Yueh-Hsiu Mathilda Chiu

Prenatal and Postnatal Maternal Stress and Wheeze in Urban Children: Effect of Maternal Sensitization

RATIONALE Critical periods for programming early wheeze risk may include pregnancy and infancy. Effects of timing remain poorly understood. OBJECTIVES Associations among prenatal and postnatal maternal stress and childrens wheeze were prospectively examined in 653 families. Effect modification by maternal sensitization was also examined. METHODS Stress was indexed by a maternal negative life events (NLEs) score (range, 0-9) ascertained during pregnancy and between 1 and 2 years postpartum. Mothers reported child wheeze every 3 months up to age 2 years. Relationships of prenatal and postnatal maternal NLEs with repeated wheeze (≥2 episodes) were examined using logistic regression adjusting for covariates. Penalized splines were implemented to explore possible nonlinear associations. We also examined the interaction between prenatal stress and maternal sensitization indexed by allergen-specific IgE from maternal prenatal serum. MEASUREMENTS AND MAIN RESULTS Adjusted models considering prenatal or postnatal NLEs alone both showed an exposure-response relationship between higher stress and child wheeze. When considering prenatal and postnatal stress concurrently, only children of mothers with high stress in both periods were significantly more likely to wheeze (adjusted odds ratio, 3.04; 95% confidence interval, 1.67-5.53) than children of mothers reporting low stress in both periods. Associations between high prenatal stress and wheeze were significant in children born to nonsensitized mothers (any IgE <0.35 kU/L) but not in the sensitized group (P for interaction = 0.03). CONCLUSIONS Although children have heightened sensitivity to maternal stress in utero and in early childhood, those with higher stress in both periods were particularly at risk for wheeze. The prenatal maternal immune milieu modified effects.

Prenatal Particulate Air Pollution and Asthma Onset in Urban Children. Identifying Sensitive Windows and Sex Differences.

RATIONALE The influence of particulate air pollution on respiratory health starts in utero. Fetal lung growth and structural development occurs in stages; thus, effects on postnatal respiratory disorders may differ based on timing of exposure. OBJECTIVES We implemented an innovative method to identify sensitive windows for effects of prenatal exposure to particulate matter with a diameter less than or equal to 2.5 μm (PM2.5) on childrens asthma development in an urban pregnancy cohort. METHODS Analyses included 736 full-term (≥37 wk) children. Each mothers daily PM2.5 exposure was estimated over gestation using a validated satellite-based spatiotemporal resolved model. Using distributed lag models, we examined associations between weekly averaged PM2.5 levels over pregnancy and physician-diagnosed asthma in children by age 6 years. Effect modification by sex was also examined. MEASUREMENTS AND MAIN RESULTS Most mothers were ethnic minorities (54% Hispanic, 30% black), had 12 or fewer years of education (66%), and did not smoke in pregnancy (80%). In the sample as a whole, distributed lag models adjusting for child age, sex, and maternal factors (education, race and ethnicity, smoking, stress, atopy, prepregnancy obesity) showed that increased PM2.5 exposure levels at 16-25 weeks gestation were significantly associated with early childhood asthma development. An interaction between PM2.5 and sex was significant (P = 0.01) with sex-stratified analyses showing that the association exists only for boys. CONCLUSIONS Higher prenatal PM2.5 exposure at midgestation was associated with asthma development by age 6 years in boys. Methods to better characterize vulnerable windows may provide insight into underlying mechanisms.

Associations between Traffic-Related Black Carbon Exposure and Attention in a Prospective Birth Cohort of Urban Children

Background: Ambient air pollution may have neurotoxic effects in children. Data examining associations between traffic-related air pollution and attention domains remain sparse. Objectives: We examined associations between black carbon (BC), a marker of traffic particles, and attention measures ascertained at 7–14 years of age among 174 children in a birth cohort based in the Boston, Massachusetts, area. Methods: We estimated BC levels using a validated spatial–temporal land-use regression model based on residence during children’s lifetime. Children completed the Conner’s Continuous Performance Test (CPT) measuring omission errors, commission errors, and hit reaction time (HRT), with higher scores indicating increased errors or slower reaction time. Multivariable-adjusted linear regression analyses were used to examine associations between BC and each attention outcome. Results: Children were primarily Hispanic (56%) and Caucasian (41%); 53% were boys. We found a positive association between higher BC levels with increased commission errors and slower HRT, adjusting for child IQ, age, sex, blood lead level, maternal education, pre- and postnatal tobacco smoke exposure, and community-level social stress. Notably, the association was weaker, though still positive, for the highest BC quartile relative to the middle two quartiles. Sex-stratified analysis demonstrated statistically significant associations between BC and both commission errors and HRT in boys, but BC was not significantly associated with any of the CPT outcomes in girls. Conclusions: In this population of urban children, we found associations between BC exposure and higher commission errors and slower reaction time. These associations were overall more apparent in boys than girls.

Associations among maternal childhood socioeconomic status, cord blood IgE levels, and repeated wheeze in urban children

BACKGROUND Independent of current socioeconomic status (SES), past maternal SES might influence asthma outcomes in children. OBJECTIVE We examined associations among the mothers SES in the first 10 years of her life (maternal childhood SES), increased cord blood IgE levels (upper 20% [1.37 IU/mL]), and repeated wheeze (≥ 2 episodes by age 2 years) in an urban pregnancy cohort (n = 510). METHODS Data on sociodemographics, discrimination, financial strain, community violence, interpersonal trauma, and other negative events were obtained prenatally. Prenatal household dust was assayed for cockroach and murine allergens, and traffic-related air pollution was estimated by using spatiotemporal land-use regression. Maternal childhood SES was defined by parental home ownership (birth to 10 years). Maternally reported child wheeze was ascertained at 3-month intervals from birth. Using structural equation models, we examined whether outcomes were dependent on maternal childhood SES directly versus indirect relationships operating through (1) cumulative SES-related adversities, (2) the mothers socioeconomic trajectory (adult SES), and (3) current prenatal environmental exposures. RESULTS Mothers were largely Hispanic (60%) or black (28%), 37% had not completed high school, and 56% reported parental home ownership. When associations between low maternal childhood SES and repeated wheeze were examined, there were significant indirect effects operating through adult SES and prenatal cumulative stress (β = 0.28, P = .003) and pollution (β = 0.24, P = .004; P value for total indirect effects ≤ .04 for both pathways). Low maternal childhood SES was directly related to increased cord blood IgE levels (β = 0.21, P = .003). Maternal cumulative adversity (interpersonal trauma) was also associated with increased cord blood IgE levels (β = 0.19, P = .01), although this did not explain maternal childhood SES effects. CONCLUSION Lower maternal childhood SES was associated with increased cord blood IgE levels and repeated wheeze through both direct and indirect effects, providing new insights into the role of social inequalities as determinants of childhood respiratory risk.

Disrupted Prenatal Maternal Cortisol, Maternal Obesity, and Childhood Wheeze. Insights into Prenatal Programming

RATIONALE Exploring prenatal factors influencing childhood wheeze may inform programming mechanisms. OBJECTIVES We examined associations among prenatal maternal cortisol profiles, maternal obesity, and repeated wheeze up to age 2 years (n = 261). METHODS Salivary cortisol was collected five times per day over 3 days at 29.0 ± 4.9 weeks gestation. Mothers were categorized as obese (body mass index ≥ 30 kg/m(2)) versus nonobese (body mass index < 30 kg/m(2)). Using logistic regression, we examined the influence of log-transformed cortisol metrics (level at each time point, morning rise, diurnal and afternoon slopes) and obesity on wheeze adjusting for covariates. Linear mixed models were implemented to examine associations between cortisol trajectories and wheezing. Interactions between maternal cortisol and obesity were considered. MEASUREMENTS AND MAIN RESULTS Mothers were primarily minority (56.5% Hispanic, 24.1% African American), 61% had less than or equal to 12 years of education, 34% were obese, and 8.4% of children had repeated wheeze. An interquartile range increase in mean log cortisol at bedtime (odds ratio, 2.2; 95% confidence interval, 1.09-4.09) and maternal obesity (odds ratio, 3.43; 95% confidence interval, 1.26-9.35) were independently associated with wheeze. Linear mixed models revealed an association between a flatter afternoon slope (slower decline in log cortisol per hour) and repeated wheeze in children of obese mothers (children with [-0.017 change] and without [-0.061 change] wheeze [P = 0.009 for time × wheeze interaction]), but not in children of nonobese mothers (with [-0.050 change] and without [-0.061 change] wheeze [P = 0.51]). CONCLUSIONS Maternal prenatal cortisol disruption and obesity were independently associated with childrens wheeze. Obese women with adverse cortisol profiles were most likely to have children with repeated wheeze.

Associations between Prenatal traffic-related air pollution exposure and birth weight: Modification by sex and maternal pre-pregnancy body mass index

BACKGROUND Prenatal traffic-related air pollution exposure is linked to adverse birth outcomes. However, modifying effects of maternal body mass index (BMI) and infant sex remain virtually unexplored. OBJECTIVES We examined whether associations between prenatal air pollution and birth weight differed by sex and maternal BMI in 670 urban ethnically mixed mother-child pairs. METHODS Black carbon (BC) levels were estimated using a validated spatio-temporal land-use regression (LUR) model; fine particulate matter (PM2.5) was estimated using a hybrid LUR model incorporating satellite-derived Aerosol Optical Depth measures. Using stratified multivariable-adjusted regression analyses, we examined whether associations between prenatal air pollution and calculated birth weight for gestational age (BWGA) z-scores varied by sex and maternal pre-pregnancy BMI. RESULTS Median birth weight was 3.3±0.6kg; 33% of mothers were obese (BMI ≥30kg/m(3)). In stratified analyses, the association between higher PM2.5 and lower birth weight was significant in males of obese mothers (-0.42 unit of BWGA z-score change per IQR increase in PM2.5, 95%CI: -0.79 to -0.06) ( PM2.5×sex×obesity Pinteraction=0.02). Results were similar for BC models (Pinteraction=0.002). CONCLUSIONS Associations of prenatal exposure to traffic-related air pollution and reduced birth weight were most evident in males born to obese mothers.

Prenatal Nitrate Exposure and Childhood Asthma. Influence of Maternal Prenatal Stress and Fetal Sex

Rationale: Impact of ambient pollution upon childrens asthma may differ by sex, and exposure dose and timing. Psychosocial stress can also modify pollutant effects. These associations have not been examined for in utero ambient nitrate exposure. Objectives: We implemented Bayesian‐distributed lag interaction models to identify sensitive prenatal windows for the influence of nitrate (NO3−) on child asthma, accounting for effect modification by sex and stress. Methods: Analyses included 752 mother‐child dyads. Daily ambient NO3− exposure during pregnancy was derived using a hybrid chemical transport (Geos‐Chem)/land‐use regression model and natural log transformed. Prenatal maternal stress was indexed by a negative life events score (high [>2] vs. low [≤2]). The outcome was clinician‐diagnosed asthma by age 6 years. Measurements and Main Results: Most mothers were Hispanic (54%) or black (29%), had a high school education or less (66%), never smoked (80%), and reported low prenatal stress (58%); 15% of children developed asthma. BDILMs adjusted for maternal age, race, education, prepregnancy obesity, atopy, and smoking status identified two sensitive windows (7‐19 and 33‐40 wk gestation), during which increased NO3− was associated with greater odds of asthma, specifically among boys born to mothers reporting high prenatal stress. Cumulative effects of NO3− across pregnancy were also significant in this subgroup (odds ratio = 2.64, 95% confidence interval = 1.27‐5.39; per interquartile range increase in ln NO3−). Conclusions: Prenatal NO3− exposure during distinct sensitive windows was associated with incident asthma in boys concurrently exposed to high prenatal stress.

Potential for Bias When Estimating Critical Windows for Air Pollution in Children’s Health

Evidence supports an association between maternal exposure to air pollution during pregnancy and childrens health outcomes. Recent interest has focused on identifying critical windows of vulnerability. An analysis based on a distributed lag model (DLM) can yield estimates of a critical window that are different from those from an analysis that regresses the outcome on each of the 3 trimester-average exposures (TAEs). Using a simulation study, we assessed bias in estimates of critical windows obtained using 3 regression approaches: 1) 3 separate models to estimate the association with each of the 3 TAEs; 2) a single model to jointly estimate the association between the outcome and all 3 TAEs; and 3) a DLM. We used weekly fine-particulate-matter exposure data for 238 births in a birth cohort in and around Boston, Massachusetts, and a simulated outcome and time-varying exposure effect. Estimates using separate models for each TAE were biased and identified incorrect windows. This bias arose from seasonal trends in particulate matter that induced correlation between TAEs. Including all TAEs in a single model reduced bias. DLM produced unbiased estimates and added flexibility to identify windows. Analysis of body mass index z score and fat mass in the same cohort highlighted inconsistent estimates from the 3 methods.

Prenatal fine particulate exposure and early childhood asthma: Effect of maternal stress and fetal sex

Background The impact of prenatal ambient air pollution on child asthma may be modified by maternal stress, child sex, and exposure dose and timing. Objective We prospectively examined associations between coexposure to prenatal particulate matter with an aerodynamic diameter of less than 2.5 microns (PM2.5) and maternal stress and childhood asthma (n = 736). Methods Daily PM2.5 exposure during pregnancy was estimated using a validated satellite‐based spatiotemporally resolved prediction model. Prenatal maternal negative life events (NLEs) were dichotomized around the median (high: NLE ≥ 3; low: NLE < 3). We used Bayesian distributed lag interaction models to identify sensitive windows for prenatal PM2.5 exposure on childrens asthma by age 6 years, and determine effect modification by maternal stress and child sex. Results Bayesian distributed lag interaction models identified a critical window of exposure (19‐23 weeks’ gestation, cumulative odds ratio, 1.15; 95% CI, 1.03‐1.26; per interquartile range [1.7 &mgr;g/m3] increase in prenatal PM2.5 level) during which children concomitantly exposed to prenatal PM2.5 and maternal stress had increased risk of asthma. No significant association was seen in children born to women reporting low prenatal stress. When examining modifying effects of prenatal stress and fetal sex, we found that boys born to mothers with higher prenatal stress were most vulnerable (19‐21 weeks’ gestation; cumulative odds ratio, 1.28; 95% CI, 1.15‐1.41; per interquartile range increase in PM2.5). Conclusions Prenatal PM2.5 exposure during sensitive windows is associated with increased risk of child asthma, especially in boys concurrently exposed to elevated maternal stress.

Bayesian distributed lag interaction models to identify perinatal windows of vulnerability in children’s health

Epidemiological research supports an association between maternal exposure to air pollution during pregnancy and adverse childrens health outcomes. Advances in exposure assessment and statistics allow for estimation of both critical windows of vulnerability and exposure effect heterogeneity. Simultaneous estimation of windows of vulnerability and effect heterogeneity can be accomplished by fitting a distributed lag model (DLM) stratified by subgroup. However, this can provide an incomplete picture of how effects vary across subgroups because it does not allow for subgroups to have the same window but different within-window effects or to have different windows but the same within-window effect. Because the timing of some developmental processes are common across subpopulations of infants while for others the timing differs across subgroups, both scenarios are important to consider when evaluating health risks of prenatal exposures. We propose a new approach that partitions the DLM into a constrained functional predictor that estimates windows of vulnerability and a scalar effect representing the within-window effect directly. The proposed method allows for heterogeneity in only the window, only the within-window effect, or both. In a simulation study we show that a model assuming a shared component across groups results in lower bias and mean squared error for the estimated windows and effects when that component is in fact constant across groups. We apply the proposed method to estimate windows of vulnerability in the association between prenatal exposures to fine particulate matter and each of birth weight and asthma incidence, and estimate how these associations vary by sex and maternal obesity status in a Boston-area prospective pre-birth cohort study.