Elinor Simons

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.

Fecal Short-Chain Fatty Acid Variations by Breastfeeding Status in Infants at 4 Months: Differences in Relative versus Absolute Concentrations

Our gut microbiota provide a number of important functions, one of which is the metabolism of dietary fiber and other macronutrients that are undigested by the host. The main products of this fermentation process are short-chain fatty acids (SCFAs) and other intermediate metabolites including lactate and succinate. Production of these metabolites is dependent on diet and gut microbiota composition. There is increasing evidence for the role of SCFAs in host physiology and metabolic processes as well as chronic inflammatory conditions such as allergic disease and obesity. We aimed to investigate differences in fecal SCFAs and intermediate metabolites in 163 infants at 3–5 months of age according to breastfeeding status. Compared to no exposure to human milk at time of fecal sample collection, exclusive breastfeeding was associated with lower absolute concentrations of total SCFAs, acetate, butyrate, propionate, valerate, isobutyrate, and isovalerate, yet higher concentrations of lactate. Further, the relative proportion of acetate was higher with exclusive breastfeeding. Compared to non-breastfed infants, those exclusively breastfed were four times more likely (aOR 4.50, 95% CI 1.58–12.82) to have a higher proportion of acetate relative to other SCFAs in their gut. This association was independent of birth mode, intrapartum antibiotics, infant sex, age, recruitment site, and maternal BMI or socioeconomic status. Our study confirms that breastfeeding strongly influences the composition of fecal microbial metabolites in infancy.

Cesarean Section, Formula Feeding, and Infant Antibiotic Exposure: Separate and Combined Impacts on Gut Microbial Changes in Later Infancy

Established during infancy, our complex gut microbial community is shaped by medical interventions and societal preferences, such as cesarean section, formula feeding, and antibiotic use. We undertook this study to apply the significance analysis of microarrays (SAM) method to quantify changes in gut microbial composition during later infancy following the most common birth and postnatal exposures affecting infant gut microbial composition. Gut microbiota of 166 full-term infants in the Canadian Healthy Infant Longitudinal Development birth cohort were profiled using 16S high-throughput gene sequencing. Infants were placed into groups according to mutually exclusive combinations of birth mode (vaginal/cesarean birth), breastfeeding status (yes/no), and antibiotic use (yes/no) by 3 months of age. Based on repeated permutations of data and adjustment for the false discovery rate, the SAM statistic identified statistically significant changes in gut microbial abundance between 3 months and 1 year of age within each infant group. We observed well-known patterns of microbial phyla succession in later infancy (declining Proteobacteria; increasing Firmicutes and Bacteroidetes) following vaginal birth, breastfeeding, and no antibiotic exposure. Genus Lactobacillus, Roseburia, and Faecalibacterium species appeared in the top 10 increases to microbial abundance in these infants. Deviations from this pattern were evident among infants with other perinatal co-exposures; notably, the largest number of microbial species with unchanged abundance was seen in gut microbiota following early cessation of breastfeeding in infants. With and without antibiotic exposure, the absence of a breast milk diet by 3 months of age following vaginal birth yielded a higher proportion of unchanged abundance of Bacteroidaceae and Enterobacteriaceae in later infancy, and a higher ratio of unchanged Enterobacteriaceae to Alcaligenaceae microbiota. Gut microbiota of infants born vaginally and exclusively formula fed became less enriched with family Veillonellaceae and Clostridiaceae, showed unchanging levels of Ruminococcaceae, and exhibited a greater decline in the Rikenellaceae/Bacteroidaceae ratio compared to their breastfed, vaginally delivered counterparts. These changes were also evident in cesarean-delivered infants to a lesser extent. The clinical relevance of these trajectories of microbial change is that they culminate in taxon-specific abundances in the gut microbiota of later infancy, which we and others have observed to be associated with food sensitization.

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.

Is breastfeeding protective against the development of asthma or wheezing in children? A systematic review and meta-analysis

Methods Prospective cohort studies of preschool (4-6 years) and school-aged (7-9 years) children were identified from Medline (1948-June 2011) and Embase (1980-June 2011). Breastfeeding exposure for at least the first 3-4 months of life was defined as exclusive (breast milk as the only source of nutrition) or any (breast milk included in the diet). Outcomes were parent-reported PDA or wheezing. Risk of bias in included studies was assessed using the Newcastle-Ottawa scale. Data were analyzed using the Revman software package and adjusted odds ratios were meta-analyzed using random-effects models.

Optimizing oral immunotherapy to cow milk protein: a decision analysis

For an 8-year-old child, OIT resulted in a 0.9 QALYs gain compared with strict avoidance; this benefit increased to 1.9 QALYs for a 16-year-old. Sensitivity analysis showed that OIT became the preferred strategy within 6 years of starting OIT. The models were sensitive to the state utilities, but not to the transition probabilities between states. Probabilities of reactions had to be over 10 times the literature-based estimates for OIT to no longer be the preferred strategy. Limitations of these models included the paucity of utility measures for children with CMA and the possible under-reporting of CMA-related reactions or death. Conclusions For children with CMA, OIT offers improved QALYs and the benefits outweigh the risks within a few years. Determination of utilities for younger children with CMA will help to further address this question.

Are dispensing patterns for epinephrine autoinjectors age-appropriate in children?

Failure to inject epinephrine in a timely manner during acute allergic reactions in community settings potentially increases the likelihood of receiving multiple doses of epinephrine in the emergency department, hospital admission, and fatality. As advised by national guidelines, patients at an increased risk of anaphylaxis in community settings should carry self-injectable epinephrine in the form of epinephrine autoinjectors (EAIs). The recommended epinephrine dose for the initial treatment of anaphylaxis in children is 0.01 mg/kg intramuscularly. In the United States and Canada, EAIs are available in fixed doses of 0.15 and 0.3 mg. Although manufacturers recommend 0.15 mg for patients weighing 15 to 30 kg and 0.3 mg for those weighing 30 kg, medical professional organization guidelines currently recommend the 0.15 mg dose for patients weighing <25 to 30 kg and the 0.3 mg dose for those weighing >25 to 30 kg. Our objectives were to determine EAI dispensing patterns and factors affecting dose selection in Manitoba children from 2011 to 2015. This project was approved by the University of Manitoba Human Research Ethics Board (H2015:254) and Health Information Privacy Committee (2015/2016-13). We studied EAI dispensing from 2011 to 2015 using the Drug Programs Information Network (DPIN), an online pointof-sale prescription drug database generated by real-time computer links with all Manitoba pharmacies for all residents, regardless of patient insurance coverage. This database is housed in the Manitoba Centre for Health Policy at the University of Manitoba and maintained by Manitoba Health and Healthy Living. We identified the number of children for whom at least one form of injectable epinephrine was dispensed from birth up to but not including the 17th birthday and their age at the time of dispensing. We also determined if, within the previous 6 months, the children had been dispensed one or more asthma medications such as inhaled corticosteroids, leukotriene modifiers and longand short-acting bronchodilators. We extracted demographic data from the Manitoba Health Registry including sex, region of residence, income quintile, and the Socio-Economic Factor Index-2 (SEFI-2) measure of social and material deprivation. We analyzed whether EAI doses were higher or lower than expected for the child’s age. Most 5-year-olds were expected to have a 0.15 mg EAI because 25 kg is approximately the 97th percentile for weight at age 5 years; the 0.3 mg dose was considered higher than expected for children 5 years. Most 12year-olds were expected to have a 0.3 mg EAI because 30 kg is approximately the 3rd percentile for weight at age 12 years; the 0.15 mg dose was considered to be lower than expected for children 12 years. We used multivariable logistic regression models to evaluate covariates that may have influenced higheror lower-than-expected dosing. From 2011 to 2015, injectable epinephrine was dispensed 32,419 times for 10,006 children comprising 2.8% of Manitoba children. Of the injectable epinephrine formulations dispensed, 98.6% were EpiPen or Allerject (Auvi-Q). The total number of EAIs dispensed increased each year (Fig 1). Among children 5 years, 3.14% (95% confidence interval [CI]: 2.83% to 3.47%) had a 0.3 mg EAI dispensed, including 233 of the 5-year-olds (9.08%), 88 of the 4-year-olds (3.57%), and 49 of the 0to 3-year-olds (0.73%). Among children 12 years, 1.83% had a 0.15 mg EAI dispensed (95% CI: 1.54% to 2.16%), including 62 of the 12-year-olds (3.72%), 37 of the 13year-olds (2.32%), 16 of the 14-year-olds (1.09%), and 23 of the 15and 16-year-olds (0.82%). In multivariable analysis, children 5 years with higher-thanexpected doses dispensed had higher odds of asthma medication being dispensed (adjusted odds ratio [OR] 1.46, 95% CI: 1.171.81), family income in the lowest 20% (OR 2.23, 95% CI: 1.62-3.07), and nonurban residence (OR 1.51, 95% CI: 1.221.88) (Table I). Children 12 years with lower-than-expected doses dispensed had lower odds of asthma medication being dispensed (OR 0.65, 95% CI: 0.46-0.91) and higher odds of family income in the lowest 20% (OR 2.02, 95% CI: 1.20-3.41) (Table I). When social and material deprivation was evaluated instead of income quintile, a 1 standard deviation increase in SEFI-2 was associated with increased odds of a higher-thanexpected dose for young children (OR 1.39, 95% CI: 1.261.53) (Table E1, available in this article’s Online Repository at www.jaci-inpractice.org).

Associations between Neighborhood Walkability and Incident and Ongoing Asthma in Children

Rationale: Childhood asthma has shown variable associations with childrens physical activity. Neighborhood walkability captures community features that promote walking and is protective against some chronic conditions, such as obesity and diabetes. Objectives: We evaluated associations between home neighborhood walkability and incident and ongoing childhood asthma. Methods: In this population‐based cohort study, we used prospectively collected administrative healthcare data for the Province of Ontario housed at the Institute for Clinical Evaluative Sciences. We followed an administrative data cohort of 326,383 Toronto children born between 1997 and 2003, inclusive, until ages 8‐15 years. Home neighborhood walkability quintile was measured using a validated walkability index with four dimensions: population density, dwelling density, access to retail and services, and street connectivity. Incident asthma was defined by time of entry into the validated Ontario Asthma Surveillance Information System database, which requires two outpatient visits for asthma within two consecutive years or any hospitalization for asthma and follows children with asthma longitudinally starting at any age. Associations between walkability and incident asthma were examined using Cox proportional hazards models. Associations between ongoing asthma and walkability in each year of life were examined using generalized linear mixed models. Results: Twenty‐one percent of children (n = 69,628) developed incident asthma and were followed longitudinally in the Ontario Asthma Surveillance Information System database. Low birth home neighborhood walkability was associated with an increased incidence of asthma (hazard ratio, 1.11; 95% confidence interval, 1.08‐1.14). Among children with asthma, low walkability in a given year of a child`s life was associated with greater odds of ongoing asthma in the same year (odds ratio, 1.12; 95% confidence interval, 1.09‐1.14). Conclusions: Children living in neighborhoods with low walkability were at increased risk of incident and ongoing asthma. Neighborhood walkability improvement, such as by adding pedestrian paths to improve street connectivity, offers potential strategies to contribute to primary asthma prevention.

Associations between second-hand smoke exposure in pregnancy and age of childhood asthma development

Background Maternal smoking during pregnancy has been associated with an increased hazard of incident childhood asthma. We investigated the association between any secondhand smoke exposure in early life and childhood asthma development. Methods In the Toronto Child Health Evaluation Questionnaire, parents of 5619 grades 1-2 students reported age of physician-diagnosed asthma development, exposure to maternal and household second-hand smoke during pregnancy and the first year of life, socio-demographic factors, and other early-life exposures such as mold and cockroach. Using Cox proportional hazard models, we evaluated the longitudinal associations between second-hand smoke exposure and age of asthma development. Results Household second-hand smoke exposure prevalence was 8.3% during pregnancy and 10.6% in the first year of life; 15.5% of children developed asthma. After adjusting for sex, prematurity, being born in Canada and maternal asthma, children exposed to home second-hand smoke during pregnancy were more likely to develop asthma and developed asthma sooner [adjusted hazard ratio (HR) 1.36, 95% confidence interval (CI): 1.09, 1.70], even after excluding children whose mothers smoked in pregnancy (HR 1.53, 95% CI: 1.09, 2.14). The association strengthened (HR 1.88, 95% CI: 1.16, 3.02) after adjusting for home second-hand smoke exposure in the first year. Conclusions Home second-hand smoke exposure during pregnancy is associated with an increased hazard of childhood asthma development, even if the mother is not a smoker. Recommendations for smoking cessation during pregnancy should focus on pregnant women and members of their households.

How do questionnaire definitions of atopy status affect sample size calculations for asthma cohort studies in a population of Canadian children

Background Skin prick tests (SPT) are the gold standard for determining atopy. In epidemiological studies of childhood allergy, questionnaire responses are often used to define atopy and predict sample size. Questionnaire-reported hayfever symptoms have shown 28-76% sensitivity and 21-94% specificity compared to SPT. We evaluated how questionnaire definitions of atopy affect sensitivity, specificity and sample size calculations in a population of Canadian children.