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Abstract Maternal stress and depression during pregnancy and the first year of the infant’s life affect a large percentage of mothers. Maternal stress and depression have been associated with adverse fetal and childhood outcomes as well as differential child DNA methylation (DNAm). However, the biological mechanisms connecting maternal stress and depression to poor health outcomes in children are still largely unknown. Here we aim to determine whether prenatal stress and depression are associated with differences in cord blood mononuclear cell DNAm (CBMC-DNAm) in newborns (n = 119) and whether postnatal stress and depression are associated with differences in peripheral blood mononuclear cell DNAm (PBMC-DNAm) in children of 12 months of age (n = 113) from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort. Stress was measured using the 10-item Perceived Stress Scale (PSS) and depression was measured using the 20-item Center for Epidemiologic Studies Depression Questionnaire (CESD). Both stress and depression were measured longitudinally at 18 weeks and 36 weeks of pregnancy and six months and 12 months postpartum. We conducted epigenome-wide association studies (EWAS) using robust linear regression followed by a sensitivity analysis in which we bias-adjusted for inflation and unmeasured confounding using the bacon and cate methods. To quantify the cumulative effect of maternal stress and depression, we created composite prenatal and postnatal adversity scores. We identified a significant association between prenatal stress and differential CBMC-DNAm at 8 CpG sites and between prenatal depression and differential CBMC-DNAm at 2 CpG sites. Additionally, we identified a significant association between postnatal stress and differential PBMC-DNAm at 8 CpG sites and between postnatal depression and differential PBMC-DNAm at 11 CpG sites. Using our composite scores, we further identified 2 CpG sites significantly associated with prenatal adversity and 7 CpG sites significantly associated with postnatal adversity. Several of the associated genes, including PLAGL1, HYMAI, BRD2, and ERC2 have been implicated in adverse fetal outcomes and neuropsychiatric disorders. These data further support the finding that differential DNAm may play a role in the relationship between maternal mental health and child health.

Abstract Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e–118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6′-sialyllactose (P = 2.2e–9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P

Abstract Background Epigenetic modifications, particularly DNA methylation (DNAm) in cord blood, are an important biological marker of how external exposures during gestation can influence the in-utero environment and subsequent offspring development. Despite the recognized importance of DNAm during gestation, comparative studies to determine the consistency of these epigenetic signals across different ethnic groups are largely absent. To address this gap, we first performed epigenome-wide association studies (EWAS) of gestational age (GA) using newborn cord blood DNAm comparatively in a white European (n = 342) and a South Asian (n = 490) birth cohort living in Canada. Then, we capitalized on established cord blood epigenetic GA clocks to examine the associations between maternal exposures, offspring characteristics and epigenetic GA, as well as GA acceleration, defined as the residual difference between epigenetic and chronological GA at birth. Results Individual EWASs confirmed 1,211 and 1,543 differentially methylated CpGs previously reported to be associated with GA, in white European and South Asian cohorts, respectively, with a similar distribution of effects. We confirmed that Bohlin’s cord blood GA clock was robustly correlated with GA in white Europeans (r = 0.71; p = 6.0 × 10–54) and South Asians (r = 0.66; p = 6.9 × 10–64). In both cohorts, Bohlin’s clock was positively associated with newborn weight and length and negatively associated with parity, newborn female sex, and gestational diabetes. Exclusive to South Asians, the GA clock was positively associated with the newborn ponderal index, while pre-pregnancy weight and gestational weight gain were strongly predictive of increased epigenetic GA in white Europeans. Important predictors of GA acceleration included gestational diabetes mellitus, newborn sex, and parity in both cohorts. Conclusions These results demonstrate the consistent DNAm signatures of GA and the utility of Bohlin’s GA clock across the two populations. Although the overall pattern of DNAm is similar, its connections with the mother's environment and the baby's anthropometrics can differ between the two groups. Further research is needed to understand these unique relationships.

Abstract Background While the impacts of atopic dermatitis (AD) on maternal and child sleep outcomes have been previously explored, less is known about the associations between infantile AD and sleep quality and quantity. Objective To describe the perceived causes of AD-associated maternal sleep disturbances and the association between AD severity and infant sleep outcomes. Methods Mothers with infants aged

Abstract Objective Breastfeeding is associated with reduced postpartum depression, stronger parent-child relationships, and fewer behavioral disorders in early childhood. We tested the mediating roles of postpartum depression and parent-child relationship in the association between breastfeeding practices and child behavior. Study design We used standardized questionnaire data from a subset of the CHILD Cohort Study (n = 1,573) to measure postpartum depression at 6 months, 1 year and 2 years, parent-child relationship 1 year and 2 years, and child behavior at 5 years using the Child Behavior Checklist (range 0-100). Breastfeeding practices were measured at 3 months (none, partial, some expressed, all direct at the breast), 6 months (none, partial, exclusive), 12 months, and 24 months (no, yes). Confounders included birth factors, maternal characteristics, and socioeconomic status. Results Breast milk feeding at 3 or 6 months was associated with − 1.13 (95% CI: -2.19-0.07) to -2.14 (95% CI: -3.46, -0.81) lower (better) child behavior scores. Reduced postpartum depression at 6 months mediated between 11.5% and 16.6% of the relationship between exclusive breast milk feeding at 3 months and better child behavior scores. Together, reduced postpartum depression at 1 year and reduced parent-child dysfunction at 2 years mediated between 21.9% and 32.1% of the relationship between breastfeeding at 12 months and better child behavior scores. Conclusion Postpartum depression and parent-child relationship quality partially mediate the relationship between breastfeeding practices and child behavior. Breastfeeding, as well as efforts to support parental mental health and parent-child relationships, may help to improve child behavior.

ABSTRACTChildhood 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.

Background: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (–0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (–0.043±0.013 kg, p=0.0011) in the combined cohorts. Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

Abstract Links between human milk (HM) and infant development are poorly understood and often focus on individual HM components. Here we apply multi-modal predictive machine learning to study HM and head circumference (a proxy for brain development) among 1022 mother-infant dyads of the CHILD Cohort. We integrated HM data (19 oligosaccharides, 28 fatty acids, 3 hormones, 28 chemokines) with maternal and infant demographic, health, dietary and home environment data. Head circumference was significantly predictable at 3 and 12 months. Two of the most associated features were HM n3-polyunsaturated fatty acid C22:6n3 (docosahexaenoic acid, DHA; p = 9.6e−05) and maternal intake of fish (p = 4.1e−03), a key dietary source of DHA with established relationships to brain function. Thus, using a systems biology approach, we identified meaningful relationships between HM and brain development, which validates our statistical approach, gives credence to the novel associations we observed, and sets the foundation for further research with additional cohorts and HM analytes.

Abstract Background The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. Results We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40% of infants, which were characterized by differences in community composition, inter-kingdom dynamics, and microbe-derived metabolites in urine, suggestive of alterations in the timing of ecosystem transitions. Known microbiome-modifying factors, such as formula feeding and delivery by C-section, were associated with atypical bacterial, but not fungal, microbiome maturation patterns. Instead, fungal microbiome maturation was influenced by prenatal exposure to artificially sweetened beverages and the bacterial microbiome, emphasizing the importance of inter-kingdom dynamics in early-life colonization patterns. Conclusions These findings highlight the ecological and environmental factors underlying atypical patterns of microbiome maturation in infants, and the need to incorporate multi-kingdom and individual-level perspectives in microbiome research to improve our understandings of gut microbiome maturation patterns in early life and how they relate to host health. Video Abstract

Abstract Background Childhood atopic dermatitis can have a negative effect on caregivers’ quality of life and stress levels due to the burdensome nature of its treatment. Given that the condition often emerges in infancy, atopic dermatitis-related stress also carries the potential to negatively affect the developing mother-infant bond. While it is plausible that atopic dermatitis has a negative impact on maternal-infant bonding, these relationships have not been studied directly. In light of this gap, the current study investigated the association between infantile atopic dermatitis and the maternal-infant bond using a mixed-method design. Methods Mothers of infants (

Abstract Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort (n = 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n = 367), asthma (As, n = 165), food allergy (FA, n = 136), and allergic rhinitis (AR, n = 187). In a subset with shotgun metagenomic and metabolomic profiling (n = 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p = 0.000014; As p = 0.0073; FA p = 0.00083; and AR p = 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (βindirect = −2.28; p = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.

Abstract Background Food allergy affects 7-8% of children worldwide. Teachers supervise children in school, where most children spend their day. Yet, teachers have variable food allergy-related knowledge. Objective We aimed to identify how Winnipeg-based elementary school teachers manage food allergy and prevent food-triggered allergic reactions in their classrooms and schools. Methods Kindergarten-Grade 6 public and private school teachers, from Winnipeg, Canada, were interviewed virtually upon providing written informed consent. Interviews were recorded and transcribed verbatim. The study followed a pragmatic framework. Data were analysed via thematic analysis by multiple researchers. Results We interviewed 16 teachers, who primarily identified as female (87.5%). Most teachers worked in public schools (87.5%) and, on average, had 5.8 years of teaching experience. We identified four themes within the data. Most teachers (68.9%) had direct or indirect experience with food allergy. Theme 1 described the minimal standardization and inconsistent enforcement of food allergy policies between and within schools. Teachers also had varied food allergy knowledge. Theme 2 reflected teachers’ variable confidence/perceived knowledge towards food allergy management, including feeling of stress and anxiety. Theme 3 captured the lack of standardized food allergy education for teachers, and concerns about the adequacy of the current provincial program. Theme 4 described how teachers spoke of relying on other school staff, families and students to have effective communication. Conclusion Teachers’ food allergy management was informed by their knowledge and lived experience, guided by their school policies and individualized students’ needs. Teachers identified gaps in knowledge and communication, and desired more training and resources.

Abstract Background Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. Methods Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). Results In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20–28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. Conclusions Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.

Background: In the first year of life, DNA methylation (DNAm) patterns are established and are particularly susceptible to exposure-induced changes. Some of these changes may leave lasting effects by persistently altering gene expression or cell type composition or function, contributing to disease. Objectives: In this discovery study, we investigated DNAm associations with sensitization to peanut, egg, or cow’s milk and hypothesized that genes demonstrating DNAm differences in immune cells may play a role in the development of food sensitization. Methods: Infant sensitization (a skin prick test wheal size that is at least 2 mm greater than the negative control) was measured to peanut, egg, and cow’s milk at age 1 year, and ages of food introduction were reported prospectively. PBMC DNAm was measured in blood samples at 1 year in 144 infants, oversampled for atopy or wheeze. Statistical analysis of Illumina 450k array DNAm data was conducted in R with adjustment for clinical and genetic covariables and a minimum effect size of 1%, false discovery rate of 5%, and medium-confidence false discovery rate threshold of 20%. Results: There were no DNAm differences between infants with and without peanut, egg, or cow’s milk sensitization. Borderline significant sites with high effect sizes were enriched for methylation quantitative trait loci, hinting at genetic factors influencing DNAm at these sites. DNAm patterns did not differ by peanut or egg introduction before or after 12 months. Conclusion: This small pilot study did not show differences in methylation by food sensitization or introduction, but it did demonstrate DNAm patterns linked to genetic variants.

The coronavirus disease 2019 (COVID-19) pandemic has affected all Canadian families, with some impacted differently than others. Our study aims to: (1) determine the prevalence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among Canadian families, (2) identify predictors of infection susceptibility and severity of SARS-CoV-2, and (3) identify health and psychosocial impacts of the COVID-19 pandemic. This study builds upon the CHILD Cohort Study, an ongoing multi-ethnic general population prospective cohort consisting of 3,454 Canadian families with children born in Vancouver, Edmonton, Manitoba, and Toronto between 2009 and 2012. During the pandemic, CHILD households were invited to participate in the CHILD COVID-19 Add-On Study involving: (1) brief biweekly surveys about COVID-19 symptoms and testing; (2) quarterly questionnaires assessing COVID-19 exposure and testing, vaccination status, physical and mental health, and pandemic-driven life changes; and (3) in-home biological sampling kits to collect blood and stool. In total, 1,462 households (5,378 participants) consented to the CHILD COVID-19 Add-On Study: 2,803 children (mean±standard deviation [SD], 9.0±2.7 years; range, 0-17 years) and 2,576 adults (mean±SD, 43.0±6.5 years; range, 18-85 years). We will leverage the wealth of pre-pandemic CHILD data to identify risk and resilience factors for susceptibility and severity to the direct and indirect pandemic effects. Our short-term findings will inform key stakeholders and knowledge users to shape current and future pandemic responses. Additionally, this study provides a unique resource to study the long-term impacts of the pandemic as the CHILD Cohort Study continues.

Abstract Background The entire school community contributes to the safety of students with food allergy. We sought to determine the food allergy perceptions and education needs of parents, students and school staff, with the goal of enhancing food allergy education in schools. Methods With ethics approval from the University of Manitoba and participating school divisions, elementary school principals emailed SurveyMonkey® Questionnaire Links to their parent/caregiver contact list and school staff. We compared anonymous responses of parents of children with and without food allergy, students with and without food allergy, and parents and school staff using chi-squared tests. Results Participants included 561 parents of school-age children (ages 7–12 years, 19% with food allergy), 61 students (23% with food allergy), and 203 school staff (62% teachers, 88% with experience managing food allergies in the classroom). Parents of children with and without food allergy considered food allergy when sending food to school (98% vs. 96%, p = 0.39). More parents of children with food allergy thought that greater information and awareness about food allergy was needed (74% vs. 44%, p

ABSTRACT The environment plays an instrumental role in the developmental origins of health and disease. Protective features of the environment in the development of asthma and atopy have been insufficiently studied. We used data from the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study to examine relationships between living near natural green spaces in early infancy in Edmonton, AB, Canada and the development of atopic sensitization at 1 year and 3 years of age in a cohort of 699 infants, and whether these associations were mediated by infant gut microbiota (measured using 16s V4 amplicon sequencing) at 4 months. The Urban Planning Land Vegetation Index (uPLVI) map of the City of Edmonton was used to assess infants’ exposure to natural spaces based on their home postal codes, and atopic sensitization was assessed using skin prink testing (SPTs) for common food and inhalant allergens. Our findings suggest there is a protective effect of natural green space proximity on the development of multiple inhalant atopic sensitizations at 3 years (odds ratio = 0.28 [95% CI 0.09, 0.90]). This relationship was mediated by changes to Actinobacteria diversity in infant fecal samples taken at 4 months. We also found a positive association between nature proximity and sensitization to at least one food or inhaled allergen; this association was not mediated by gut microbiota. Together, these findings underscore the importance of promoting natural urban greenspace preservation to improve child health by reducing atopic disease susceptibility. IMPORTANCE Our findings highlight the importance of preserving natural green space in urban settings to prevent sensitization to environmental allergens and promote early-life gut microbiota pathways to this health benefit. These findings support a mediating role of gut microbiome compositions in health and disease susceptibility. This study used unique, accurate, and comprehensive methodology to classify natural space exposure via a high-resolution topographical map of foliage subtypes within the City of Edmonton limits. These methods are improvements from other methods previously used to classify natural space exposure, such as the normalized density vegetation index from satellite imagery, which is not able to distinguish anthropogenic from green space. The use of these methods and the associations found between natural green space exposure and atopic sensitization outcomes support their use in future studies. Our findings also provide many avenues for future research including longer term follow up of this cohort and investigation of a causal role of reduced Actinobacteria diversity on atopic sensitization development.

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].

BackgroundPreterm 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 findingsWe 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.ConclusionsThis 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.

BackgroundThe 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.MethodsProteins were analyzed in milk samples from a subset of 300 mother-child 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.ResultsUsing 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.ConclusionTogether, 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.

IntroductionFood sensitization is a first and strong indicator of immune deviation in the progression to other allergic conditions. Sensitization to food or other allergens and related inflammation during critical windows of infant development may adversely affect neurodevelopmental milestones. However, additional research is needed to test this association further.MethodsAssociations between atopic (any food or aeroallergen) or food sensitization (specific to egg, soybean, peanut, and milk) at age 1 year and neurodevelopment up to 2 years of age were evaluated in the national CHILD Cohort Study, with a secondary aim examining whether these associations were sex-specific. Food and atopic sensitization were assessed by skin prick tests (SPT) in 1-year-old infants, with neurodevelopment assessed using the cognitive, language, motor, and social-emotional subscales of the Bayley Scales of Infant Development (BSID-III) administered at 1 and 2 years of age.ResultsAtopic sensitization was present among 16.4% of infants, while 13.4% had food sensitizations. Only socioemotional scores reached statistical significance among the four BSID-III domains. Both atopic and food sensitization at 1 year of age was associated with lower social-emotional scores, independent of the infant's ethnicity. These findings were sex-specific and only observed among boys, among whom social-emotional scores were lowered by 5 points if atopic sensitization was present (−5.22 [95% CI: −9.96, −0.47], p = 0.03) or if food sensitization was present (−4.85 [95% CI: −9.82,0.11], p = 0.06). Similar results were observed using the standard SPT cut-off of ≥3 mm — for atopic sensitization (−5.17 [95% CI: −11.14, −0.80], p = 0.09) and for food sensitization (−4.61 [95% CI: −10.96, 1.74], p = 0.15).ConclusionIn our study of term infants, we found an inverse, cross-sectional association between atopic and food sensitization status and social-emotional development scores in male children but not female children.

BackgroundThe COVID-19 pandemic has affected the supply, cost, and demand for certain foods, but it is not clear how these changes have affected food-allergic households.ObjectiveTo describe the changes in food-related costs that have followed COVID-19, as reported by higher- and lower-income households with a food-allergic member.MethodsBetween May 1-June 30, 2020, Canadian households, with at least one food-allergic member, completed an online survey on food shopping and preparation habits before and during the COVID-19 pandemic. The sample was divided into binary groups, either higher or lower than the sample median income. Data were analyzed using descriptive statistics and multiple regression.ResultsThe sample was comprised of 102 participants (i.e., 51/ income group). The three most common food allergies amongst both groups were peanuts, tree nuts and milk. Since the start of the pandemic, both groups reported greater monthly direct grocery costs, although costs amongst the higher-income group were twice as high as the lower-income group ($212.86 vs. $98.89, respectively). Indirect food preparation costs were similarly elevated. Higher-income households with food procurement difficulties reported increased indirect shopping costs following the outbreak of COVID-19, whereas those without such difficulties reported decreased costs. Lower-income households with allergies to milk, wheat, or eggs (i.e., staple allergy) experienced a larger change in indirect food preparation costs following the outbreak of COVID-19 relative to those with other food allergies ($244.58 vs. –$20.28, respectively; p = 0.03).ConclusionBoth higher and lower income households with food allergy reported greater direct food costs and indirect food preparation costs following the COVID-19. Households with staple allergy and those with difficulties finding their typical food items were particularly affected.

Abstract Background The impact of childhood food allergy on household costs has not been examined in Canada. The current study sought to examine differences in direct, indirect, and intangible costs among Canadian families with and without a food-allergic child. Methods Families with a child with a specialist-diagnosed food allergy (cases) were recruited from two tertiary pediatric allergy clinics in the Province of Manitoba, Canada, and matched, based on age and sex, to families without a food-allergic child (controls). Cost data for the two groups were collected via an adapted version of the Food Allergy Economic Questionnaire (FA-EcoQ). Consideration was given to income, defined as above vs. below the provincial annual median income. Results Results from 35 matched case/control pairs revealed that while total household costs did not significantly differ between cases and controls, food-allergic families did incur higher direct costs ($12,455.69 vs. $10,078.93, p = 0.02), which were largely attributed to spending on food. In contrast, cases reported lower, but not statistically significant, total indirect costs compared to controls ($10,038.76 vs. $12,294.12, p = 0.06). Families also perceived their food-allergic child as having poorer quality of life relative to their healthy peers. Lastly, stratification of the analyses by annual income revealed several differences between the higher and lower income groups. Conclusions Relative to families without a food-allergic child, food-allergic families incurred higher direct costs across a number of different areas.

Abstract Pediatric food allergy is associated with direct, indirect and intangible costs. However, it remains unclear if intangible costs of pediatric food allergy influence parental career choices. Using data from 63 parents whose children had been diagnosed by a pediatric allergist with food allergy, we sought to (a) establish perceived life status of families with a food allergic child, and (b) to describe any career limitations viewed as attributable to food allergy. Compared to responding parents whose children had one to two food allergies, those with three or more food allergies had significantly poorer perceived life status (ß − 0.74; 95%CI − 1.41; − 0.07; p

Abstract Background In Canada, anaphylaxis-level food allergy constitutes a legal disability. Yet, no nationwide policies exist to support families. We sought to understand what parents of children with food allergy perceive as the most pressing food allergy-related policy concerns in Canada. Methods Between March–June 2019, we interviewed 23 families whose food allergic children (N = 28mean age 7.9 years) attending an allergy clinic in Winnipeg, Canada. Interviews were audio-recorded, transcribed and analyzed using content analysis. Results Over 40% of children had multiple food allergies, representing most of Health Canada’s priority allergens. We identified four themes: (1) High prevalence. High priority?. (2) Food labels can be misleading, (3) Costs and creative ideas, and (4) Do we have to just deal with the status quo around allergies? Conclusion Food allergy ought to be a national policy priority, to improve the process for precautionary labelling, to improve funding, educational tools access to care, and knowledge of current allergy guidelines.

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.

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.

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.

Background and Aims: Few studies consider the joint effect of multiple factors related to birth, delivery mode, intrapartum antibiotic prophylaxis and the onset of labour, on the abundance of Bifidobacterium and the quantity of this genus and its species Bifidobacterium longum subsp. infantis in the infant gut microbiota. We implemented such a study. Methods: Among 1654 Canadian full-term infants, the gut microbiota of faecal samples collected at 3 months were profiled by 16S rRNA sequencing; the genus Bifidobacterium and Bifidobacterium longum subsp. infantis were quantified by qPCR. Associations between Bifidobacterium and other gut microbiota were examined by Spearman’s rank correlation. Results: Following vaginal birth, maternal IAP exposure was associated with reduced absolute quantities of bifidobacteria among vaginally delivered infants (6.80 vs. 7.14 log10 (gene-copies/g faeces), p < 0.05), as well as their lowered abundance relative to other gut microbiota. IAP differences in infant gut bifidobacterial quantity were independent of maternal pre-pregnancy body-mass-index (BMI), and remarkably, they were limited to breastfed infants. Pre-pregnancy BMI adjustment revealed negative associations between absolute quantities of bifidobacteria and CS with or without labour in non-breastfed infants, and CS with labour in exclusively breastfed infants. Significant correlations between Bifidobacterium abundance and other microbial taxa were observed. Conclusions: This study documented the impact of the birth mode and feeding status on the abundance of gut Bifidobacterium, and pointed to the important ecological role of the genus Bifidobacterium in gut microbiota due to its strong interaction with other gut microbiota in early infancy.

Rationale. Material deprivation has been proposed as a more comprehensive measure of socioeconomic status than parental income. Stronger associations between childhood emergency department visits for asthma and air pollution have been demonstrated among children living in neighborhoods with high levels of deprivation, but the associations with asthma development and ongoing asthma are not known. Objectives. We determined the associations between neighborhood material deprivation and the development of new and ongoing childhood asthma. Methods. Prospectively collected administrative data housed at the Institute for Clinical Evaluative Sciences were examined for Toronto children born from 1997 to 2003. Neighborhood material deprivation, comprising no high school graduation, lone parent families, government transfers, unemployment, low income, and homes needing major repairs, was reported in the Ontario Marginalization Index. Incident asthma was defined by the time of entry into the Ontario Asthma Surveillance Information System (OASIS) database. We measured the risk of incident asthma using Cox proportional hazards models and the associations between ongoing asthma visits and deprivation by year of life with generalized linear mixed models. Results. OASIS asthma criteria were met for 21% of the 326,383 children. After adjustment for characteristics strongly associated with asthma, including male sex, prematurity, obesity, and atopic conditions other than asthma, children with high birth neighborhood deprivation were at increased risk of incident asthma (HR 1.11; 95% CI, 1.09–1.13). High deprivation in a given year of life was associated with increased odds of ongoing asthma during that year of life (OR 1.03; 95% CI, 1.02–1.05). Conclusions. Children living in high-deprivation neighborhoods are at increased risk of incident and ongoing asthma. This study suggests that neighborhood material deprivation may represent a helpful tool for evaluating the effects of disparities in health and social advantages on the likelihood of developing and continuing to need healthcare visits for ongoing childhood asthma.