected population-matched women and full sisters, using multivariable regressions. Women with an AD had a 30% higher risk of subsequent PND (95% CI 1.2-1.5) and women exposed to PND had a 30% higher risk of a subsequent AD (95% CI 1.3-1.4). Comparable associations were found when comparing exposed women with their unaffected sisters (nested case-control OR: 1.3, 95% CI 1.2-1.5, matched cohort HR: 1.3, 95% CI 1.1-1.6), and when studying antepartum and postpartum depression. The bidirectional association was more pronounced among women without psychiatric comorbidities (nested case-control OR: 1.5, 95% CI 1.4-1.6, matched cohort HR: 1.4, 95% CI 1.4-1.5) and strongest for multiple sclerosis (nested case-control OR: 2.0, 95% CI 1.6-2.3, matched cohort HR: 1.8, 95% CI 1.0-3.1). These findings demonstrate a bidirectional association between AD and PND independent of psychiatric comorbidities, suggesting possibly shared biological mechanisms. If future translational science confirms the underlying mechanisms, healthcare providers need to be aware of the increased risk of PND among women with ADs and vice versa.

Infant lung function and early skin barrier impairment in the development of asthma at age 3 years.

BACKGROUND: Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin (FLG) mutations in infancy were associated with asthma in early childhood. METHODS: From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) <0.25, and skin barrier impairment as a high TEWL >9.50 g/m2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma-like symptoms (≥3 episodes of bronchial obstruction) between age 2-3 years as well as a history of doctor-diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). RESULTS: Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). CONCLUSION: Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.

Risk of Urological Cancer Among Boys and Men Born with Hypospadias: A Swedish Population-based Study.

Background: Hypospadias is a common genital malformation among boys. Studies indicate that hypospadias is associated with a higher risk of testicular cancer. Other forms of urological cancer may be linked to hypospadias via a mutual aetiology, hormonal dysfunction, or hypospadias complications, but this has not yet been studied. Objective: To investigate the association between hypospadias and testicular cancer and the risk of other urological cancers among individuals born with hypospadias. Design setting and participants: The study used a population-based male cohort born in Sweden in 1964-2018. Exposure was hypospadias diagnosis in national registers. Outcomes were defined using the Swedish Cancer Register. An extended cohort born from 1940 was used to study cancers among older men. Biological brothers and fathers were linked to investigate familial coaggregation. Outcome measurements and statistical analysis: Associations were assessed using Cox proportional-hazards regression analysis, with results presented as hazard ratios. Results and limitations: We found that hypospadias was associated with a higher risk of testicular cancer (hazard ratio 2.04, 95% confidence interval 1.42-2.92), especially for proximal hypospadias, but did not observe any clear familial coaggregation of hypospadias and testicular cancer. Hypospadias was associated with Wilms' tumour in childhood. We also found an association between hypospadias and bladder and urethral cancers, but not prostate cancer. The number of cases with hypospadias was small and the results for cancers among older men may be impacted by limitations in register coverage. Conclusions: Our study supports the hypothesis of a higher risk of testicular cancer for men with hypospadias, especially with proximal phenotypes. Hypospadias may also be associated with a higher risk of lower urinary tract cancers, although this requires further investigation in older cohorts. Patient summary: Boys and men in whom the opening of the urethra is not at the end of the penis (called hypospadias) at birth are at higher risk of developing testicular cancer, although their overall risk is still low. They may also have a higher risk of developing other forms of cancer in the urinary tract.

Risk factors for severe respiratory syncytial virus infection during the first year of life: development and validation of a clinical prediction model.

BACKGROUND: Novel immunisation methods against respiratory syncytial virus (RSV) are emerging, but knowledge of risk factors for severe RSV disease is insufficient for optimal targeting of interventions against them. Our aims were to identify predictors for RSV hospital admission from registry-based data and to develop and validate a clinical prediction model to guide RSV immunoprophylaxis for infants younger than 1 year. METHODS: In this model development and validation study, we studied all infants born in Finland between June 1, 1997, and May 31, 2020, and in Sweden between June 1, 2006, and May 31, 2020, along with the data for their parents and siblings. Infants were excluded if they died or were admitted to hospital for RSV within the first 7 days of life. The outcome was hospital admission due to RSV bronchiolitis during the first year of life. The Finnish study population was divided into a development dataset (born between June 1, 1997, and May 31, 2017) and a temporal hold-out validation dataset (born between June 1, 2017, and May 31, 2020). The development dataset was used for predictor discovery and selection in which we screened 1511 candidate predictors from the infants', parents', and siblings' data, and developed a logistic regression model with the 16 most important predictors. This model was then validated using the Finnish hold-out validation dataset and the Swedish dataset. FINDINGS: In total, there were 1 124 561 infants in the Finnish development dataset, 130 352 infants in the Finnish hold-out validation dataset, and 1 459 472 infants in the Swedish dataset. In addition to known predictors such as severe congenital heart defects (adjusted odds ratio 2·89, 95% CI 2·28-3·65), we confirmed some less established predictors for RSV hospital admission, most notably oesophageal malformations (3·11, 1·86-5·19) and lower complexity congenital heart defects (1·43, 1·25-1·63). The prediction model's C-statistic was 0·766 (95% CI 0·742-0·789) in Finnish data and 0·737 (0·710-0·762) in Swedish validation data. The infants in the highest decile of predicted RSV hospital admission probability had 4·5 times higher observed risk compared with others. Calibration varied according to epidemic intensity. The model's performance was similar to a machine learning (XGboost) model using all 1511 candidate predictors (C-statistic in Finland 0·771, 95% CI 0·754-0·788). The prediction model showed clinical utility in decision curve analysis and in hypothetical number needed to treat calculations for immunisation, and its C-statistic was similar across different strata of parental income. INTERPRETATION: The identified predictors and the prediction model can be used in guiding RSV immunoprophylaxis in infants, or as a basis for further immunoprophylaxis targeting tools. FUNDING: Sigrid Jusélius Foundation, European Research Council, Pediatric Research Foundation, and Academy of Finland.

Neonatal screening for congenital hypothyroidism in Sweden 1980-2013: effects of lowering the thyroid-stimulating hormone threshold.

OBJECTIVE: This study aims to evaluate the neonatal screening for congenital hypothyroidism (CH) and the diagnosis CH in the national health registers and to study the effects of lowering screening thyroid-stimulating hormone (TSH) threshold on the incidence of CH and birth characteristics of screening positive and negative CH children. DESIGN: This is a nationwide register-study of all children (n = 3 427 240) in the Swedish Medical Birth Register (MBR) and national cohort for screening positive infants (n = 1577) in 1980-2013. METHODS: The study population was further linked to several other Swedish health registers. Evaluation of the CH screening and CH diagnosis was performed with levothyroxine use in the first year of life as reference. The incidence of CH was estimated by the Clopper-Pearson method. Regression models were used to study associations between CH and birth characteristics. RESULTS: The neonatal CH screening had high efficacy, but 50% of all children with a CH diagnosis were screening negative. The incidence of screening positive CH increased (1/3375 to 1/2222), and the incidence of screening negative CH decreased (1/2563 to 1/7841) after lowering the TSH screening threshold in 2009. Screening negative CH was associated with female sex, twinning, prematurity, low birth weight, birth defects, and need of neonatal intensive care, and 42% had transient disease. CONCLUSIONS: Despite high efficacy of the CH screening, 50% of children diagnosed as CH was screening negative. Although other factors influencing the incidence of the CH diagnosis cannot be ruled out, the incidence of screening negative CH decreased with lowering of the TSH threshold. Birth characteristics differed between screening positive and negative CH.

Maternal depression or anxiety during pregnancy and offspring type 1 diabetes: a population-based family-design cohort study.

INTRODUCTION: To investigate the association between maternal depression/anxiety during pregnancy and offspring type 1 diabetes, to assess the specific importance of exposure during pregnancy by comparing across different exposure periods before and/or after pregnancy, and to explore potential unmeasured familial confounding. RESEARCH DESIGN AND METHODS: This was a population-based cohort including 1 807 809 offspring born in Sweden 2002-2019. From national registers, data were available on diagnosis or medication prescription for depression/anxiety in and around pregnancy, as well as incident cases of type 1 diabetes defined through diagnosis or insulin treatment. Associations were examined using flexible parametric and Cox regression models. Familial confounding was explored using paternal exposure as a negative control and by comparing offspring exposed to maternal depression/anxiety with their unexposed siblings. RESULTS: For exposure during pregnancy, maternal depression/anxiety was associated with an increased risk of offspring type 1 diabetes onset after, but not before, 8 years of age (adjusted HR (aHR) 1.21 (95% CI 1.03 to 1.42]). Exposure occurring only during pregnancy was similarly associated to type 1 diabetes (aHR 1.24 (0.96 to 1.60)), whereas exposure occurring only before pregnancy was not (aHR 0.91 (0.64 to 1.30)). Associations were close to the null for paternal depression/anxiety (aHR 0.95 (0.72 to 1.25)), and point estimates were above 1 in sibling comparisons, although with wide CIs (aHR 1.36 (0.82 to 2.26)). CONCLUSIONS: Maternal depression/anxiety specifically during pregnancy seems to be associated with offspring type 1 diabetes. Paternal negative control and sibling comparisons indicate that the results cannot entirely be explained by familial confounding.

Genetic and environmental contributions to co-occurring physical health conditions in autism spectrum condition and attention-deficit/hyperactivity disorder.

BACKGROUND: Autism spectrum condition and attention-deficit/hyperactivity disorder (ADHD) are associated with a range of physical health conditions. The aim of this study was to examine the etiological components contributing to co-occurring physical health conditions in autism and ADHD. METHODS: In this nationwide Child and Adolescent Twin Study in Sweden, we analyzed data from 10,347 twin pairs aged 9 and 12. Clinical diagnoses of autism, ADHD, and physical health conditions were identified through the Swedish National Patient Register. Subclinical phenotypes of autism and ADHD were defined by symptom thresholds on a standardized parent-interview, the Autism-Tics, ADHD, and Other Comorbidities inventory. Associations between physical health conditions and autism/ADHD phenotypes were examined using generalized estimating equations. Bivariate twin models were applied to estimate the extent to which genetic and environmental risk factors accounted for physical health comorbidities. RESULTS: Similar patterns of association with physical health conditions were found in clinical and subclinical autism/ADHD, with odds ratios ranging from 1.31 for asthma in subclinical ADHD to 8.03 for epilepsy in clinical autism. The estimated genetic correlation (ra) with epilepsy was 0.50 for clinical autism and 0.35 for subclinical autism. In addition, a modest genetic correlation was estimated between clinical autism and constipation (ra = 0.31), functional diarrhea (ra = 0.27) as well as mixed gastrointestinal disorders (ra = 0.30). Genetic effects contributed 0.86 for mixed gastrointestinal disorders in clinical ADHD (ra = 0.21). Finally, subclinical ADHD shared genetic risk factors with epilepsy, constipation, and mixed gastrointestinal disorders (ra = 0.30, 0.17, and 0.17, respectively). LIMITATIONS: Importantly, since medical records from primary care were not included in the registry data used, we probably identified only more severe rather than the full range of physical health conditions. Furthermore, it needs to be considered that the higher prevalence of physical health conditions among autistic children and children with ADHD could be associated with the increased number of medical visits. CONCLUSIONS: Shared genetic effects contribute significantly to autism and ADHD phenotypes with the co-occurring physical health conditions across different organ systems, including epilepsy and gastrointestinal disorders. The shared genetic liability with co-occurring physical health conditions was present across different levels of autism and ADHD symptom severity.

Biological age is increased by stress and restored upon recovery.

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.

Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma.

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10-8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= -0.015, p = 2.53 × 10-9) and nominally associated in nasal samples (coefficient = -0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.

Association of maternal snuff use and smoking with Sudden Infant Death Syndrome: a national register study.

BACKGROUND: The aim was to study whether non-combustible nicotine (Swedish snuff) use in pregnancy is associated with elevated risk of post neonatal mortality, Sudden Infant Death Syndrome (SIDS), and Sudden Unexpected Infant Death (SUID) and to study how cessation before the antenatal booking influenced these risks. METHODS: This was a population-based register study of all infants with information on tobacco exposure in early pregnancy born in Sweden 1999-2019, n = 2,061,514. Self-reported tobacco use in early pregnancy was categorized as nonuse, snuff use, and moderate and heavy smoking. Multiple logistic regression models were used to estimate crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: Maternal snuff use was associated with increased risks of post neonatal mortality, SIDS, and SUID. The risks of snuff use and moderate smoking were of similar magnitude. Heavy smoking was associated with the highest risks. Cessation of smoking and snuff use before the antenatal booking was associated with lower risks of SIDS and SUID compared to that of continuous usage. CONCLUSIONS: Maternal snuff use was associated with increased risks of post neonatal mortality, SIDS, and SUID. Nicotine is the common substance in cigarette smoke and snuff. These findings support the hypothesis that nicotine contributes to an elevated risk of SIDS. IMPACT: Maternal snuff use and smoking in early pregnancy were associated with increased risks of post neonatal mortality, SIDS, and SUID. Cessation of smoking and snuff use before the first antenatal visit was associated with reduced risks of SIDS and SUID. The common substance in cigarette smoke and snuff is nicotine. Our findings suggest that nicotine contributes to an elevated risk of SIDS and SUID. The implication of our findings is that all forms of nicotine should be avoided in pregnancy.

In-utero antibiotic exposure and subsequent infections in infancy: a register-based cohort study with sibling analysis.

BACKGROUND: Prenatal antibiotic use, the ensuing maternal dysbiosis, and subsequent acquisition of altered microbiota in early life have been linked to the offspring's increased susceptibility to childhood infections. However, infection risks during the first year of life associated with in-utero antibiotic exposure have not been comprehensively explored. OBJECTIVE: To investigate the associations between exposure to antibiotics in utero and subsequent infections during infancy and whether such associations differ by antibiotic class. STUDY DESIGN: All data were retrieved from Swedish population-based registers. Singletons live-born between 2006 and 2018 were followed up from birth to their first birthday. Exposure was maternal filling of at least 1 antibiotic prescription between the last menstrual period and delivery. Outcomes were the infants' antimicrobial prescription fills, incident infections diagnosed in specialist care, and deaths with infections indicated as underlying or contributing causes ("infection-related deaths"). Birth year, birth season, maternal age, place of residence, parity, comorbidity indicator, body mass index, proxies for general health status, education level, and smoking status were considered covariates. Poisson regression was used to estimate crude and adjusted incidence rate ratios with 95% confidence intervals for the number of antimicrobial prescriptions filled to the infant. Cox regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for incident infections diagnosed in specialist care and at death. Sibling analyses were used to account for shared familial factors. Sensitivity of the results to exposure definition and perinatal factors prognostic for the outcomes were assessed in supplementary analyses. RESULTS: Of 1,347,018 infants in the full cohort, 294,657 (21.9%) were exposed to antibiotics in utero. There were 677,430 antimicrobial prescriptions filled (1.380 per 1000 person-days), 423,705 incident infections diagnosed in specialist care (0.870 per 1000 person-days), and 2800 infection-related deaths (0.006 deaths per 1000 person-days) during follow-up. Compared to unexposed, infants exposed to antibiotics in utero had higher rates of antimicrobial prescription fills (adjusted incidence rate ratio, 1.34; 95% confidence interval, 1.33-1.34), incident infections diagnosed in specialist care (adjusted hazard ratio, 1.28; 95% confidence interval, 1.27-1.29), and infection-related mortality (adjusted hazard ratio, 1.15; 95% confidence interval, 1.05-1.25). For antimicrobial prescriptions and infections diagnosed in specialist care, associations were consistent across most antibiotic classes but were attenuated in the sibling analyses: adjusted incidence rate ratio of 1.05 (95% confidence interval, 1.04-1.06) and adjusted hazard ratio of 1.05 (95% confidence interval, 1.03-1.07), respectively. No association with infant mortality was found in the sibling cohort (adjusted hazard ratio, 0.93; 95% confidence interval, 0.81-1.08). CONCLUSION: The minor associations between exposure to antibiotics in utero and infections during infancy were partly explained by shared familial factors and did not differ across frequently used antibiotic classes.

Mode of delivery and offspring atopic dermatitis in a Swedish nationwide study.

BACKGROUND: Atopic dermatitis is a common chronic childhood disease associated with significant morbidity and healthcare costs. There is a known association between caesarean section and asthma, but the relationship between caesarean section and offspring atopic dermatitis remains uncertain. METHODS: We conducted a register-based nationwide cohort study including children born in Sweden between January 2006 and December 2018. Data on health and socioeconomic variables were extracted from the national registers for children aged ≤5 years. Time-to-event analyses were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) adjusting for confounders and familial factors. RESULTS: 1,399,406 children were included (6,029,542 person-years at risk). Atopic dermatitis was observed in 17.2% of the 1,150,896 children born by vaginal delivery and 18.3% of the 248,510 born by caesarean section. The mean age of onset of atopic dermatitis was 2.72 years (SD 1.8). Birth by caesarean section was associated with a higher risk of atopic dermatitis (adj-HR 1.12, 95% CI: 1.10-1.14). A higher risk of atopic dermatitis was found in children born by instrumental vaginal delivery (adj-HR 1.10, 1.07-1.13); emergency caesarean section (adj-HR 1.12, 1.10-1.15), and elective caesarean section (adj-HR 1.13, 1.10-1.16) than uncomplicated vaginal delivery in children <1 year of age. Similar hazards were observed in those ≥1 year of age. In sibling control analysis, greater risks remained in children aged <1 year but not in age ≥1 year. CONCLUSIONS: In our study population, it was observed that children born by caesarean section or instrumental vaginal delivery were at higher risk of early childhood atopic dermatitis. Although familial confounding attenuates the risk in children aged ≥1 year, this was not observed in the first year of life.