Hsiao-Hsien Leon Hsu

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.

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.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents

Introduction: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school‐age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. Methods: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right‐handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11–14 years old. We examined the relationships of tooth Mn (ln‐transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. Results: We found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn × sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye‐hand coordination in boys compared to girls in sex‐stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right‐hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). Conclusions: This study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex‐specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex‐specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period. HighlightsLiterature on perinatal Mn exposure and motor function in adolescents is limited.We used a novel tooth biomarker to reconstruct prenatal and childhood Mn exposure.Sex‐specific association between Mn exposure and neuromotor functions was observed.Prenatal Mn was associated with better body stability in boys but instability in girls.

Prenatal particulate air pollution exposure and body composition in urban preschool children: Examining sensitive windows and sex-specific associations

Background Evolving animal studies and limited epidemiological data show that prenatal air pollution exposure is associated with childhood obesity. Timing of exposure and child sex may play an important role in these associations. We applied an innovative method to examine sex‐specific sensitive prenatal windows of exposure to PM2.5 on anthropometric measures in preschool‐aged children. Methods Analyses included 239 children born ≥ 37 weeks gestation in an ethnically‐mixed lower‐income urban birth cohort. Prenatal daily PM2.5 exposure was estimated using a validated satellite‐based spatio‐temporal model. Body mass index z‐score (BMI‐z), fat mass, % body fat, subscapular and triceps skinfold thickness, waist and hip circumferences and waist‐to‐hip ratio (WHR) were assessed at age 4.0 ± 0.7 years. Using Bayesian distributed lag interaction models (BDLIMs), we examined sex differences in sensitive windows of weekly averaged PM2.5 levels on these measures, adjusting for child age, maternal age, education, race/ethnicity, and pre‐pregnancy BMI. Results Mothers were primarily Hispanic (55%) or Black (26%), had ≤ 12 years of education (66%) and never smoked (80%). Increased PM2.5 exposure 8–17 and 15–22 weeks gestation was significantly associated with increased BMI z‐scores and fat mass in boys, but not in girls. Higher PM2.5 exposure 10–29 weeks gestation was significantly associated with increased WHR in girls, but not in boys. Prenatal PM2.5 was not significantly associated with other measures of body composition. Estimated cumulative effects across pregnancy, accounting for sensitive windows and within‐window effects, were 0.21 (95%CI = 0.01–0.37) for BMI‐z and 0.36 (95%CI = 0.12–0.68) for fat mass (kg) in boys, and 0.02 (95%CI = 0.01–0.03) for WHR in girls, all per &mgr;g/m3 increase in PM2.5. Conclusions Increased prenatal PM2.5 exposure was more strongly associated with indices of increased whole body size in boys and with an indicator of body shape in girls. Methods to better characterize vulnerable windows may provide insight into underlying mechanisms contributing to sex‐specific associations. HighlightsData‐driven method to identify sensitive windows of prenatal PM2.5 on anthropometry.Findings suggested time‐dependent associations and effect modification by sex.Sex‐specific temporal associations may provide insights into underlying mechanisms.

Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex

Objectives To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. Study design Analyses included 314 mother–infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist‐Revised. Fenton birthweight for gestational age z‐scores (BWGA‐z) were calculated. A 3‐cm scalp‐nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA‐z and examine 2‐ and 3‐way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA‐z as a function of cortisol. Results Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1‐unit increase in trauma score was associated with a 0.19‐unit decrease in BWGA‐z (95% CI, −0.34 to −0.04). Associations among females were nonsignificant, regardless of cortisol level. Conclusions These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.

Association between particulate air pollution exposure during pregnancy and postpartum maternal psychological functioning

Postpartum psychological functioning impacts both women’s health and outcomes in children. Lower income, ethnic minority women may be at particular risk for adverse postpartum mental health outcomes. Studies link ambient air pollution exposure with psychological dysfunction in adults although this association has not been examined among postpartum women. Methods We studied associations between prenatal exposure to particulate matter with diameter ≤ 2.5 μm (PM2.5) and postpartum psychological functioning in a lower income, ethnically mixed sample of urban US women enrolled in a pregnancy cohort study. Analyses included 557 mothers who delivered at ≥37 weeks gestation. Daily estimates of residential PM2.5 over gestation were derived using a satellite-based spatio-temporally resolved model. Outcomes included the Edinburgh Postnatal Depression Scale (EPDS) score from 6 or 12 months postpartum and subscale scores for anhedonia, depressive and anxiety symptoms. Associations were also examined within racial/ethnic groups. Distributed lag models (DLMs) were implemented to identify windows of vulnerability during pregnancy. Results Most mothers had less than a high school education (64%) and were primarily Hispanic (55%) and Black (29%). In the overall sample, a DLM adjusted for age, race, education, prenatal smoking, and season of delivery, we found significant associations between higher PM2.5 exposure in the second trimester and increased anhedonia subscale scores postpartum. In race stratified analyses, mid-pregnancy PM2.5 exposure was significantly associated with increased total EPDS scores as well as higher anhedonia and depressive symptom subscale scores among Black women. Conclusions Increased PM2.5 exposure in mid-pregnancy was associated with increased depressive and anhedonia symptoms, particularly in Black women.

Prenatal nitrate air pollution exposure and reduced child lung function: Timing and fetal sex effects

Background: Prenatal particulate air pollution exposure may alter lung growth and development in utero in a time‐sensitive and sex‐specific manner, resulting in reduced lung function in childhood. Such relationships have not been examined for nitrate (NO3‐). Methods: We implemented Bayesian distributed lag interaction models (BDLIMs) to identify sensitive prenatal windows for the influence of NO3‐ on lung function at age 7 years, assessing effect modification by fetal sex. Analyses included 191 mother‐child dyads. Daily ambient NO3‐ exposure over pregnancy was estimated using a hybrid chemical transport (Geos‐Chem)/land‐use regression model. Spirometry was performed at mean (SD) age of 6.99 (0.89) years, with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) z‐scores accounting for child age, sex, height and race/ethnicity. Results: Most mothers were Hispanic (65%) or Black (22%), had ≤ high school education (67%), and never smoked (71%); 17% children had asthma. BDILMs adjusted for maternal age and education and childs asthma identified an early sensitive window of 6–12 weeks gestation, during which increased NO3‐ was significantly associated with reduced FEV1 z‐scores specifically among boys. BDLIM analyses demonstrated similar sex‐specific patterns for FVC. Conclusion: Early gestational NO3‐ exposure is associated with reduced child lung function, especially in boys. HighlightsPrenatal nitrate exposure is associated with reduced lung function at age 7 yearsLink between prenatal nitrate exposure and lung function deficits is male‐specificSignificant effects occur during early sensitive window of 6‐12 weeks gestation