BackgroundThis study investigated the relationship between objectively measured physical activity (PA) and gut microbiota composition during pregnancy.MethodsIn an ongoing birth cohort study, the Fitbit Charge wearable activity monitor was used to objectively measure PA during pregnancy. To profile the composition of gut bacterial microbiota, 16S rRNA sequencing was performed on a third trimester stool sample. Differences in alpha diversity metrics (richness, Pielou’s evenness, and Faith’s phylogenetic diversity) by PA were determined using linear regression, whereas beta diversity (unweighted and weighted UniFrac, Canberra, and Bray-Curtis) relationships were assessed using permutational multivariate analysis of variance (PERMANOVA). Differential abundance testing at both the amplicon sequence variants and genus level was conducted using Analysis of Compositions of Microbiomes with Bias Correction 2; tests were corrected for false discovery rate (FDR) and considered significant if pFDR < 0.05.ResultsThe analytic sample included 68 pregnant women with both PA and 16S rRNA sequencing data (median age [quartile 1; quartile 3] = 30.7 [26.6; 33.3] years; 56% Black). Women typically took around 5000 steps per day (second trimester median = 5486; third trimester median = 5074) and the majority of activity minutes were classified as sedentary (second trimester median = 77%; third trimester median = 78%). None of the PA variables during the second or third trimester were associated with gut microbiota richness, evenness, or diversity. After covariate adjustment, the proportion sedentary during the second (Weighted UniFrac p = 0.035, R2 = 0.038) and third (Bray-Curtis p = 0.034, R2 = 0.025) trimesters were significantly associated with stool microbiota composition. Additionally, the proportion “fairly” or “very active” during the third trimester was significantly associated with stool microbiota composition (PERMANOVA; Bray-Curtis p = 0.047, R2 = 0.025). These compositional differences were partly characterized by significantly lower abundances of Prevotella and Pasteurellaceae ASVs and higher abundances of Acidaminococcus and Finegoldia in pregnant women with higher second and third trimester sedentary time (pFDR < 0.05). Two specific 16S rRNA sequence variants (ASV_84 [Acidaminococcus intestine] and ASV_134 [Oscillospirales sp.]) were also positively associated with sedentary behavior. No significant microbial changes were observed with the proportion of time spent “fairly” or “very active” during the third trimester.ConclusionsThese findings highlight sedentary behavior as a potential modifiable factor related with maternal gut microbiota composition during pregnancy. This study forms the basis for future studies on the impact of sedentary time on gut microbiota during pregnancy.

“One-chemical-at-a-time” approaches are typically used to investigate adverse health outcomes associated with exposure to environmental chemicals during pregnancy. However, nontargeted high-resolution mass spectrometry (HRMS) approaches can instead measure complex, real-world mixtures of xenobiotics and metabolic products and may better explain mechanisms of toxicity and identify biomarkers of exposure than single-chemical approaches during pregnancy, a particularly sensitive exposure window. Here, our objective was to use a nontargeted, HRMS approach that monitors endogenous and xenobiotic compounds to identify associations of pollutant mixtures with metabolic pathways in serum of 100 pregnant women from the MARCH cohort (Michigan Archive for Research on Child Health). Xenobiotic mixtures were identified based on in-house libraries as well as a discovery-based approach, FluoroMatch 3.0, to identify nonlegacy/emerging fluorinated chemicals in these same samples. Metabolic pathways of interest were determined using MetaboAnalyst software and effect estimates on metabolic profiles were estimated for both individual contaminants and mixtures of all identified chemicals. 415 endogenous metabolites and 21 individual chemical pollutants were detected with high identification confidence and included per- and poly-fluoroalkyl substances (PFAS), phthalates, bisphenols, organophosphate esters (OPEs), and parabens. An additional 105 tentative fluorinated compounds were identified via FluoroMatch. As classes of toxicants, bisphenol and PFAS mixtures showed the greatest number of associations with metabolic pathways related to arginine, proline, glycine, serine, and threonine metabolism. When the total mixture of all 21 contaminants was modeled after covariate-adjustment, biosynthesis of unsaturated fatty acids remained (FDR < 0.05). Taken together, these findings illustrate that serum concentrations of environmental contaminants may be associated with some metabolic pathways in pregnancy and that mixture modeling identified fatty acid metabolism as a possible pathway of interest for future validation. These findings further demonstrate the potential of robust nontargeted exposome-wide approaches as tools to study and identify the mechanisms of toxicity underlying human disease.

Vaccine hesitancy is a growing concern in public health. Since its introduction, Black/African Americans have been less likely to receive the first dose of the COVID-19 vaccine despite the alarming death rate observed for this community. Past studies on vaccine hesitancy have placed an emphasis on the role of parental decision-making in their child's vaccination. In this study, we explore how the role of racial identity contributes to COVID-19 vaccine hesitancy among Black/African American adults, as a foundational step prior to tailored intervention development. We administered a survey to a convenience sample of 501 Black/African American individuals in Detroit. Random forest models were built to predict vaccine hesitancy using demographics, racial factors, perceived vaccine risk, and perceived risk of contracting COVID-19 (COVID-19 risk). We observed eight important variables predictive of vaccine hesitancy including perceived vaccine risk, trait reactance, age, vaccine actual knowledge score, perceived COVID risk, conspiracy theories, racial consciousness, and racial fairness. The prediction accuracy of these eight variables combined was high, achieving an Area Under the Curve (AUC) of 0.87, a sensitivity of 75%, and a specificity of 89%. In this convenience sample of Black/African Americans, racial variables, among other factors, were associated with vaccine hesitancy. Given that tailored interventions have shown promise in behavior change, results suggest that these variables may be effective in targeting the concerns of Black/African American adults contemplating receipt of the COVID-19 vaccine.

DNA methylation (DNAm), capturing biological gestational age (GA) and epigenetic gestational age acceleration (EGAA), can be modified by environmental exposures. The Asthma&Allergy array is a new DNAm array developed with content focused on asthma and allergy loci. The association between content on the Asthma&Allergy array and chronological GA and EGAA has not been evaluated alone or in the context of perinatal exposures. We performed an epigenome wide association study(EWAS) based on chronological GA at single CpG sites and regions. We further constructed a multi-CpG site methylation model to predict chronological GA in cord blood from 391 newborn children from a Detroit-based birth cohort. Associations between perinatal environmental factors with GA, epigenetic gestational age (EGA), and EGAA were assessed. We identified 2,435 CpG sites associated with chronological GA. HLA class II (HLA-DRB1,HLA-DQB1,HLA-DRB6) were the most significantly associated with chronological GA. Our multi-CpG site model attained predictive accuracy (cross-validated Pearson's correlation=0.75) comparable to other EGA methods. Using genes implicated in region-based analyses (n=395 regions), the pathways most significantly enriched with chronological GA-associated CpGs included T helper 1(Th1) and 2(Th2) activation, macrophage classical activation, and IL10 signaling, which were also enriched in at least one of the other published epigenetic clocks. In multi-exposure models, prenatal indoor pet exposure and unplanned C-section were associated with EGA deceleration, while infant's first-born status was associated with EGAA. Our findings highlight enrichment for T cell modulated pathways and antigen presentation as biological processes enriched in chronological GA, as well as novel perinatal factors that may impact EGAA.

BACKGROUND:Elevated IgE levels, a higher prevalence of allergic disorders, and a higher incidence of asthma have been reported among Black children compared with White children. Racial classification is a social construct that is partially influenced by genetic ancestry. The factors contributing to racial health disparities remain uncertain but likely reflect complex interactions between genetic susceptibility and environmental exposures. OBJECTIVE:To assess the associations of genetic ancestry with allergic disorders, IgE production, and lung function among Black children. METHODS:Prospective data from the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study (WHEALS) birth cohort were analyzed. Race was assigned by maternal report, and Black, non-Hispanic/non-Arabic children were identified (n = 345, 53.3% male). Genome-wide continental percent African ancestry (PAA) was estimated. Associations between PAA and longitudinal total IgE trajectory (from birth to age 10), allergic sensitization, allergic disorders, and spirometry at 10 years were examined. Models were adjusted for confounders, including available variables associated with social determinants of health. RESULTS:A total of 102 participants (56%) were sensitized to 1 or more allergens; 47 (27.5%) had asthma. Each 10-percentage-point increase in PAA was associated with a 68% increased risk of asthma (relative risk [RR], 1.68; 95% CI, 1.16-2.45; P = .007), a 30% higher risk of sensitization to common allergens (RR, 1.30; 95% CI, 1.04-1.63; P = .019), and a decrease in forced expiratory volume in 1 second (FEV1%) predicted by 2.67% (β -2.57; 95% CI, -5.19 to 0.06; P = .055). No association was identified between PAA and total IgE trajectory (P = .11). CONCLUSION:Among Black children, PAA is associated with an increased risk of asthma, allergen-specific IgE sensitization, and decreased lung function at 10 years.

Rationale: Race-based estimates of pulmonary function in children could influence the evaluation of asthma in children from racial and ethnic minoritized backgrounds. Objectives: To determine if race-neutral (Global Lung Function Initiative [GLI]-Global) versus race-specific (GLI-Race-Specific) reference equations differentially impact spirometry evaluation of childhood asthma. Methods: The analysis included 8,719 children aged 5 to <12 years from 27 cohorts across the United States grouped by parent-reported race and ethnicity. We analyzed how the equations affected FEV1, FVC, and FEV1/FVC z-scores. We used multivariable logistic models to evaluate associations between z-scores calculated with different equations and asthma diagnosis, emergency department visits, and hospitalization. Measurements and Main Results: For Black children, the GLI-Global versus GLI-Race-Specific equations estimated significantly lower z-scores for FEV1 and FVC but similar values for FEV1/FVC, thus increasing the proportion of children classified with low FEV1 by 14%. Although both equations yielded strong inverse relationships between FEV1 and FEV1/FVC z-scores and asthma outcomes, these relationships varied across racial and ethnic groups (P < 0.05). For any given FEV1 or FEV1/FVC z-score, asthma diagnosis and emergency department visits were higher among Black and Hispanic than among White children (P < 0.05). For FEV1, GLI-Global equations estimated asthma outcomes that were more uniform across racial and ethnic groups. Conclusions: Parent-reported race and ethnicity influenced relationships between lung function and asthma outcomes. Our data show no advantage to race-specific equations for evaluating childhood asthma, and the potential for race-specific equations to obscure lung impairment in disadvantaged children strongly supports using race-neutral equations.

Structural racism (SR) refers to the discriminatory beliefs, methods and strategies that are systemically embedded in the policies and practices of the US. Racial residential segregation, termed "a fundamental cause of health inequities", is central to SR in the US because it impacts economic stability, education, healthcare, neighborhood and built environment, and social and community context for residents. Segregation systematically injects chronic stress in the lives of residents through a variety of mechanisms including polluting industries and liquor stores in Black communities, chronic unemployment fueled by job loss and decentralization, aggressive policing, increased incarceration rates for Black residents, and under-resourced schools. Spatial manifestations of SR have been linked to stress responses, immune dysregulation, and heightened chronic inflammation among US Black individuals consistent with accumulation of tissue damage or allostatic load which refers to the "cumulative burden of chronic stress and life events". This chronic stress has been termed "weathering", a concept which posits that the stress of racial discrimination, including residential segregation, has biological effects that are pro-inflammatory, and predictive of chronic conditions, such as heart disease, diabetes, and cancer. Maternal exposure to chronic stress, resulting in weathering, can create an inflammatory fetal environment that is transferable to the infant. We hypothesize that a heightened propensity in mothers toward chronic inflammation due to mother's exposure to structural racism can be transferred to her offspring in utero, creating an intergenerational cycle of disadvantage and poor health. Recent and emerging research have introduced methods of objectively measuring exposure to SR as well as measuring the outcome of maternal transfer of the effects of exposure to SR to offspring. Given the evidence that chronic racial stress could lead to inflammation, the observation of elevated levels of inflammatory markers in neonatal dried blood spots (DBS) in relation to maternal exposure to SR, could provide evidence of maternal transfer. Infant blood spots are routinely collected and stored and can be analyzed using untargeted metabolomics to measure metabolite features representing biologically relevant pathways, including biomarkers of inflammation, lipid mediators, and exogenous exposures. Empirical evidence of how SR can initiate processes in early life that manifest in adult disease can corroborate existing theories and generate a paradigm shift that informs interventional research as well as policy.

Long-term birth cohorts are essential for studying health and disease over the life course. The retention of participants remains a challenge in study design. Previous research works on attrition are limited in length of follow-up time and lack of racial/ethnic diversity. Using data from the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study (WHEALS; United States cohort born between 2004 and 2007, n = 1258), we first performed longitudinal latent class analyses to identify patterns of participation spanning the prenatal period and six follow-up timepoints: 1, 6, 12, and 24 months; 3-6 years; and 10-12 years. Data collection included a combination of in-person visits, home visits, home specimen kits, and staff-administered questionnaires. We examined associations between baseline factors and participation class using multinomial logistic regression modeling, and with conditional inference modeling to identify variables most strongly associated with class. We identified four participation classes: high early participation with gradual loss-to-follow-up, sporadic participation, consistently high participation, and consistently low participation. Multiple baseline characteristics were associated with participation class. The "consistently high participation" class was disproportionately composed of participants who were older, were of higher education, had private insurance, had suburban residence, and were with higher income. Conditional inference trees identified maternal education, insurance, and income as most strongly associated with participation class. Through latent class modeling, we show that participants who were lost to follow-up fell into distinct groupings of participation. In the future, preparatory communications with those who are at the highest risk of study discontinuation may improve long-term retention.

Importance:Hypertensive disorders in pregnancy (HDPs) are common and increase the risk of maternal and fetal morbidity and mortality. HDPs may impact fetal growth; however, sex-specific effects have been understudied. Objective:To examine whether sex-specific differences exist in the association between HDPs and birthweight and placental weight. Methods:A birth cohort based in Detroit, Michigan, was utilized (n = 1258). HDPs and birthweight were abstracted from medical records; placental weight was obtained from placental pathology reports. Linear regression was used to model sex-specific associations, after multiple imputation, confounder adjustment, and inverse probability weighting to account for selection bias. Results:The primary analysis included all pregnancies (n = 853), while the secondary analysis included those sent for placental pathology, reflective of complicated pregnancies (n = 165). In the primary analysis subset, males of mothers with gestational hypertension had birthweight Z-scores that were on average 0.90 standard deviations higher, but this association was not found among females (interaction P = 0.019; male β [95% confidence interval {CI}]: 0.90 [0.28, 1.52]; female β [95% CI]: -0.12 [-0.65, 0.41]). However, in the subset of complicated pregnancies, female mothers with gestational hypertension also had reduced birthweight (interaction P = 0.013; male β [95% CI]: 1.50 [0.15, 2.86]; female β [95% CI]: -1.14 [-2.13, -0.16]). For fetoplacental weight ratio, any HDP was associated with a lower ratio among females only (interaction P = 0.028; male β [95% CI]: -0.04 [-0.71, 0.64]; female β [95% CI]: -0.95 [-1.57, -0.33]). Interpretation:Male fetuses may prioritize growth, whereas females may prioritize placental development when exposed to HDPs.

Importance:Atopic dermatitis (AD) is the most common inflammatory disease in childhood, and children with AD are more likely to develop other allergic diseases, including food allergy, allergic rhinitis, and asthma. Objective:To determine the phenotypes of AD expression across 12 US birth cohorts and identify factors associated with phenotype and development of allergic diseases. Design, Setting, and Participants:This cohort study compiled longitudinal data from 12 observational US birth cohorts across decades (children born from April 1980 to June 2019) in the Environmental Influences on Child Health Outcomes (ECHO) Children's Respiratory and Environmental Workgroup with follow-up to September 2022. Participants were enrolled prenatally; children with 3 or more AD assessments across the first 84 months of life were included in analyses. Data were analyzed from December 2020 to April 2024. Exposures:Exposures included decade of birth, cohort type (population-based or high-risk), family history of asthma (mother, father, or sibling), birth order, gestational age at birth, delivery mode, breastfeeding, pet exposure, antibiotic use, environmental tobacco smoke exposure, allergic sensitization, peripheral blood eosinophil count, and total IgE. Main Outcomes and Measures:Primary outcomes were AD phenotype, food allergy, allergic rhinitis, asthma, and wheeze. Longitudinal latent class analysis was used to identify underlying longitudinal patterns of AD expression, and associations of AD phenotype with allergic outcomes were examined using logistic regression, multinomial logistic regression, and linear regression. Results:In 5314 children from 9 cohorts (1896 born in the 2000s [35.7%]; 2585 female [48.6%]; 1083 Black or African American [20.4%]; 3344 White [62.9%]; 350 other reported race [6.6%; including 8 American Indian or Alaska Native (0.2%); 58 Asian (1.1%); 4 Native Hawaiian or Pacific Islander (0.1%) and 280 multiracial or with any race not otherwise specified (5.3%)]), 3382 (63.6%) were from a population-based cohort, while 1932 (36.4%) were from a high-risk cohort. AD prevalence ranged from 24.1% (540 children) to 28.4% (1156 children) at each time point, and 5 phenotypes of AD were identified: transient early AD, early AD with potential reoccurrence, late-onset AD, persistent AD, and minimal or no AD. Compared with White children, Black children were at higher risk for AD (transient early AD: aOR, 3.26; 95% CI, 2.06-5.18; early AD with potential reoccurrence: aOR, 3.72; 95% CI, 2.35-5.90; persistent AD: aOR, 2.01; 95% CI, 1.54-2.63), as were children with other reported race (transient early AD: aOR, 2.31; 95% CI, 1.13-4.70; early AD with potential reoccurrence: aOR, 3.27; 95% CI, 1.73-6.18). Female children were significantly less likely to have early AD with potential reoccurrence (aOR, 0.45; 95% CI, 0.27-0.74) and persistent AD (aOR, 0.60; 95% CI, 0.49-0.74) than male children. Compared with miniml or no AD, phenotypes with early AD expression were associated with food allergy (transient early AD: adjusted odds ratio [aOR], 2.15; 95% CI, 1.48-3.08; early AD with potential reoccurrence: aOR, 2.43; 95% CI, 1.66-3.50; persistent AD: aOR, 2.26; 95% CI, 1.84-2.78), later AD expression was associated with allergic rhinitis (late-onset AD: aOR, 1.84; 95% CI, 1.38-2.43; persistent AD: aOR, 2.02; 95% CI, 1.64-2.48), and any AD disease was associated with asthma. Conclusions and Relevance:In this birth cohort study of 5314 children, timing of AD expression was associated with increased risk for atopic march pathways. Identifying risk factors for AD phenotypes may inform targeted therapeutic prevention strategies.

BACKGROUND:Nocturnal cough affects approximately 1 in 3 children, can negatively affect child health, and is often attributable to asthma. The association of the gut microbiome with nocturnal cough has not been investigated. OBJECTIVE:We investigated the association between early-life gut microbiome composition and nocturnal cough overall and in the context of asthma. METHODS:Gut microbiota 1-month (neonate) and 6-month (infant) specimens from 512 children in the Wayne County, Health, Environment, Allergy, and Asthma Longitudinal Study were profiled using 16S ribosomal RNA V4 sequencing. Nocturnal cough (parental report) and asthma (parent-reported doctor's diagnosis) were assessed at age 4 years. Microbiome regression-based kernel association tests (MiRKAT) were used to assess the relationship between gut microbiota composition and nocturnal cough overall and in the context of asthma. Operational taxonomic unit (OTU) associations were conducted using negative binomial regression, adjusting for multiple comparisons using the false discovery rate. RESULTS:Stool microbial composition differences during infancy were associated with nocturnal cough (weighted UniFrac P = .045); 78 OTUs were significantly associated with nocturnal cough overall (false discovery rate < 0.05); and 110 OTUs were significantly associated with nocturnal cough and differed by asthma status (interaction false discovery rate < 0.05), with a predominance of Lachnospiraceae genera Blautia and Dorea. Thirty-two OTU were identified as having both overall effects and differences by asthma status. Among OTUs with significant nocturnal cough-by-asthma interactions, 84 retained significance in children with asthma, with 45 exclusive to those with asthma (predominance of Bacteroidaceae genus Bacteroides and Lachnospiraceae genus Dorea). CONCLUSION:Infantile gut microbiome development is associated with nocturnal cough and differed by asthma status by age 4 years. Further studies are needed to determine if the gut microbiome may provide additional information for the early identification of children at risk for nocturnal cough, with and without asthma.

The composition of the gut microbiome is dependent on factors including diet, lifestyle, and exposure to environmental chemicals, and has implications for human health. Per- and polyfluoroalkyl substances (PFAS), a class of man-made chemicals that have nonstick and flame-retardant properties may impact on gut microbiome composition. Our objective was to elucidate links between PFAS and maternal gut microbiome composition in two geographically diverse sites of the Environmental Influences on Child Health Outcomes program. The present analysis includes participants in the Atlanta African American Maternal Child Cohort; ATL AA and a predominately non-Hispanic White subsample of the Michigan Archive for Research on Child Health Cohort; MARCH with serum or plasma PFAS concentrations measured in early or late pregnancy and 16s rRNA sequencing from maternal gut microbiome samples available primarily in later pregnancy (2nd-3rd trimester). Linear regression models tested associations between prenatal PFAS levels (separately for the 1st/3rd trimesters) and measures of alpha diversity, bacterial composition differences, and differential taxonomic abundance. Bayesian Kernel Machine Regression and Elastic net regression mixture modeling were also incorporated. In both cohorts, multiple PFAS were significantly associated with the relative abundance of specific microbiome taxa even after adjustment for covariates including maternal diet, age, race, BMI, and smoking; A total of 16 significant family-level associations were identified for ATL AA (e.g., PFOA with Clostridiaceae; natural log fold change = 0.94) and 13 significant family-level associations identified for MARCH e.g., PFOS with Desulfovibrionaceae; natural log fold change = -1.53 (pFDR<0.05), but similarities between cohorts were lacking. Mixture analyses did not identify interactive or combined effects but did provide modest evidence of inclusion of individual PFAS in beta diversity models in both cohorts. In 2 distinct cohorts, there were significant associations between prenatal PFAS and the relative abundance of several bacterial taxa, but these differences were cohort-specific. This work suggests that PFAS may modulate the gut microbiome during pregnancy.

Atopic conditions are common and represent a substantial healthcare burden. Investigation of cord blood IgE as a predictor of future atopic disease has yielded varying results. We aimed to investigate these associations in a racially diverse population through our Wayne County Health, Environment and Allergy Longitudinal (WHEALS) population-based birth cohort.

Introduction The impact of COVID-19 on the placenta is poorly described, particularly among minority women. Materials and methods This is a retrospective case-control study. Micro- and macroscopic placental pathologic findings were compared for 15 COVID-19 positive and 36 negative mothers. Cases and controls were frequency matched on gestational age, race, maternal comorbidities, and delivery type. Data from the electronic medical record were supplemented with independent review of microscopic slides. Results Placentas from cases and controls were similar except the median distance from the site of the cord insertion to the nearest disk margin was statistically significantly shorter among placentas from COVID-19 positive cases (3.5 versus 6.0 cm, p = 0.006). Case status was not associated with an increased risk of placental pathologies. Conclusion There are few pathologic differences between placentas of COVID-19 positive and negative mothers. Additional studies are needed to investigate the role of timing of infection.