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Author(s): Johan L. Vinther, Tim Cadman, Demetris Avraam, Claus T. Ekstrøm, Thorkild I. A. Sørensen, Ahmed Elhakeem, Ana C. Santos, Angela Pinot de Moira, Barbara Heude, Carmen Iñiguez, Costanza Pizzi, [...]

Background Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. Methods and findings We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. Conclusions This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term., Author(s): Johan L. Vinther 1,*, Tim Cadman 2, Demetris Avraam 3, Claus T. Ekstrøm 4, Thorkild I. A. Sørensen 1,5, Ahmed Elhakeem 2, Ana C. Santos 6,7, Angela Pinot de [...]

BACKGROUND: Evidence suggests that prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. It remains unclear whether DNAm alterations present at birth persist through early life. Identifying persistent DNAm changes would provide greater insight into the molecular mechanisms contributing to the association of prenatal air pollution exposure with atopic diseases. OBJECTIVES: This study investigated DNAm differences associated with prenatal nitrogen dioxide (NO2) exposure (a surrogate measure of trafficrelated air pollution) at birth and 1 y of age and examined their role in atopic disease. We focused on regions showing persistent DNAm differences from birth to 1 y of age and regions uniquely associated with postnatal NO2 exposure. METHODS: Microarrays measured DNAm at birth and at 1 y of age for an atopy-enriched subset of Canadian Health Infant Longitudinal Development (CHILD) study participants. Individual and regional DNAm differences associated with prenatal NO2 (푛= 128) were identified, and their persistence at age 1 y were investigated using linear mixed effects models (푛= 124). Postnatal-specific DNAm differences (푛= 125) were isolated, and their association with NO2 in the first year of life was examined. Causal mediation investigated whether DNAm differences mediated associations between NO2 and age 1 y atopy or wheeze. Analyses were repeated using biological sex-stratified data. RESULTS: At birth (푛= 128), 18 regions of DNAm were associated with NO2, with several annotated to HOX genes. Some of these regions were specifically identified in males (푛= 73), but not females (푛= 55). The effect of prenatal NO2 across CpGs within altered regions persisted at 1 y of age. No significant mediation effects were identified. Sex-stratified analyses identified postnatal-specific DNAm alterations. DISCUSSION: Regional cord blood DNAm differences associated with prenatal NO2 persisted through at least the first year of life in CHILD participants. Some differences may represent sex-specific alterations, but replication in larger cohorts is needed. The early postnatal period remained a sensitive window to DNAm perturbations. [ABSTRACT FROM AUTHOR]

Background. Di-(2-ethylhexyl) phthalate (DEHP), which is ubiquitous in indoor environments, was the predominant phthalate measured in house dust in the Canadian CHILD Cohort and was found to be associated with a large increased risk of childhood asthma. Objective. To inform interventions by identifying sources of DEHP in dust and assessing behaviors related to DEHP concentrations in house dust. Methods. DEHP levels were measured in 726 dust samples collected at ~3 months of age in CHILD as well as in ~50 homes at two time points (June and November) in the CHILD pilot study. DEHP metabolites were measured in urine for a subset of the ~3-month-old infants. Housing characteristics were assessed at the time of dust and urine collection. Numerous factors from these surveys were investigated as potential sources of DEHP using univariate analyses and multivariable regressions. Correlations between DEHP in dust and urinary metabolites and between repeat dust samples were examined to study the relationship between dust measurement and DEHP exposure. Results. Overall, DEHP dust concentrations were higher for lower-income families. Homes with vinyl flooring in the kitchen and bathroom showed higher levels of DEHP than those without vinyl flooring. The quantity of vinyl furniture and the presence of mold were associated with higher DEHP concentrations, while the use of mattress covers reduced concentration. No other significant associations were found. DEHP concentrations in dust were consistent over 6 months, although the correlation between dust and DEHP metabolites in urine was low. Conclusion. DEHP in house dust persisted over multiple months, contributed to infant internal exposure, and was associated with specific housing characteristics. These findings may inform the public on their choice of building materials and products, as well as future policies, aimed at reducing the health risk associated with exposures in the indoor environment especially for children. [ABSTRACT FROM AUTHOR]

Infant vitamin D liquid formulations often contain non-medicinal excipients such as glycerin (ie. glycerol) and 1,2-propanediol (1,2-PD). We examined whether infant vitamin D supplementation is associated with fecal glycerol and 1,2-PD concentrations at 3 months of age and characterized associations between these two molecules, and gut microbiota and their metabolites. Fecal metabolites and microbiota were quantified using Nuclear Magnetic Resonance Spectroscopy and 16S rRNA sequencing, respectively, in 575 infants from the CHILD Study at 3 months of age. Vitamin D supplement use was determined using questionnaires. Vitamin D supplementation was associated with greater odds of high 1,2-PD (adjusted OR 1.65 95% CI: 1.06, 2.53) and with decreased odds of high fecal glycerol (adjusted OR: 0.62 95% CI: 0.42, 0.90) after adjustment for breastfeeding and other covariates. Our findings were confirmed in linear regression models; vitamin D supplementation was positively associated with fecal 1,2-PD and inversely associated with glycerol (aβ: 0.37, 95% CI 0.03, 0.71 & aβ: −0.23 95% CI −0.44, −0.03, respectively). Fecal 1,2-PD and glycerol concentrations were negatively correlated with each other. Positive correlations between fecal 1,2-PD, Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae and acetate levels were observed. Our research demonstrates that infant vitamin D supplement administration may differentially and independently influence infant gut microbiota metabolites. [ABSTRACT FROM AUTHOR]

How gut immunity in early life is shaped by birth in relation to delivery mode, intrapartum antibiotic prophylaxis (IAP) and labor remains undetermined. We aimed to address this gap with a study of secretory Immunoglobulin A (SIgA) in the infant gut that also tested SIgA-stimulating pathways mediated by gut microbiota and metabolites. Among 1017 Canadian full-term infants, gut microbiota of fecal samples collected at 3 and 12 months were profiled using 16S rRNA sequencing; C. difficile was quantified by qPCR; fecal metabolites and SIgA levels were measured by NMR and SIgA enzyme-linked immunosorbent assay, respectively. We assessed the putative causal relationships from birth events to gut microbiota and metabolites, and ultimately to SIgA, in statistical sequential mediation models, adjusted for maternal gravida status in 551 infants. As birth mode influences the ability to breastfeed, the statistical mediating role of breastfeeding status and milk metabolites was also evaluated. Relative to vaginal birth without maternal IAP, cesarean section (CS) after labor was associated with reduced infant gut SIgA levels at 3 months (6.27 vs. 4.85 mg/g feces, p < 0.05); this association was sequentially mediated through gut microbiota and metabolites of microbial or milk origin. Mediating gut microbiota included Enterobacteriaceae, C. difficile, and Streptococcus. The milk or microbial metabolites in CS-SIgA mediating pathways were galactose, fucose, GABA, choline, lactate, pyruvate and 1,2-propanediol. This cohort study documented the impact of birth on infant gut mucosal SIgA. It is the first to characterize gut microbe-metabolite mediated pathways for early-life SIgA maturation, pathways that require experimental verification. [ABSTRACT FROM AUTHOR]

Background: The human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child. Methods: Proteins were analyzed in milk samples from a subset of 300 motherchild dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of "allergy" included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses. Results: Using univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk's immunological potential, which might be related to the development of the infant's immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status. Conclusion: Together, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy. [ABSTRACT FROM AUTHOR]

Introduction: Previously developed cesarean section (CS) and emergency CS prediction tools use antenatal and intrapartum risk factors. We aimed to develop a predictive model for the risk of emergency CS before the onset of labour utilizing antenatal obstetric and non-obstetric factors. Methods: We completed a secondary analysis of data collected from the CHILD Cohort Study. The analysis was limited to term (≥37 weeks), singleton pregnant women with cephalic presentation. The sample was divided into a training and validation dataset. The emergency CS prediction model was developed in the training dataset and the performance accuracy was assessed by the area under the receiver operating characteristic curve(AUC) of the receiver operating characteristic analysis (ROC). Our final model was subsequently evaluated in the validation dataset. Results: The participant sample consisted of 2,836 pregnant women. Mean age of participants was 32 years, mean BMI of 25.4 kg/m2 and 39% were nulliparous. 14% had emergency CS delivery. Each year of increasing maternal age increased the odds of emergency CS by 6% (adjusted Odds Ratio (aOR 1.06,1.02–1.08). Likewise, there was a 4% increase odds of emergency CS for each unit increase in BMI (aOR 1.04,1.02–1.06). In contrast, increase in maternal height has a negative association with emergency CS. The final emergency CS delivery predictive model included six variables (hypertensive disorders of pregnancy, antenatal depression, previous vaginal delivery, age, height, BMI). The AUC for our final prediction model was 0.74 (0.72–0.77) in the training set with a similar AUC in the validation dataset (0.77; 0.71–0.82). Conclusion: The developed and validated emergency CS delivery prediction model can be used in counselling prospective parents around their CS risk and healthcare resource planning. Further validation of the tool is suggested. [ABSTRACT FROM AUTHOR]

Objective: To identify factors associated with breast-feeding initiation and continuation in Canadian-born and non-Canadian-born women. Design: Prospective cohort of mothers and infants born from 2008 to 2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study. Setting: General community setting in four Canadian provinces. Participants: In total, 3455 pregnant women from Vancouver, Edmonton, Winnipeg and Toronto between 2008 and 2012. Results: Of 3010 participants included in the current study, the majority were Canadian-born (75·5 %). Breast-feeding initiation rates were high in both non-Canadian-born (95·5 %) and Canadian-born participants (92·7 %). The median breast-feeding duration was 10 months in Canadian-born participants and 11 months in non-Canadian-born participants. Among Canadian-born participants, factors associated with breast-feeding initiation and continuation were older maternal age, higher maternal education, living with their partner and recruitment site. Rooming-in during the hospital stay was also associated with higher rates of breast-feeding initiation, but not continuation at 6-month postpartum. Factors associated with non-initiation of breast-feeding and cessation at 6-month postpartum were maternal smoking, living with a current smoker, caesarean birth and early-term birth. Among non-Canadian-born participants, maternal smoking during pregnancy was associated with lower odds of breast-feeding initiation and lower odds of breast-feeding continuation at 6 months, and older maternal age and recruitment site were associated with breast-feeding continuation at 6 months. Conclusions: Although Canadian-born and non-Canadian-born women in the CHILD cohort have similar breast-feeding initiation rates, breast-feeding initiation and continuation are more strongly associated with socio-demographic characteristics in Canadian-born participants. Recruitment site was strongly associated with breast-feeding continuation in both groups and may indicate geographic disparities in breast-feeding rates nationally. [ABSTRACT FROM AUTHOR]

Limited data exist on pharmaceutical product use by infants, although available data suggests higher prevalence of use among children under 12 months of age. We conducted a descriptive study of 3050 infants recruited in the CHILD Cohort Study, a prospective, multicenter, longitudinal cohort following children from pregnancy through childhood. Parents were surveyed for use of prescription and over-the-counter drugs, and natural health products (NHPs, including homeopathic products and vitamins) at 3, 6, and 12 months after delivery. By one year of age, 96.0% of children had taken at least one pharmaceutical product. Among 307 reported products, 32 were given to at least 1% of cohort infants. Vitamin D, acetaminophen, ibuprofen, topical hydrocortisone, amoxicillin, and nystatin were the most common medications and natural health products (NHPs) received, with 8/32 of the most frequently used products being NHPs. Overall, 14.7% of pharmaceutical products administered to children were off-label and 35.8% were NHPs or products without a Drug Identification Number (DIN). The use of over-the-counter medications and NHPs is common and off-label use of drugs is frequent, even in the first year of life. This study highlights the importance of conducting studies on medication use in infants, and of infant medication use monitoring by healthcare providers. [ABSTRACT FROM AUTHOR]

The relationship between antibiotic use and Clostridioides difficile (C. difficile) has been well established in adults and older children but remains unclear and is yet to be fully examined in infant populations. This study aimed to determine the separate and cumulative impact from antibiotics and household cleaning products on C. difficile colonization in infants. This study included 1429 infants at 3–4 months of age and 1728 infants at 12 months of age from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. The levels of infant antimicrobial exposure were obtained from hospital birth charts and standardized questionnaires. Infant gut microbiota was characterized by Illumina 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Analysis of C. difficile was performed using a quantitative polymerase chain reaction (qPCR). Overall, C. difficile colonized 31% and 46% of infants at 3–4 months and 12 months, respectively. At 3–4 months, C. difficile colonization was significantly higher in infants exposed to both antibiotics and higher (above average) usage of household cleaning products (adjusted odds ratio (aOR) 1.50, 95% CI 1.03–2.17; p = 0.032) than in infants who had the least antimicrobial exposure. This higher colonization persisted up to 12 months of age. Our study suggests that cumulative exposure to systemic antibiotics and higher usage of household cleaning products facilitates C. difficile colonization in infants. Further research is needed to understand the future health impacts. [ABSTRACT FROM AUTHOR]

Background World Health Organization (WHO) growth standards for children aged 0 to 5 years describe growth under optimal conditions and were adopted for use in Canada in 2012. We are seeking to validate these charts in a well-characterized, longitudinal cohort of healthy, Canadian youngsters, assess tracking over time, and evaluate the prognostic implications of early growth. Methods Data from 2,795 mother–infant dyads from the CHILD birth cohort were classified by feeding modality at 6 months as exclusively breastfed, partially breastfed, or formula-fed. WHO z-scores (z) were calculated at birth, 3 months, 1 year, and 3 years. Receiver operator characteristics (ROC) assessed the predictive performance of early weight (WT), weight-for-length (WfL), or body mass index (BMI) z-scores for overweight/obesity at 3 years. Results Compared to WHO standards, Canadian children at birth had lower median WfLz (−0.73) and BMIz (−0.29), with more positive scores by 3 years (WfLz=BMIz=0.58). At both 1 and 3 years, formula feeding was associated with higher scores than breastfeeding, even after regression adjustment for covariates. Head circumference z-score was typically positive at all times and regardless of feeding modality. At 1 year, ROC area under the curve was 0.79 for WTz, WfLz, and BMIz, and BMIz>0.88 identified children with increased risk of overweight/obesity (BMIz >2) at age 3 years (20.3% versus 3.0%, P<0.001). Conclusions Compared to WHO growth charts, Canadian children at 3 years show an upward shift in BMIz and WfLz, particularly when formula-fed. Infant growth parameters may identify infants with increased risk of overweight/obesity at age 3 years; early recognition may allow targeting infants at higher risk. [ABSTRACT FROM AUTHOR]

BACKGROUND: The role of traffic-related air pollution (TRAP) exposure in the development of allergic sensitization in children is unclear, and few birth cohort studies have incorporated spatiotemporal exposure assessment. OBJECTIVES: We aimed to examine the association between TRAP and atopy in 1-year-old children from an ongoing national birth cohort study in four Canadian cities. METHODS: We identified 2,477 children of approximately 1 year of age with assessment of atopy for inhalant (Alternaria, Der p, Der f, cat, dog, cockroach) and food-related (milk, eggs, peanuts, soy) allergens. Exposure to nitrogen dioxide (NO2) was estimated from city-specific land use regression models accounting for residential mobility and temporal variability in ambient concentrations. We used mixed models to examine associations between atopy and exposure during pregnancy and the first year of life, including adjustment for covariates (maternal atopy, socioeconomic status, pets, mold, nutrition). We also conducted analyses stratified by time-location patterns, daycare attendance, and modeled home ventilation. RESULTS: Following spatiotemporal adjustment, TRAP exposure after birth increased the risk for development of atopy to any allergens [adjusted odds ratio (aOR) per 10 µg/[m.sup.3] N[O.sub.2] = 1.16; 95% CI: 1.00, 1.41], but not during pregnancy (aOR = 1.02; 95% CI: 0.86, 1.22). This association was stronger among children not attending daycare (aOR = 1.61; 95% CI: 1.28, 2.01) compared with daycare attendees (aOR = 1.05; 95% CI: 0.81, 1.28). Trends to increased risk were also found for food (aOR = 1.17; 95% CI: 0.95, 1.47) and inhalant allergens (aOR = 1.28; 95% CI: 0.93, 1.76). CONCLUSION: Using refined exposure estimates that incorporated temporal variability and residential mobility, we found that traffic-related air pollution during the first year of life was associated with atopy. http://dx.doi.org/10.1289/ehp.1408700, Introduction The incidence of allergic diseases has increased sharply, especially for people living in urban areas, which raises an important public health concern given the trend to urbanization worldwide (D'Amato [...]

Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13–7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75–22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization. [Display omitted] [ABSTRACT FROM AUTHOR]

Rationale: There are limited tools to identify which children are at greatest risk for developing sleep-disordered breathing (SDB)-associated behavioral morbidity.Objectives: To examine associations between age of onset and duration of parent-reported symptoms of SDB and behavioral problems at the age of 5 years.Methods: Data were collected and analyses were completed for participants in the CHILD (Canadian Healthy Infant Longitudinal Development) cohort at the Edmonton and Toronto sites. We generated an SDBeasy score on the basis of the age of onset and duration of SDB symptoms as reported by parents completing the Pediatric Sleep Questionnaire. Using CHILD-Edmonton data, we completed multivariate linear regression to determine whether the SDBeasy score was associated with behavioral problems at the age 5 years of age as assessed by using the Child Behavior Checklist (CBCL). We then validated the SDBeasy score using CHILD-Toronto data.Measurements and Main Results: At the 5-year visit, 581 of 716 (81%) CHILD-Edmonton participants still enrolled had CBCL data. Of the 581 children with data, 77% (446 of 581) had an SDBeasy score of 0 (never had SDB symptoms), whereas 20 of 581 children (3.4%) had persistent SDB symptoms from infancy through 5 years of age (SDBeasy score of 24). Children had a 0.35-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.24-0. 5; P < 0.01). We found consistent results among CHILD-Toronto participants; children had a 0.26-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.08-0.44; P = 0.005).Conclusions: The SDBeasy score, based on the Pediatric Sleep Questionnaire, enables identification of children with higher behavioral-problem scores. [ABSTRACT FROM AUTHOR]