Diana L. Lefebvre

The Canadian Healthy Infant Longitudinal Development (CHILD) Study: examining developmental origins of allergy and asthma

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study recruited 3624 pregnant women, most partners and 3542 eligible offspring. We hypothesise that early life physical and psychosocial environments, immunological, physiological, nutritional, hormonal and metabolic influences interact with genetics influencing allergic diseases, including asthma. Environmental and biological sampling, innate and adaptive immune responses, gene expression, DNA methylation, gut microbiome and nutrition studies complement repeated environmental and clinical assessments to age 5. This rich data set, linking prenatal and postnatal environments, diverse biological samples and rigorous phenotyping, will inform early developmental pathways to allergy, asthma and other chronic inflammatory diseases.

The Canadian Healthy Infant Longitudinal Development Birth Cohort Study: Biological Samples and Biobanking

BACKGROUND It is hypothesised that complex interactions between genetic and environmental factors give rise to allergy and asthma in childhood. The Canadian Healthy Infant Longitudinal Development (CHILD) study was designed to explore these factors. METHODS CHILD is a longitudinal, general population birth cohort study following infants from mid-pregnancy to age 5 years. Over this time period, biological samples, questionnaires, clinical measures and environmental data are collected. RESULTS A total of 3624 families have been recruited, and many thousands of samples and questionnaires have been collected, annotated, and archived. This report outlines the rationale and methodology for collecting and storing diverse biological samples from parents and children in this study, and the mechanisms for their release for analyses. CONCLUSIONS The CHILD sample and data repository is a tremendous current and future resource and will provide a wealth of information not only informing studies of asthma and allergy, but also potentially in many other aspects of health relevant for Canadian infants and children.

Timing of food introduction and development of food sensitization in a prospective birth cohort

The effect of infant feeding practices on the development of food allergy remains controversial. We examined the relationship between timing and patterns of food introduction and sensitization to foods at age 1 year in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study.

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures

The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set.

Breastfeeding, maternal asthma and wheezing in the first year of life: a longitudinal birth cohort study

The impact of breastfeeding on respiratory health is uncertain, particularly when the mother has asthma. We examined the association of breastfeeding and wheezing in the first year of life. We studied 2773 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Caregivers reported on infant feeding and wheezing episodes at 3, 6 and 12 months. Breastfeeding was classified as exclusive, partial (supplemented with formula or complementary foods) or none. Overall, 21% of mothers had asthma, 46% breastfed for at least 12 months and 21% of infants experienced wheezing. Among mothers with asthma, breastfeeding was inversely associated with infant wheezing, independent of maternal smoking, education and other risk factors (adjusted rate ratio (aRR) 0.52; 95% CI 0.35–0.77 for ≥12 versus <6 months breastfeeding). Compared with no breastfeeding at 6 months, wheezing was reduced by 62% with exclusive breastfeeding (aRR 0.38; 95% CI 0.20–0.71) and by 37% with partial breastfeeding supplemented with complementary foods (aRR 0.63; 95% CI 0.43–0.93); however, breastfeeding was not significantly protective when supplemented with formula (aRR 0.89; 95% CI 0.61–1.30). Associations were not significant in the absence of maternal asthma (p-value for interaction <0.01). Breastfeeding appears to confer protection against wheezing in a dose-dependent manner among infants born to mothers with asthma. When mums with asthma #breastfeed longer, their babies are less likely to wheezehttp://ow.ly/KWEk3089ZEn

Modes of Infant Feeding and the Risk of Childhood Asthma: A Prospective Birth Cohort Study

Objective To determine whether different modes of infant feeding are associated with childhood asthma, including differentiating between direct breastfeeding and expressed breast milk. Study design We studied 3296 children in the Canadian Healthy Infant Longitudinal Development birth cohort. The primary exposure was infant feeding mode at 3 months, reported by mothers and categorized as direct breastfeeding only, breastfeeding with some expressed breast milk, breast milk and formula, or formula only. The primary outcome was asthma at 3 years of age, diagnosed by trained healthcare professionals. Results At 3 months of age, the distribution of feeding modes was 27% direct breastfeeding, 32% breastfeeding with some expressed breast milk, 26% breast milk and formula, and 15% formula only. At 3 years of age, 12% of children were diagnosed with possible or probable asthma. Compared with direct breastfeeding, any other mode of infant feeding was associated with an increased risk of asthma. These associations persisted after adjusting for maternal asthma, ethnicity, method of birth, infant sex, gestational age, and daycare attendance (some expressed breast milk: aOR, 1.64, 95% CI, 1.12‐2.39; breast milk and formula, aOR, 1.73, 95% CI, 1.17‐2.57; formula only: aOR, 2.14, 95% CI, 1.37‐3.35). Results were similar after further adjustment for total breastfeeding duration and respiratory infections. Conclusions Modes of infant feeding are associated with asthma development. Direct breastfeeding is most protective compared with formula feeding; indirect breast milk confers intermediate protection. Policies that facilitate and promote direct breastfeeding could have impact on the primary prevention of asthma.

Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study

Background: The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years. Methods: Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available. Results: Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11‐1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7‐fold (RR, 7.04; 95% CI, 4.13‐11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33‐11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20‐27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19‐35.36). Conclusions: Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

Adiponectin, leptin and insulin in breast milk: associations with maternal characteristics and infant body composition in the first year of life

Background/Objectives:Breastfeeding may protect against excessive weight gain during infancy. However, the breast milk components responsible for this effect are unknown. We examined the variation of three breast milk hormones (adiponectin, leptin and insulin) according to maternal characteristics and determined their association with infant body composition.Subjects/Methods:We studied a representative subset of 430 breastfed infants in the CHILD birth cohort. Breast milk was collected at 4 months postpartum and hormone concentrations were measured using the MesoScale Discovery System. Weight-for-length (WFL) and body mass index (BMI) z-scores were calculated according to the World Health Organization reference standard from infant anthropometrics measured at 4 months and 1 year. Maternal BMI and demographics were self-reported.Results:Breast milk hormone concentrations varied widely between mothers. The geometric mean (range) was 19.4 (3.7–74.4) ngml−1 for adiponectin; 361 (31–3968) pgml−1 for leptin; and 589 (53–5557) pgml−1 for insulin. Maternal BMI was positively correlated with breast milk insulin (r=+0.40, P<0.0001) and leptin (r=+0.71, P<0.0001), but not adiponectin (r=−0.02, P=0.68). Breast milk hormone concentrations were also associated with maternal ethnicity, parity and breastfeeding exclusivity at sample collection. Independent of these factors and maternal diabetes, smoking and breastfeeding duration, higher breast milk leptin was associated with lower infant WFL z-score at 4 months (β −0.67, 95% confidence interval (CI): −1.17, −0.17 for highest vs lowest quintile) and 1 year (β −0.58, 95% CI: −1.02, −0.14). Insulin showed a U-shaped association, with intermediate concentrations predicting the lowest infant WFL z-score at 4 months (β −0.51, 95% CI: −0.87, −0.15 for third vs lowest quintile) and 1 year (β −0.35, 95% CI: −0.66, −0.04). Similar results were seen with infant BMI. Breast milk adiponectin was not significantly associated with infant body composition.Conclusions:Breast milk hormone concentrations were associated with several fixed and modifiable maternal characteristics. Higher concentrations of leptin and intermediate concentrations of insulin were associated with lower infant WFL in the first year of life.

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

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p < 0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p < 0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca2 +-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.

Association of Exposure to Formula in the Hospital and Subsequent Infant Feeding Practices With Gut Microbiota and Risk of Overweight in the First Year of Life

Importance The effect of neonatal and infant feeding practices on childhood obesity is unclear. The gut microbiome is strongly influenced by feeding practices and has been linked to obesity. Objective To characterize the association between breastfeeding, microbiota, and risk of overweight during infancy, accounting for the type and timing of supplementary feeding. Design, Setting, and Participants In this study of a subset of 1087 infants from the prospective CHILD pregnancy cohort, mothers were recruited between January 1, 2009, and December 31, 2012. Statistical analysis was performed from February 1 to December 20, 2017. Main Outcomes and Measures Feeding was reported by mothers and documented from hospital records. Fecal microbiota at 3 to 4 months (from 996 infants) and/or 12 months (from 821 infants) were characterized by 16S ribosomal RNA sequencing. Infants with a weight for length exceeding the 85th percentile were considered to be at risk for overweight. Results There were 1087 infants in the study (507 girls and 580 boys); at 3 months, 579 of 1077 (53.8%) were exclusively breastfed according to maternal report. Infants who were exclusively formula fed at 3 months had an increased risk of overweight in covariate-adjusted models (53 of 159 [33.3%] vs 74 of 386 [19.2%]; adjusted odds ratio, 2.04; 95% CI, 1.25-3.32). This association was attenuated (adjusted odds ratio, 1.33; 95% CI, 0.79-2.24) after further adjustment for microbiota features characteristic of formula feeding at 3 to 4 months, including higher overall richness and enrichment of Lachnospiraceae. A total of 179 of 579 infants who were exclusively breastfed (30.9%) received formula as neonates; this brief supplementation was associated with lower relative abundance of Bifidobacteriaceae and higher relative abundance of Enterobacteriaceae at 3 to 4 months but did not influence the risk of overweight. At 12 months, microbiota profiles differed significantly according to feeding practices at 6 months; among partially breastfed infants, formula supplementation was associated with a profile similar to that of nonbreastfed infants (higher diversity and enrichment of Bacteroidaceae), whereas the introduction of complementary foods without formula was associated with a profile more similar to that of exclusively breastfed infants (lower diversity and enrichment of Bifidobacteriaceae and Veillonellaceae). Microbiota profiles at 3 months were more strongly associated with risk of overweight than were microbiota profiles at 12 months. Conclusions and Relevance Breastfeeding may be protective against overweight, and gut microbiota may contribute to this effect. Formula feeding appears to stimulate changes in microbiota that are associated with overweight, whereas other complementary foods do not. Subtle microbiota differences emerge after brief exposure to formula in the hospital. These results identify important areas for future research and distinguish early infancy as a critical period when transient gut dysbiosis may lead to increased risk of overweight.