The use of prescription medications and non-prescription medications during lactation in a prospective Canadian cohort study.

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.

Antibiotics within first year are linked to infant gut microbiome disruption and elevated atopic dermatitis risk.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD. OBJECTIVE: This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD. METHODS: We used statistical modelling and differential analysis to link CHILD participants' history of antibiotic usage and early-life gut microbiome alterations to atopic dermatitis. RESULTS: Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio (aOR) = 1.81 [95% CI = 1.28 - 2.57], p < 0.001), with an increased number of antibiotic courses corresponding to a dose-response-like increased risk of AD risk (1 course: aOR = 1.67 [95% CI = 1.17 - 2.38]; 2 or more courses: aOR = 2.16 [95% CI = 1.30 - 3.59]). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (ßindirect = 0.072, p < 0.001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium, Eubacterium spp., and fermentative pathways. CONCLUSION: Our findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.

Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity.

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.

Pre-labor and post-labor cesarean delivery and early childhood adiposity in the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study.

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.

Maternal Iron and Vitamin D Status during the Second Trimester Is Associated with Third Trimester Depression Symptoms among Pregnant Participants in the APrON Cohort.

BACKGROUND: The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. OBJECTIVES: This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. METHODS: The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. RESULTS: Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (ß: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (ß: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (ß: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 µg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (ß: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 µg/L) and vitamin D (25(OH)D <75 nmol/L) (ß: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. CONCLUSIONS: A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.

Perinatal and early life factors and asthma control among preschoolers: a population-based retrospective cohort study.

BACKGROUND: Preventing poor childhood asthma control is crucial for short-term and long-term respiratory health. This study evaluated associations between perinatal and early-life factors and early childhood asthma control. METHODS: This retrospective study used administrative health data from mothers and children born 2010-2012 with a diagnosis of asthma before age 5 years, in Alberta, Canada. The outcome was asthma control within 2 years after diagnosis. Associations between perinatal and early-life factors and risk of partly and uncontrolled asthma were evaluated by multinomial logistic regression. RESULTS: Of 7206 preschoolers with asthma, 52% had controlled, 37% partly controlled and 12% uncontrolled asthma 2 years after diagnosis. Compared with controlled asthma, prenatal antibiotics (adjusted risk ratio (aRR): 1.19; 95% CI 1.06 to 1.33) and smoking (aRR: 1.18; 95% CI 1.02 to 1.37), C-section delivery (aRR: 1.11; 95% CI 1.00 to 1.25), summer birth (aRR: 1.16; 95% CI 1.00 to 1.34) and early-life hospitalisation for respiratory illness (aRR: 2.24; 95% CI 1.81 to 2.76) increased the risk of partly controlled asthma. Gestational diabetes (aRR: 1.41; 95% CI 1.06 to 1.87), C-section delivery (aRR: 1.18; 95% CI 1.00 to 1.39), antibiotics (aRR: 1.32; 95% CI 1.08 to 1.61) and hospitalisation for early-life respiratory illness (aRR: 1.65; 95% CI 1.19 to 2.27) were associated with uncontrolled asthma. CONCLUSION: Maternal perinatal and early-life factors including antibiotics in pregnancy and childhood, gestational diabetes, prenatal smoking, C-section and summertime birth, and hospitalisations for respiratory illness are associated with partly or uncontrolled childhood asthma. These results underline the significance of perinatal health and the lasting effects of early-life experiences on lung development and disease programming.

Delayed gut microbiota maturation in the first year of life is a hallmark of pediatric allergic disease.

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 (ßindirect = -2.28; p = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.

Maternal Iron Status Is Dynamic Throughout Pregnancy and Might Predict Birth Outcomes in a Sex Dependent Manner: Results from the Alberta Pregnancy Outcomes and Nutrition (APrON) Cohort Study.

BACKGROUND: Developmental responses to nutrient deprivation may differ by fetal sex. Despite this, relationships between maternal prenatal iron biomarkers and birth outcomes when stratifying by offspring sex are poorly described, especially in healthy cohorts. OBJECTIVES: This study aimed to determine associations between maternal iron biomarkers and birth weights (BWs) and birth head circumferences (BHCs) among female and male newborns to assess whether the potential predictive ability of iron biomarkers on birth outcomes differs by offspring sex. METHODS: The Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study recruited 2189 pregnant individuals from Calgary and Edmonton, Canada. Maternal blood was drawn at each trimester and 3 mo postpartum. Maternal serum ferritin (SF) concentrations were measured using chemiluminescent immunoassays and erythropoietin (EPO), hepcidin, and soluble transferrin receptor (sTfR) using enzyme-linked immunosorbent assays. Ratios of sTfR:SF and hepcidin:EPO were calculated and birth outcomes accessed through delivery records. Directed acyclic graphs informed multivariate regression models. RESULTS: The risk of maternal iron deficiency increased throughout pregnancy because ∼61% showed depleted iron stores (SF < 15 µg/L) by the third trimester. Maternal hepcidin, SF, sTfR, and sTfR:SF concentrations changed across time (P < 0.01), and participants carrying female fetuses consistently (across 6 biomarkers) showed a lower iron status during the third trimester compared with those with male fetuses (P < 0.05). Higher maternal SF and hepcidin:EPO during the third trimester was associated with lower BWs in males (P = 0.006 for SF; P = 0.03 for hepcidin:EPO) and females (P = 0.02 for SF; P = 0.02 for hepcidin:EPO). There were additional inverse associations between BWs and third trimester maternal hepcidin (P = 0.03) and hemoglobin (P = 0.004) and between BHCs and maternal SF (second trimester; P < 0.05) and Hb (third trimester P = 0.02) but only in males. CONCLUSIONS: Relationships between maternal iron biomarkers and BWs and BHCs may depend on the timing of pregnancy and offpsring sex. There was a high risk of third trimester iron storage depletion among generally healthy pregnant individuals.

Natural Green Spaces, Sensitization to Allergens, and the Role of Gut Microbiota during Infancy.

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.

Impact of Cesarean Delivery and Breastfeeding on Secretory Immunoglobulin A in the Infant Gut Is Mediated by Gut Microbiota and Metabolites.

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 Supplements, Fecal Microbiota and Their Metabolites at 3 Months of Age in the CHILD Study Cohort.

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 (aß: 0.37, 95% CI 0.03, 0.71 & aß: -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.

Breastfeeding enrichment of B. longum subsp. infantis mitigates the effect of antibiotics on the microbiota and childhood asthma risk.

BACKGROUND: Early antibiotic exposure is linked to persistent disruption of the infant gut microbiome and subsequent elevated pediatric asthma risk. Breastfeeding acts as a primary modulator of the gut microbiome during early life, but its effect on asthma development has remained unclear. METHODS: We harnessed the CHILD cohort to interrogate the influence of breastfeeding on antibiotic-associated asthma risk in a subset of children (n = 2,521). We then profiled the infant microbiomes in a subset of these children (n = 1,338) using shotgun metagenomic sequencing and compared human milk oligosaccharide and fatty acid composition from paired maternal human milk samples for 561 of these infants. FINDINGS: Children who took antibiotics without breastfeeding had 3-fold higher asthma odds, whereas there was no such association in children who received antibiotics while breastfeeding. This benefit was associated with widespread "re-balancing" of taxonomic and functional components of the infant microbiome. Functional changes associated with asthma protection were linked to enriched Bifidobacterium longum subsp. infantis colonization. Network analysis identified a selection of fucosylated human milk oligosaccharides in paired maternal samples that were positively associated with B. infantis and these broader functional changes. CONCLUSIONS: Our data suggest that breastfeeding and antibiotics have opposing effects on the infant microbiome and that breastfeeding enrichment of B. infantis is associated with reduced antibiotic-associated asthma risk. FUNDING: This work was supported in part by the Canadian Institutes of Health Research; the Allergy, Genes and Environment Network of Centres of Excellence; Genome Canada; and Genome British Columbia.

The maternal prenatal and offspring early-life gut microbiome of childhood asthma phenotypes.

BACKGROUND: The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown. METHODS: Our objective was to identify associations between features of the prenatal and early-life fecal microbiomes and child asthma phenotypes. We analyzed fecal 16 s rRNA microbiome profiling and fecal metabolomic profiling from stool samples collected from mothers during the third trimester of pregnancy (n = 120) and offspring at ages 3-6 months (n = 265), 1 (n = 436) and 3 years (n = 506) in a total of 657 mother-child pairs participating in the Vitamin D Antenatal Asthma Reduction Trial. We used clinical data from birth to age 6 years to characterize subjects with asthma as having early, transient or active asthma phenotypes. In addition to identifying specific genera that were robustly associated with asthma phenotypes in multiple covariate-adjusted models, we clustered subjects by their longitudinal microbiome composition and sought associations between fecal metabolites and relevant microbiome and clinical features. RESULTS: Seven maternal and two infant fecal microbial taxa were robustly associated with at least one asthma phenotype, and a longitudinal gut microenvironment profile was associated with early asthma (Fisher exact test p = .03). Though mode of delivery was not directly associated with asthma, we found substantial evidence for a pathway whereby cesarean section reduces fecal Bacteroides and microbial sphingolipids, increasing susceptibility to early asthma. CONCLUSION: Overall, our results suggest that the early-life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years.

Sex-specific associations among infant food and atopic sensitizations and infant neurodevelopment.

Introduction: Food 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. Methods: Associations 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. Results: Atopic 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). Conclusion: In 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.

From Prescription Drugs to Natural Health Products: Medication Use in Canadian Infants.

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.

Moving beyond descriptive studies: harnessing metabolomics to elucidate the molecular mechanisms underpinning host-microbiome phenotypes.

Advances in technology and software have radically expanded the scope of metabolomics studies and allow us to monitor a broad transect of central carbon metabolism in routine studies. These increasingly sophisticated tools have shown that many human diseases are modulated by microbial metabolism. Despite this, it remains surprisingly difficult to move beyond these statistical associations and identify the specific molecular mechanisms that link dysbiosis to the progression of human disease. This difficulty stems from both the biological intricacies of host-microbiome dynamics as well as the analytical complexities inherent to microbiome metabolism research. The primary objective of this review is to examine the experimental and computational tools that can provide insights into the molecular mechanisms at work in host-microbiome interactions and to highlight the undeveloped frontiers that are currently holding back microbiome research from fully leveraging the benefits of modern metabolomics.

Early Life Antimicrobial Exposure: Impact on Clostridioides difficile Colonization in Infants.

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.

Pathways of atopic disease and neurodevelopmental impairment: assessing the evidence for infant antibiotics.

INTRODUCTION: Epidemiologic studies are starting to report associations between antibiotic use in early life and neurodevelopmental disorders. Through mechanisms within the gut microbiota-brain axis, indeed, it is plausible that infant antibiotic treatment plays a role in the development of atopic disease and neurodevelopmental disorders. AREAS COVERED: This narrative review summarizes and interprets published evidence on infant antibiotic use in future outcomes of atopic disease, and neurodevelopmental delay and disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). To this end, we critically assess study bias from two main confounding factors, maternal/infant infection and infant feeding status. We also discuss common mechanisms that link atopy and neurodevelopment, and propose hypotheses related to immune activation and the gut microbiome. EXPERT OPINION: Atopic disease and neurodevelopmental disorders share many risk factors and biological pathways. Infant antibiotic use has been linked to both disorders and is likely a marker for prenatal or infant infection. The mediating role of breastfeeding can also not be discounted. The exploration of causal pathways along the gut-brain axis leading toward neurodevelopmental impairment is evolving and of future interest.

Childhood body mass index and associations with infant gut metabolites and secretory IgA: findings from a prospective cohort study.

BACKGROUND/OBJECTIVES: Differences in gut microbiota, metabolites and immune markers have been observed between individuals with and without obesity. Our study determined the temporal association between infant fecal gut metabolites, sIgA and body mass index (BMI) z score of preschool children, independent of pre/postnatal factors. SUBJECTS/METHODS: The study includes a subset of 647 infants from the CHILD Cohort Study (recruited between January 1, 2009, and December 31, 2012). Fecal metabolites and sIgA were measured at 3-4 months of age, and age and sex adjusted BMI z scores at 1 and 3 years of age. Associations between the metabolites, IgA, and child BMI z scores at age 1 and 3 years were tested using linear regression adjusted for pre/postnatal factors (breastfeeding, birthweight-for-gestational age, birthmode and IAP, solid food introduction). RESULTS: Mean BMI z score for all infants was 0.34 (SD 1.16) at 1 year (N = 647) and 0.71 (SD 1.06) at 3 years (N = 573). High fecal formate in infancy was associated with a significantly lower BMI z score (adjusted mean difference -0.23 (95% CI -0.42, -0.04)) and high butyrate was associated with a higher BMI z score (adjusted mean difference 0.21 (95% CI 0.01, 0.41)) at age 3 years only. The influence of formate and butyrate on BMI z score at age 3 were seen only in those that were not exclusively breastfed at stool sample collection (adjusted mean difference for high formate/EBF- group: -0.33 (95%CI -0.55, -0.10) and 0.25 (95% CI 0.02, 0.47) for high butyrate/EBF- group). No associations were seen between sIgA and BMI z score at age 1 or 3 years in adjusted regression models. CONCLUSION AND RELEVANCE: Differences in fecal metabolite levels in early infancy were associated with childhood BMI. This study identifies an important area of future research in understanding the pathogenesis of obesity.