Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity.

Childhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.

DNA methylation changes in cord blood and the developmental origins of health and disease - a systematic review and replication study.

BACKGROUND: Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance. METHODS: We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data. RESULTS: We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts. CONCLUSIONS: Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants' methylome.

Assessing secondhand and thirdhand tobacco smoke exposure in Canadian infants using questionnaires, biomarkers, and machine learning.

BACKGROUND: As smoking prevalence has decreased in Canada, particularly during pregnancy and around children, and technological improvements have lowered detection limits, the use of traditional tobacco smoke biomarkers in infant populations requires re-evaluation. OBJECTIVE: We evaluated concentrations of urinary nicotine biomarkers, cotinine and trans-3'-hydroxycotinine (3HC), and questionnaire responses. We used machine learning and prediction modeling to understand sources of tobacco smoke exposure for infants from the CHILD Cohort Study. METHODS: Multivariable linear regression models, chosen through a combination of conceptual and data-driven strategies including random forest regression, assessed the ability of questionnaires to predict variation in urinary cotinine and 3HC concentrations of 2017 3-month-old infants. RESULTS: Although only 2% of mothers reported smoking prior to and throughout their pregnancy, cotinine and 3HC were detected in 76 and 89% of the infants' urine (n = 2017). Questionnaire-based models explained 31 and 41% of the variance in cotinine and 3HC levels, respectively. Observed concentrations suggest 0.25 and 0.50 ng/mL as cut-points in cotinine and 3HC to characterize SHS exposure. This cut-point suggests that 23.5% of infants had moderate or regular smoke exposure. SIGNIFICANCE: Though most people make efforts to reduce exposure to their infants, parents do not appear to consider the pervasiveness and persistence of secondhand and thirdhand smoke. More than half of the variation in urinary cotinine and 3HC in infants could not be predicted with modeling. The pervasiveness of thirdhand smoke, the potential for dermal and oral routes of nicotine exposure, along with changes in public perceptions of smoking exposure and risk warrant further exploration.

Maternal Metabolic Complications in Pregnancy and Offspring Behavior Problems at 2 Years of Age.

Objectives Prenatal maternal metabolic problems such as pre-pregnancy adiposity, excess gestational weight gain, and gestational diabetes mellitus (GDM) are associated with an increased risk of psychopathology in offspring. We examined whether these exposures were linked to symptoms of emotional and behavioral problems in offspring at 2 years of age, or if associations were due to confounding variables. Methods Data from 815 mother-child pairs enrolled at the Edmonton site of the Canadian Healthy Infant Longitudinal Development cohort were used to examine associations between gestational metabolic complications and scores on the externalizing and internalizing scales of the Child Behavior Checklist (CBCL-1½ to 5) at age two. Associations between maternal metabolic complications and offspring psychopathology were assessed before and after adjustment for gestational diet, socioeconomic status (SES), postpartum depression (PPD), prenatal smoking and breastfeeding. Results Pre-pregnancy body mass index and GDM, but not gestational weight gain, predicted more offspring externalizing and internalizing problems. However, after adjustment for confounding variables, these associations were no longer statistically significant. Post-hoc analyses revealed that gestational diet accounted for unique variance in both externalizing (semi-partial rdiet = - 0.20, p < 0.001) and internalizing (semi-partial rdiet = - 0.16, p = 0.01) problems. PPD and SES also accounted for a similar amount of variance for both externalizing (semi-partial rPPD = 0.17, p < 0.001; rses = - 0.11, p = 0.03) and internalizing problems (semi-partial rPPD = 0.21, p < 0.001; rses = - 0.14, p = 0.004). Conclusions for Practice Since the confounding effect of gestational diet persisted after adjustment for, and was similar in magnitude to, SES and PPD, future research should consider the impact of unhealthy prenatal diets on offspring neurodevelopment.

Ventilation inhomogeneity in infants with recurrent wheezing.

BACKGROUND: The care of infants with recurrent wheezing relies largely on clinical assessment. The lung clearance index (LCI), a measure of ventilation inhomogeneity, is a sensitive marker of early airway disease in children with cystic fibrosis, but its utility has not been explored in infants with recurrent wheezing. OBJECTIVE: To assess ventilation inhomogeneity using LCI among infants with a history of recurrent wheezing compared with healthy controls. METHODS: This is a case-control study, including 37 infants with recurrent wheezing recruited from outpatient clinics, and 113 healthy infants from a longitudinal birth cohort, the Canadian Healthy Infant Longitudinal Development study. All infants, at a time of clinical stability, underwent functional assessment including multiple breath washout, forced expiratory flows and body plethysmography. RESULTS: LCI z-score values among infants with recurrent wheeze were 0.84 units (95% CI 0.41 to 1.26) higher than healthy infants (mean (95% CI): 0.26 (-0.11 to 0.63) vs -0.58 (-0.79 to 0.36), p<0.001)). Nineteen percent of recurrently wheezing infants had LCI values that were above the upper limit of normal (>1.64 z-scores). Elevated exhaled nitric oxide, but not symptoms, was associated with abnormal LCI values in infants with recurrent wheeze (p=0.05). CONCLUSIONS: Ventilation inhomogeneity is present in clinically stable infants with recurrent wheezing.

Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms.

OBJECTIVE: Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age. METHODS: Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype. RESULTS: Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p < 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p < 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p < 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03). CONCLUSION: Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors.

Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model.

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p<0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p<0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca(2+)-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.

Patient and stone characteristics associated with surgical intervention in pediatrics.

BACKGROUND: The incidence of kidney stones in children is increasing. While guidelines exist for acute surgical intervention, there is limited data to inform the decision as to when to intervene non-urgently. OBJECTIVES: To identify patient and stone characteristics predicting stone surgery in children. DESIGN: Retrospective chart review. SETTING: Stollery Children's Hospital, Edmonton, Alberta, Canada from 1990 to 2013. PATIENTS: Sixty-three children aged 0-18 years old who presented with a total of 142 stones. MEASUREMENTS: Patient's surgical history, demographics, metabolic measures, and stone number, type, and location. METHODS: Univariate and multivariate analysis, controlling for presentation number and individual-level variation by repeated measures analysis were conducted to assess for patient and stone characteristics associated with surgical intervention. RESULTS: Sixty-five percent (41/63) required surgery during a mean follow-up of 19 months. Stone characteristics associated with surgical intervention by multivariate analysis included larger stone size (>6 mm), and stone composition of calcium oxalate. LIMITATIONS: Single center study with a limited sample size and duration of follow up, thereby limiting predictive power. There were some missing data (i,e. stone type was not always available). Despite this, stone type remained significant in multivariate modeling. CONCLUSION: Stone size > 6mm and composition with calcium oxalate but not patient age or symptoms associated with presentation predicted surgical intervention. These observations can be used to inform decisions as to whether urolithiasis should be surgically managed electively or observed.

CONTEXTE: La fréquence des calculs rénaux chez les enfants est en hausse. Bien que des lignes directrices encadrent les interventions chirurgicales urgentes, les données qui permettent d'éclairer la décision sur le moment opportun d'une intervention non urgente sont limitées. OBJECTIFS: Cerner les caractéristiques des patients et des calculs rénaux qui pronostiquent le recours à la chirurgie chez les enfants. TYPE D'ÉTUDE: Examen rétrospectif des dossiers. CONTEXTE: L'hôpital pour enfants Stollery, à Edmonton, en Alberta, au Canada, de 1990 à 2013. PATIENTS: Soixante-trois enfants de 0 à 18 ans, qui présentaient un total de 142 calculs rénaux. MESURES: Les antécédents chirurgicaux des patients, les données démographiques, les mesures métaboliques, de même que le nombre de calculs, leur type et leur emplacement. MÉTHODES: Analyses unidimensionnelles et multidimensionnelles, qui permettent de contrôler le nombre d'occurrences et les variations sur le plan individuel, grâce à une analyse par mesures répétées, et qui visent à cerner les caractéristiques des patients et des calculs rénaux associées au recours à la chirurgie. RÉSULTATS: Soixante-cinq pour cent (41/63) des cas ont requis une opération au cours de la période de suivi moyenne de 19 mois. À la lumière de l'analyse multidimensionnelle, les caractéristiques des calculs rénaux qui ont nécessité une opération comprenaient leur taille importante (de plus de 6 mm), de même que leur composition en oxalate calcique. LIMITES DE L'ÉTUDE: L'efficacité prédictive est réduite, étant donné que l'étude se penche sur un échantillon restreint, dans un seul centre, et au cours d'une période de suivi limitée. Certaines données étaient manquantes (c.-à-d. : le type de calculs n'était pas toujours connu). Pourtant, le type de calculs occupait une place importante dans le modèle multidimensionnel. CONCLUSION: Une taille de plus de 6 mm, de même que la composition en oxalate calcique, et non pas l'âge du patient, ni les symptômes associés à la présentation, sont associées au recours à une opération chirurgicale. Ces observations peuvent aider à prendre la décision d'intervenir de manière chirurgicale dans les cas d'urolithiases qui ne présentent pas de critères urgents d'intervention.'.

Full-night versus 4h evening polysomnography in children less than 2years of age.

OBJECTIVE: Pediatric polysomnogaphy (PSG) is associated with significant burden in terms of personnel time, resource use, and patient/family discomfort. We hypothesized that 4-h abbreviated PSG may be a suitable alternative to full-night PSG in children 24months of age and younger. METHODS: PSG results from the first 4-h were compared to the full-length studies from 105 children. Outcomes included total, obstructive, and central apnea indices. Sleep disordered breathing (SDB) was defined as an apnea-hypopnea index (AHI) >1.5events/h and obstructive sleep apnea (OSA) was defined as an obstructive AHI>1.5 events/h. Cutoffs for central apneas were 3events/h for subjects >6months of age and 10events/h for subjects ⩽6months of age. RESULTS: All but one subject had abnormal SDB by the full-night PSG and all individuals had at least one REM period in the first 4h of sleep. Mean oxygen saturations and end-tidal CO(2), did not significantly differ between full-night and 4-h PSG. 4-h PSG showed high sensitivity for total AHI (100% for ⩽6months and 92.9% for >6months respectively), obstructive AHI (97.9%; 91.1% respectively), and central apnea index (100%; 72.2% respectively). Agreement was lower for those with lower AHI. CONCLUSIONS: The high prevalence of SDB observed suggests that the goals of PSG in this age group at our center may be to determine the type and severity of SDB rather than presence or absence. The high sensitivity between full-night and 4-h PSG supports the use of 4-h PSG in children 24months and under, especially those ⩽6months of age.

Changes in exhaled nitric oxide related to estrogen and progesterone during the menstrual cycle.

BACKGROUND: Significant changes in asthma and atopy occur throughout the menstrual cycle. We hypothesized that the characteristics of asthma (eg, symptoms, exhaled nitric oxide [eNO] levels as a marker of airway inflammation, pulmonary function, and atopy) vary throughout the menstrual cycle in relation to changes in the levels of estrogen or progesterone and that this variation is attenuated in women using oral contraception (OC). METHODS: Seventeen women with asthma were studied over the course of their menstrual cycle through daily measurements of symptoms, eNO, spirometry, 17beta-estradiol, and progesterone levels, and through the performance of alternate-day allergy skin-prick tests (SPTs). RESULTS: Of 534 potential daily visits, 526 (98.5%) were completed. Women not using OC (n = 8) had higher mean eNO levels (48.2 parts per billion [ppb]; 95% CI, 43.1 ppb to 53.3 ppb) than women using OC (27.0 ppb; 95% CI, 24.2 ppb to 29.7 ppb; p

Factors affecting exhaled nitric oxide measurements: the effect of sex.

BACKGROUND: Exhaled nitric oxide (F(E)NO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect F(E)NO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting F(E)NO in a well characterised adult population. METHODS: Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on F(E)NO were explored by unadjusted and adjusted linear regression analyses. RESULTS: The effect of sex on F(E)NO was both statistically and clinically significant, with F(E)NO levels approximately 25% less in females. Overall, current smoking reduced F(E)NO up to 50%, but this effect occurred predominantly in those who smoked on the day of the F(E)NO measurement. Atopy increased F(E)NO by 60%. The sex-related differences in F(E)NO remained significant (p < 0.001) after controlling for all other significant factors affecting F(E)NO. CONCLUSION: Even after adjustment, F(E)NO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.