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There is concern that during a low-risk pregnancy, women are consuming more than recommended (400 µg/day) supplemental folic acid and may not meet recommendations for other nutrients. The objective of this study was to determine folic acid supplement use and dietary folate intakes in the second trimester (week 18) of pregnancy in women (n = 2996) in the Canadian CHILD cohort study. Vitamin B12 and choline intakes were also assessed because they are metabolically related to folate. The majority of participants (71.6%) were consuming a daily prenatal supplement. Twenty-eight percent of women (n = 847) reported consuming a folic acid supplement and of these women, 45.3% had daily supplemental folic acid intakes above the upper intake level (UL; 1000 µg/day). Daily dietary folate intakes were (mean (SD)) 575 (235) DFE µg/day. In contrast, only 24.8% of women met the dietary choline adequate intake (AI) recommendation (AI ≥ 450 mg/day) with a mean (SD) intake of 375 (151) mg/day. Further understanding of the impact of supplemental folic acid intake above the UL and low choline intake during pregnancy requires further investigation. [ABSTRACT FROM AUTHOR]

Objectives Asthma is a chronic lung condition that can be exacerbated when triggered by viruses. Pandemic public health restrictions aimed to reduce COVID-19 transmission indirectly effected other circulating viruses. This study assessed the impact of the pandemic and associated public health measures on acute paediatric asthma across four tertiary sites in three Canadian provinces. We queried whether pandemic-related changes would impair preventive care and delay presentation to care, increasing asthma exacerbation severity. Methods This retrospective study compared the frequency of acute care access and severity of presentation to emergency departments (ED) for acute asthma to four tertiary care children's hospitals during the COVID-19 pandemic (from March 17, 2020 to June 30, 2021) to a pre-lockdown control period (July 1, 2018 to March 16, 2020). Data was subjected to interrupted time series and Chi-square analysis. Results Our study included 26,316 acute asthma visits to ED. Sites experienced a 63% to 89% reduction in acute asthma visits during the pandemic, compared with pre-lockdown controls, and a 17% to 85% reduction in asthma, that is out of proportion as a fraction of all-cause ED visits. For asthma, there was no difference in severity measured by rate of ward admission or rate of Paediatric Intensive Care Unit (PICU) admission. Conclusions Public health measures appear to have resulted in a specific protective association on acute asthma with reduced acute care utilization over and above the reduction in all-cause presentations, without an increase in severity upon presentation. Our study indicates an importance to antiviral public health and engineering strategies to reduce viral transmission and thereby asthma morbidity. [ABSTRACT FROM AUTHOR]

Background: A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. Methods: Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. Results: A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p < 0.0001), The most commonly used non-prescription medications were multivitamins and Vitamin D at 3, 6 and 12 months postpartum. Conclusions: In Canada, medication use is common postpartum; 40% of breastfeeding women use prescription medications in the first 3 months postpartum. A diverse range of medications were used, with many women taking more than one prescription and non-prescription medicines. The most commonly used prescription medication by breastfeeding women were domperidone for off-label lactation support, signalling a need for more data on the efficacy of domperidone for this indication. This data should inform research priorities and communication strategies developed to optimize care during lactation. [ABSTRACT FROM AUTHOR]

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]

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]

While its etiology is not fully elucidated, preterm birth represents a major public health concern as it is the leading cause of child mortality and morbidity. Stress is one of the most common perinatal conditions and may increase the risk of preterm birth. In this paper we aimed to investigate the association of maternal perceived stress and anxiety with length of gestation. We used harmonized data from five birth cohorts from Canada, France, and Norway. A total of 5297 pregnancies of singletons were included in the analysis of perceived stress and gestational duration, and 55,775 pregnancies for anxiety. Federated analyses were performed through the DataSHIELD platform using Cox regression models within intervals of gestational age. The models were fit for each cohort separately, and the cohort-specific results were combined using random effects study-level meta-analysis. Moderate and high levels of perceived stress during pregnancy were associated with a shorter length of gestation in the very/moderately preterm interval [moderate: hazard ratio (HR) 1.92 (95%CI 0.83, 4.48); high: 2.04 (95%CI 0.77, 5.37)], albeit not statistically significant. No association was found for the other intervals. Anxiety was associated with gestational duration in the very/moderately preterm interval [1.66 (95%CI 1.32, 2.08)], and in the early term interval [1.15 (95%CI 1.08, 1.23)]. Our findings suggest that perceived stress and anxiety are associated with an increased risk of earlier birth, but only in the earliest gestational ages. We also found an association in the early term period for anxiety, but the result was only driven by the largest cohort, which collected information the latest in pregnancy. This raised a potential issue of reverse causality as anxiety later in pregnancy could be due to concerns about early signs of a possible preterm birth., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Early identification of children at risk of asthma can have significant clinical implications for effective intervention and treatment. This study aims to disentangle the relative timing and importance of early markers of asthma., Methods: Using the CHILD Cohort Study, 132 variables measured in 1754 multi-ethnic children were included in the analysis for asthma prediction. Data up to 4 years of age was used in multiple machine learning models to predict physician-diagnosed asthma at age 5 years. Both predictive performance and variable importance was assessed in these models., Results: Early-life data (≤1 year) has limited predictive ability for physician-diagnosed asthma at age 5 years (area under the precision-recall curve (AUPRC) < 0.35). The earliest reliable prediction of asthma is achieved at age 3 years, (area under the receiver-operator curve (AUROC) > 0.90) and (AUPRC > 0.80). Maternal asthma, antibiotic exposure, and lower respiratory tract infections remained highly predictive throughout childhood. Wheezing status and atopy are the most important predictors of early childhood asthma from among the factors included in this study., Conclusions: Childhood asthma is predictable from non-biological measurements from the age of 3 years, primarily using parental asthma and patient history of wheezing, atopy, antibiotic exposure, and lower respiratory tract infections., Impact: Machine learning models can predict physician-diagnosed asthma in early childhood (AUROC > 0.90 and AUPRC > 0.80) using ≥3 years of non-biological and non-genetic information, whereas prediction with the same patient information available before 1 year of age is challenging. Wheezing, atopy, antibiotic exposure, lower respiratory tract infections, and the child's mother having asthma were the strongest early markers of 5-year asthma diagnosis, suggesting an opportunity for earlier diagnosis and intervention and focused assessment of patients at risk for asthma, with an evolving risk stratification over time., (© 2024. The Author(s).)

Background/objectives: Delivery by cesarean section (CS) compared to vaginal delivery has been associated with increased risk of overweight in childhood. Our study examined if the presence or absence of labor events in CS delivery altered risk of overweight in early childhood (1-5 years) compared to vaginal delivery and if this association differed according to infant sex., Subjects/methods: The study included 3073 mother-infant pairs from the CHILD Cohort Study in Canada. Data from birth records were used to categorize infants as having been vaginally delivered, or delivered by CS, with or without labor events. Age and sex adjusted weight-for-length (WFL) and body mass index (BMI) z scores were calculated from height and weight data from clinic visits at 1, 3 and 5 years and used to classify children as overweight. Associations between delivery mode and child overweight at each timepoint were assessed using regression models, adjusting for relevant confounding factors including maternal pre-pregnancy BMI. Effect modification by infant sex was tested., Results: One in four infants (24.6%) were born by CS delivery; 13.0% involved labor events and 11.6% did not. Infants born by CS without labor had an increased odds of being overweight at age 1 year compared to vaginally delivered infants after adjustment for maternal pre-pregnancy BMI, maternal diabetes, smoking, infant sex and birthweight-for-gestational age (aOR 1.68 [95% CI 1.05-2.67]). These effects did not persist to 3 or 5 years of age and, after stratification by sex, were only seen in boys (aOR at 1 year 2.21 [95% CI 1.26-3.88])., Conclusion and Relevance: Our findings add to the body of evidence that CS, in particular CS without labor events, may be a risk factor for overweight in early life, and that this association may be sex-specific. These findings could help to identify children at higher risk for developing obesity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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 ( NO 2 ) exposure (a surrogate measure of traffic-related 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 NO 2 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 NO 2 ( n = 128 ) were identified, and their persistence at age 1 y were investigated using linear mixed effects models ( n = 124 ). Postnatal-specific DNAm differences ( n = 125 ) were isolated, and their association with NO 2 in the first year of life was examined. Causal mediation investigated whether DNAm differences mediated associations between NO 2 and age 1 y atopy or wheeze. Analyses were repeated using biological sex-stratified data., Results: At birth ( n = 128 ), 18 regions of DNAm were associated with NO 2 , with several annotated to HOX genes. Some of these regions were specifically identified in males ( n = 73 ), but not females ( n = 55 ). The effect of prenatal NO 2 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 NO 2 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. https://doi.org/10.1289/EHP13034.

We hypothesize that children characterized by deprived factors have poorer health outcomes. We aim to identify clustering of determinants and estimate risk of early childhood diseases. This 1993-2019 longitudinal cohort study combines three Canadian pediatric cohorts and their families. Mothers and children are clustered using latent class analysis (LCA) by 16 indicators in three domains (maternal and newborn; socioeconomic status [SES] and neighbourhood; environmental exposures). Hazard ratios (HR) of childhood asthma, allergic rhinitis (AR), and eczema are quantified with Cox proportional hazard (PH) regression. Rate ratios (RR) of children's health services use (HSU) are estimated with Poisson regression. Here we report the inclusion of 15,724 mother-child pairs; our LCA identifies four mother-clusters. Classes 1 and 2 mothers are older (30-40 s), non-immigrants with university education, living in high SES neighbourhoods; Class 2 mothers have poorer air quality and less greenspace. Classes 3 and 4 mothers are younger (20-30 s), likely an immigrant/refugee, with high school-to-college education, living in lower SES neighborhoods with poorer air quality and less greenspace. Children's outcomes differ by Class, in comparison to Class 1. Classes 3 and 4 children have higher risks of asthma (HR 1.24, 95% CI 1.11-1.37 and HR 1.39, 95% CI 1.22-1.59, respectively), and similar higher risks of AR and eczema. Children with AR in Class 3 have 20% higher all-cause physician visits (RR = 1.20, 95% CI 1.10-1.30) and those with eczema have 18% higher all-cause emergency department visits (RR = 1.18, 95% CI 1.09-1.28) and 14% higher all-cause physician visits (RR = 1.14, 95% CI 1.09-1.19). Multifactorial-LCA mother-clusters may characterize associations of children's health outcomes and care, adjusting for interrelationships., (© 2024. The Author(s).)

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.

Organophosphate ester flame retardants and plasticizers (OPEs) are common exposures in modern built environments. Toxicological models report that some OPEs reduce dopamine and serotonin in the brain. Deficiencies in these neurotransmitters are associated with anxiety and depression. We hypothesized that exposure to higher concentrations of OPEs in house dust would be associated with a greater risk of depression and stress in mothers across the prenatal and postpartum periods. We conducted a nested prospective cohort study using data collected on mothers (n = 718) in the CHILD Cohort Study, a longitudinal multi-city Canadian birth cohort (2008-2012). OPEs were measured in house dust sampled at 3-4 months postpartum. Maternal depression and stress were measured at 18 and 36 weeks gestation and 6 months and 1 year postpartum using the Centre for Epidemiologic Studies for Depression Scale (CES-D) and Perceived Stress Scale (PSS). We used linear mixed models to examine the association between a summed Z-Score OPE index and continuous depression and stress scores. In adjusted models, one standard deviation increase in the OPE Z-score index was associated with a 0.07-point (95% CI: 0.01, 0.13) increase in PSS score. OPEs were not associated with log-transformed CES-D (β: 0.63%, 95% CI: -0.18%, 1.46%). The effect of OPEs on PSS score was strongest at 36 weeks gestation and weakest at 1 year postpartum. We observed small increases in maternal perceived stress levels, but not depression, with increasing OPEs measured in house dust during the prenatal and early postpartum period in this cohort of Canadian women. Given the prevalence of prenatal and postpartum anxiety and the ubiquity of OPE exposures, additional research is warranted to understand if these chemicals affect maternal mental health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

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.

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diet is known to affect the gut microbiota and the serum metabolome in adults, but this has not been fully explored in infants. Infancy is an important developmental period that may influence a person's long-term health. Infant development can be affected by diet, which also interacts with the developing gut microbiota., Objectives: This study aimed to explore the associations between diet, the gut microbiota, and the serum metabolome of 1-y-old infants with the overarching goal of identifying serum biomarkers of diet and/or the gut microbiota., Methods: We derived dietary patterns of 1-y-old infants (n = 182) participating in the Canadian South Asian Birth Cohort (START) study. We compared gut microbiota α-diversity and β-diversity and taxa relative abundance from 16S rRNA gene profiles with dietary patterns (PERMANOVA, Envfit) and investigated diet-serum metabolite associations using a multivariate analysis (partial least squares-discriminant analysis) and univariate analysis (t test). We explored the effect of nondietary factors on diet-serum metabolite relationships by incorporating diet, the gut microbiota, and maternal, perinatal, and infant characteristics in a multivariable forward stepwise regression. We replicated this analysis in White European infants, from the CHILD Cohort Study (n = 81)., Results: A dietary pattern characterized by formula consumption and negatively associated with breastfeeding most strongly predicted variation in the gut microbiota (R 2 = 0.109) and serum metabolome (R 2 = 0.547). Breastfed participants showed higher abundance of microbes from the genera Bifidobacterium (3.29 log2-fold) and Lactobacillus (7.93 log2-fold) and higher median concentrations of the metabolites S-methylcysteine (1.38 μM) and tryptophan betaine (0.43 μM) than nonbreastfed participants. Formula consuming infants showed higher median concentrations of branched-chain/aromatic amino acids (average 48.3 μM) than non-formula-consuming infants., Conclusions: Formula consumption and breastfeeding most strongly predicted the serum metabolites of 1-y-old infants, even when the gut microbiota, solid food consumption, and other covariates were considered., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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 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., 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., Competing Interests: MA holds a Tier 2 Canada Research Chair in the Developmental Origins of Chronic Disease at the University of Manitoba and is a Fellow in the Canadian Institutes for Advanced Research (CIFAR) Humans and the Microbiome Program. She receives research funding from the Canadian Institutes of Health Research, Research Manitoba, the Canada Foundation for Innovation, the Bill and Melinda Gates Foundation, the Manitoba Children’s Hospital Foundation, Prolacta Biosciences, Mitacs, CIFAR, the Garfield Weston Foundation, Health Data Research UK, and Canadian COVID Immunity Task Force. She regularly speaks at conferences and workshops on infant nutrition, some sponsored by Prolacta Biosciences, and has spoken at a conference sponsored by AstraZeneca. She has contributed without remuneration to online courses on breast milk and the infant microbiome produced by Microbiome Courses. She serves in a volunteer capacity for the International Society for Research on Human Milk and Lactation and as a member of the US Canada Joint Human Milk Initiative. She has consulted for DSM Nutritional Products and serves on the Malaika Vx Scientific Advisory Board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dekker, Azad, Boeren, Mandhane, Moraes, Simons, Subbarao, Turvey, Saccenti and Hettinga.)

Importance: Despite advances in asthma therapeutics, the burden remains highest in preschool children; therefore, it is critical to identify primary care tools that distinguish preschool children at high risk for burdensome disease for further evaluation. Current asthma prediction tools, such as the modified Asthma Predictive Index (mAPI), require invasive tests, limiting their applicability in primary care and low-resource settings., Objective: To develop and evaluate the use of a symptom-based screening tool to detect children at high risk of asthma, persistent wheeze symptoms, and health care burden., Design, Setting, and Participants: The cohort for this diagnostic study included participants from the CHILD Study (n = 2511) from January 1, 2008, to December 31, 2012, the Raine Study from January 1, 1989, to December 31, 2012 (n = 2185), and the Canadian Asthma Primary Prevention Study (CAPPS) from January 1, 1989, to December 31, 1995 (n = 349), with active follow-up to date. Data analysis was performed from November 1, 2019, to May 31, 2022., Exposures: The CHILDhood Asthma Risk Tool (CHART) identified factors associated with asthma in patients at 3 years of age (timing and number of wheeze or cough episodes, use of asthma medications, and emergency department visits or hospitalizations for asthma or wheeze) to identify children with asthma or persistent symptoms at 5 years of age., Main Outcomes and Measures: Within the CHILD Study cohort, CHART was evaluated against specialist clinician diagnosis and the mAPI. External validation was performed in both a general population cohort (Raine Study [Australia]) and a high-risk cohort (CAPPS [Canada]). Predictive accuracy was measured by sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and positive and negative predicted values., Results: Among 2511 children (mean [SD] age at 3-year clinic visit, 3.08 [0.17] years; 1324 [52.7%] male; 1608 of 2476 [64.9%] White) with sufficient questionnaire data to apply CHART at 3 years of age, 2354 (93.7%) had available outcome data at 5 years of age. CHART applied in the CHILD Study at 3 years of age outperformed physician assessments and the mAPI in predicting persistent wheeze (AUROC, 0.94; 95% CI, 0.90-0.97), asthma diagnosis (AUROC, 0.73; 95% CI, 0.69-0.77), and health care use (emergency department visits or hospitalization for wheeze or asthma) (AUROC, 0.70; 95% CI, 0.61-0.78). CHART had a similar predictive performance for persistent wheeze in the Raine Study (N = 2185) in children at 5 years of age (AUROC, 0.82; 95% CI, 0.79-0.86) and CAPPS (N = 349) at 7 years of age (AUROC, 0.87; 95% CI, 0.80-0.94)., Conclusions and Relevance: In this diagnostic study, CHART was able to identify children at high risk of asthma at as early as 3 years of age. CHART could be easily incorporated as a routine screening tool in primary care to identify children who need monitoring, timely symptom control, and introduction of preventive therapies.

Background/objective: The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories., Methods: BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed., Results: Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium., Conclusion: This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

Background: The "old friends" hypothesis posits that reduced exposure to previously ubiquitous microorganisms is one factor involved in the increased rates of allergic diseases. Cytomegalovirus (CMV) may be one of the "old friends" hypothesized to help prevent allergic diseases. We sought to elucidate whether early-life CMV infection is associated with childhood atopy via perturbations of the gut microbiota., Methods: Participants were recruited from a population-based birth cohort (CHILD study) and followed prospectively until age 5 years in four Canadian cities. A total of 928 participants provided stool microbiome data, urine for CMV testing, skin prick tests, and questionnaire-based detailed environmental exposures. Cytomegalovirus infection was assessed in the first year of life while the main outcome was defined by persistent sensitization to any allergen at ages 1, 3, and 5 years., Results: Early CMV infection was associated with increased beta and decreased alpha diversity of the gut microbiota. Both changes in diversity measures and early CMV infection were associated with persistent allergic sensitization at age 5 years (aOR = 2.08; 95% CI: 1, 4.33). Mediation analysis demonstrated that perturbation of gut microbial composition explains 30% of the association., Conclusions: Early-life CMV infection is associated with an alteration in the intestinal microbiota, which mediates the effect of the infection on childhood atopy. This work indicates that preventing CMV infection would not put children at increased risk of developing atopy. Rather, a CMV vaccine, in addition to preventing CMV-associated morbidity and mortality, might reduce the risk of childhood allergic diseases., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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., (© 2021. The Author(s).)

Purpose: This is a pilot study that describes the feasibility and clinical course of a cohort of preschool children with severe asthma undergoing a combined adenotonillectomy (TA), bronchoscopy (B), and bronchoalveolar lavage (BAL) procedure., Methods: A retrospective cohort study of preschool patients with severe asthma who underwent a combined TA-B-BAL procedure between 2012 and 2019. Subjects were treated at a tertiary care asthma clinic and had a diagnosis of preschool asthma according to the Canadian Thoracic Society Guidelines. Data on demographics, clinical characteristics, medication use, virology and microbiology from bronchoalveolar lavage, and asthma control questionnaires were collected. Variables were analyzed using paired t test., Results: Eighteen preschool subjects (mean age 3.19 ± 1.13 years) with severe asthma were identified through the asthma clinic. Patients treated with standard asthma care and a combined  TA-B-BAL procedure  experienced a decrease in the number of oral steroid courses (p = 0.017), emergency department visits (p = 0.03) and wheezing exacerbations (p = 0.026) following the procedure. Ten patients experienced clinically meaningful improvements in TRACK scores after the procedure (p < 0.001)., Conclusion: This pilot study provides early evidence that a combined TA-B-BAL procedure is feasible in preschool children with severe asthma and that the procedure may reduce asthma medication use and hospital visits., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)