Incident hypertension in relation to aircraft noise exposure: results of the DEBATS longitudinal study in France.

BACKGROUND: Although several cross-sectional studies have shown that aircraft noise exposure was associated with an increased risk of hypertension, a limited number of longitudinal studies have addressed this issue. This study is part of the DEBATS (Discussion on the health effect of aircraft noise) research programme and aimed to investigate the association between aircraft noise exposure and the incidence of hypertension. METHODS: In 2013, 1244 adults living near three major French airports were included in this longitudinal study. Systolic and diastolic blood pressure, as well as demographic and lifestyle factors, were collected at baseline and after 2 and 4 years of follow-up during face-to-face interviews. Exposure to aircraft noise was estimated for each participant's home address using noise maps. Statistical analyses were performed using mixed Poisson and linear regression models adjusted for potential confounding factors. RESULTS: A 10 dB(A) increase in aircraft noise levels in terms of Lden was associated with a higher incidence of hypertension (incidence rate ratio (IRR)=1.36, 95% CI 1.02 to 1.82). The association was also significant for Lday (IRR 1.41, 95% CI 1.07; to 1.85) and Lnight (IRR 1.31, 95% CI 1.01 to 1.71). Systolic and diastolic blood pressure increased with all noise indicators. CONCLUSION: These results strengthen those obtained from the cross-sectional analysis of the data collected at the time of inclusion in DEBATS, as well as those from previous studies conducted in other countries. Hence, they support the hypothesis that aircraft noise exposure may be considered as a risk factor for hypertension.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

The Influence of Meteorological Factors and Atmospheric Pollutants on the Risk of Preterm Birth.

Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the -5°C to 15°C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure.

A systematic comparison of statistical methods to detect interactions in exposome-health associations.

BACKGROUND: There is growing interest in examining the simultaneous effects of multiple exposures and, more generally, the effects of mixtures of exposures, as part of the exposome concept (being defined as the totality of human environmental exposures from conception onwards). Uncovering such combined effects is challenging owing to the large number of exposures, several of them being highly correlated. We performed a simulation study in an exposome context to compare the performance of several statistical methods that have been proposed to detect statistical interactions. METHODS: Simulations were based on an exposome including 237 exposures with a realistic correlation structure. We considered several statistical regression-based methods, including two-step Environment-Wide Association Study (EWAS2), the Deletion/Substitution/Addition (DSA) algorithm, the Least Absolute Shrinkage and Selection Operator (LASSO), Group-Lasso INTERaction-NET (GLINTERNET), a three-step method based on regression trees and finally Boosted Regression Trees (BRT). We assessed the performance of each method in terms of model size, predictive ability, sensitivity and false discovery rate. RESULTS: GLINTERNET and DSA had better overall performance than the other methods, with GLINTERNET having better properties in terms of selecting the true predictors (sensitivity) and of predictive ability, while DSA had a lower number of false positives. In terms of ability to capture interaction terms, GLINTERNET and DSA had again the best performances, with the same trade-off between sensitivity and false discovery proportion. When GLINTERNET and DSA failed to select an exposure truly associated with the outcome, they tended to select a highly correlated one. When interactions were not present in the data, using variable selection methods that allowed for interactions had only slight costs in performance compared to methods that only searched for main effects. CONCLUSIONS: GLINTERNET and DSA provided better performance in detecting two-way interactions, compared to other existing methods.

Within-subject Pooling of Biological Samples to Reduce Exposure Misclassification in Biomarker-based Studies.

BACKGROUND: For chemicals with high within-subject temporal variability, assessing exposure biomarkers in a spot biospecimen poorly estimates average levels over long periods. The objective is to characterize the ability of within-subject pooling of biospecimens to reduce bias due to exposure misclassification when within-subject variability in biomarker concentrations is high. METHODS: We considered chemicals with intraclass correlation coefficients of 0.6 and 0.2. In a simulation study, we hypothesized that the chemical urinary concentrations averaged over a given time period were associated with a health outcome and estimated the bias of studies assessing exposure that collected 1 to 50 random biospecimens per subject. We assumed a classical type error. We studied associations using a within-subject pooling approach and two measurement error models (simulation extrapolation and regression calibration), the latter requiring the assay of more than one biospecimen per subject. RESULTS: For both continuous and binary outcomes, using one sample led to attenuation bias of 40% and 80% for compounds with intraclass correlation coefficients of 0.6 and 0.2, respectively. For a compound with an intraclass correlation coefficient of 0.6, the numbers of biospecimens required to limit bias to less than 10% were 6, 2, and 2 biospecimens with the pooling, simulation extrapolation, and regression calibration methods (these values were, respectively, 35, 8, and 2 for a compound with an intraclass correlation coefficient of 0.2). Compared with pooling, these methods did not improve power. CONCLUSION: Within-subject pooling limits attenuation bias without increasing assay costs. Simulation extrapolation and regression calibration further limit bias, compared with the pooling approach, but increase assay costs.

Air pollution during pregnancy and childhood cognitive and psychomotor development: six European birth cohorts.

BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 µm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 µg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

Effects of aircraft noise exposure on self-reported health through aircraft noise annoyance: Causal mediation analysis in the DEBATS longitudinal study in France.

BACKGROUND: Previous studies reported an association between transportation noise and self-reported health status (SRHS). They also suggested a mediating role of noise annoyance using conventional statistical methods. These methods are subject to bias in longitudinal studies with time-dependent exposure, mediator and confounding factors. This study aims to investigate the mediating role of aircraft noise annoyance in the effect of aircraft noise on SRHS using a causal inference approach to address time-dependent variables issues. METHODS: We used data from 881 participants in all three visits in the DEBATS longitudinal study conducted around three French airports. Participants over 18 years of age reported their self-perceived health status, aircraft noise annoyance, and noise sensitivity by completing a questionnaire at three visits in 2013, 2015 and 2017. Noise maps were used to estimate aircraft noise levels outside their homes. Marginal structural models with inverse probability weighting were used to estimate the total effect of aircraft noise levels on SRHS and its decomposition into direct and indirect effect through aircraft noise annoyance. RESULTS: This study showed a deleterious effect of aircraft noise on SRHS. The odds ratio (OR) corresponding to the total effect and comparing the highest aircraft noise category (≥60 dBA) to the reference category (<50 dBA) was significant (ORpoor/fair_SHRS = 1.25 (95%CI: 1.06 to 2.08)). It also showed no direct effect of aircraft noise levels on SRHS, but an indirect effect through annoyance. This indirect effect increased as aircraft noise levels increased, with a statistically significant OR when comparing the highest noise category (≥60 dBA) to the lowest (<50 dBA) (ORpoor/fair_SHRS = 1.16 (95%CI: 1.03 to 1.52)). Nearly 66% of aircraft noise's effect on SRHS was mediated by aircraft noise annoyance. CONCLUSION: This study supports the deleterious causal effect of aircraft noise on SRHS. The results highlight the important mediating role of aircraft noise annoyance in the causal pathway from exposure to aircraft noise to poor/fair SRHS.

Short-term impact of atmospheric pollution on fecundability.

BACKGROUND: Epidemiologic studies have reported associations between air pollution levels and semen characteristics, which might in turn affect a couple's ability to achieve a live birth. Our aim was to characterize short-term effects of atmospheric pollutants on fecundability (the month-specific probability of pregnancy among noncontracepting couples). METHODS: For a cohort of births between 1994 and 1999 in Teplice (Czech Republic), we averaged fine particulate matter (PM2.5), carcinogenic polycyclic aromatic hydrocarbons, ozone, nitrogen dioxide (NO2), and sulfur dioxide levels estimated from a central measurement site over the 60-day period before the end of the first month of unprotected intercourse. We estimated changes in the probability of occurrence of a pregnancy during the first month of unprotected intercourse associated with exposure, using binomial regression and adjusting for maternal behaviors and time trends. RESULTS: Among the 1,916 recruited couples, 486 (25%) conceived during the first month of unprotected intercourse. Each increase of 10 µg/m in PM2.5 levels was associated with an adjusted decrease in fecundability of 22% (95% confidence interval = 6%-35%). NO2 levels were also associated with decreased fecundability. There was no evidence of adverse effects with the other pollutants considered. Biases related to pregnancy planning or temporal trends in air pollution were unlikely to explain the observed associations. CONCLUSIONS: In this polluted area, we highlighted short-term decreases in a couple's ability to conceive in association with PM2.5 and NO2 levels assessed in a central monitoring station.

The Role of Noise Annoyance and Noise Sensitivity in the Effect of Aircraft Noise on Self-Reported Health: The Results of the DEBATS Longitudinal Study in France.

Background: Transportation noise seems to impair self-reported health status (SRHS). However, only a few studies have considered the role of noise annoyance and noise sensitivity in this deleterious effect. This study aims investigating mediator and moderator roles of noise annoyance and noise sensitivity. Methods: In 2013, the DEBATS longitudinal study included 1244 participants aged over 18 years and living around three French airports. These participants were followed up in 2015 and 2017. They self-reported their perceived health status, aircraft noise annoyance, and their noise sensitivity via a questionnaire during the three visits. Noise maps were used to estimate aircraft noise levels at the facade of participants' residence. Generalized linear mixed models with a random intercept at the participant level were used. Results: Aircraft noise levels were associated with severe annoyance. Severe annoyance tent to be associated with impaired SRHS. Aircraft noise levels were associated with impaired SRHS only in men (odds ratio [OR] = 1.47, 95% confidence interval [CI] = [1.02, 2.11], for a 10-dBA Lden increase in aircraft noise levels) with a weaker association adjusted for annoyance (OR = 1.36, 95% CI = [0.94, 1.98]). The association was stronger in men who reported high noise sensitivity (OR = 1.84, 95% CI = [0.92, 3.70], versus OR = 1.39, 95% CI = [0.90, 2.14], for men who were not highly sensitive to noise). Conclusion: From our results, the deleterious effect of aircraft noise on SRHS could be mediated by noise annoyance and moderated by noise sensitivity. Further studies using causal inference methods are needed for identifying causal effect of exposure, mediator, and moderator.

Pooling and Comparing Noise Annoyance Scores and "High Annoyance" (HA) Responses on the 5-Point and 11-Point Scales: Principles and Practical Advice.

The use of different noise annoyance scales across studies and socio-acoustic surveys, in particular the popular 5-point verbal and 11-point numerical scales, has made the evaluation, comparison, and pooling of noise annoyance responses among studies a taxing issue. This is particularly the case when "high annoyance" (HA) responses need to be compared and when the original studies used different scales; thus, there are different so-called cutoff points that define the part of the scale that indicates the HA status. This paper provides practical guidance on pooling and comparing the respective annoyance data in both the linear and logistic regression context in a statistically adequate manner. It caters to researchers who want to carry out pooled analyses on annoyance data that have been collected on different scales or need to compare exposure-HA relationships between the 5-point and 11-point scales. The necessary simulation of a cutoff point non-native to an original scale can be achieved with a random assignment approach, which is exemplified in the paper using original response data from a range of recent noise annoyance surveys. A code example in the R language is provided for easy implementation of the pertinent procedures with one's own survey data. Lastly, the not insignificant limitations of combining and/or comparing responses from different noise annoyance scales are discussed.

Quantification of Sound Exposure from Wind Turbines in France.

The WHO guidelines on environmental noise highlight that evidence on the health effects of wind turbine sound levels is either non-existent or of poor quality. In this context, a feasibility study was conducted in France in 2017. The objective was to suggest a methodology for calculating wind turbine sound levels in order to quantify the number of windfarms' residents exposed to this sound. Based on a literature review, the Harmonoise model was selected for sound exposure calculation. It was validated by quantifying its uncertainties, and finally used to estimate the population exposed to wind turbine sound in metropolitan France. Compared to other environmental noise sources (e.g., transportation), sound exposure is very moderate, with more than 80% of the exposed people exposed to sound levels below 40 dBA. The total number of people exposed to more than 30 dBA is about 686,000 and 722,000 people for typical daytime and night-time meteorological conditions respectively, i.e., about 1% of the French population in 2017. These results represent the first ever assessment of sound exposure from wind turbines at the scale of the entire metropolitan France.

Term birthweight and critical windows of prenatal exposure to average meteorological conditions and meteorological variability.

BACKGROUND: Heat stress during pregnancy may limit fetal growth, with ramifications throughout the life course. However, critical exposure windows are unknown, and effects of meteorological variability have not been investigated. OBJECTIVES: We aimed to identify sensitive windows for the associations of mean and variability of temperature and humidity with term birthweight. METHODS: We analyzed data from two French mother-child cohorts, EDEN and PELAGIE (n = 4771), recruited in 2002-2006. Temperature exposure was assessed using a satellite-based model with daily 1-km2 resolution, and relative humidity exposure data were obtained from Météo France monitors. Distributed lag models were constructed using weekly means and standard deviation (SD, to quantify variability) from the first 37 gestational weeks. Analyses were then stratified by sex. Results for each exposure were adjusted for the other exposures, gestational age at birth, season and year of conception, cohort and recruitment center, and individual confounders. RESULTS: There was no evidence of association between term birthweight and mean temperature. We identified a critical window in weeks 6-20 for temperature variability (cumulative change in term birthweight of -54.2 g [95% CI: -102, -6] for a 1 °C increase in SD of temperature for each week in that window). Upon stratification by sex of the infant, the relationship remained for boys (weeks 1-21, cumulative change: -125 g [95% CI: -228, -21]). For mean humidity, there was a critical window in weeks 26-37, with a cumulative change of -28 g (95% CI: -49, -7) associated with a 5% increase in humidity for each week. The critical window was longer and had a stronger association in boys (weeks 29-37; -37 g, 95% CI: -63, -11) than girls (week 14; -1.8 g, 95% CI: -3.6, -0.1). DISCUSSION: Weekly temperature variability and mean humidity during critical exposure windows were associated with decreased term birthweight, especially in boys.

Understanding the relationship between air traffic noise exposure and annoyance in populations living near airports in France.

Since the 2000s, increased aircraft noise annoyance has been observed in the populations living near airports. The DEBATS-study compared the exposure-response relationship estimated among airports' residents in France with old and new EU standard curves. It also examines whether non-acoustical factors may explain this annoyance. For 1244 adults living near three French airports, information about demographic and socio-economic factors as well as aircraft noise annoyance, situational, personal and attitudinal factors was collected with a face-to-face questionnaire. Outdoor aircraft noise exposure was estimated by linking home address to noise exposure maps. Logistic regression models were used to investigate the association between annoyance and a broad range of other variables in addition to the Lden. Severe noise annoyance was associated not only with increased aircraft noise levels, but also with non-acoustical factors. Annoyance was higher than predicted by the old EU standard curve when estimated with the model including non-acoustical factors in addition to the Lden. It was even higher when only noise exposure was considered. However, annoyance was lower in DEBATS than predicted by the new EU standard curve provided by WHO. The increase of noise annoyance does not seem to be explained by the factors already mentioned in the literature as possible explanations. However, it cannot be ruled out that methodological differences in the HA assessment may be the reason for changes in annoyance over the years. For this reason, we argue for a definition of HA derived substantially as recommended by ICBEN. The findings of the DEBATS study also confirm that taking into account non-acoustical factors such as situational, personal and attitudinal factors would improve annoyance predictions.

Association between the pregnancy exposome and fetal growth.

BACKGROUND: Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes. METHODS: Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure-exposure and sex-exposure interactions. RESULTS: The DSA model identified lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified. CONCLUSIONS: This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation.

Dexmedetomidine to facilitate non-invasive ventilation after blunt chest trauma: A randomised, double-blind, crossover, placebo-controlled pilot study.

BACKGROUND: Although non-invasive ventilation (NIV) is recommended in patients with chest trauma, this procedure may expose to discomfort and even failure due to agitation or excessive pain. We tested the impact of dexmedetomidine on the duration of the first session of NIV. METHODS: This randomised, crossover study enrolled 19 patients with blunt chest trauma who needed NIV. During one cycle comprising two NIV sessions, patients received in a random order an intravenous infusion of dexmedetomidine (0.7mcg/kg/h) and placebo (saline solution) that was initiated 60min prior to NIV. Dexmedetomidine (or placebo) was titrated to maintain a Richmond Agitation Sedation Scale (RASS) score between 0 and -3. A 6-h washout period was observed between NIV sessions. The reproducibility of the drug-related effects was tested during a second cycle of two NIV sessions. RESULTS: During the first cycle, dexmedetomidine prolonged the duration of NIV compared to placebo: 280min (118-450) (median, 25-75th quartiles) versus 120min (68-287) respectively, corresponding to a median increased duration of 96min (12-180) (P=0.03). Dexmedetomidine was associated with a lower score for RASS: -0.8 (-1.0;0.0) versus 0.0 (-0.5;0.0) (P<0.01), and reduced respiratory discomfort according to the 10cm visual similar scale: 0.6cm (0.0-3.0) versus 2.2cm (0.0-5.3) (P=0.05). Pain scores, morphine consumption, and blood gas measurements were comparable between groups. No difference in the duration of non-invasive ventilation was found during the second cycle. CONCLUSIONS: In this pilot trial, dexmedetomidine could facilitate the acceptance of the first session of non-invasive ventilation for patients with chest trauma.

Influence of the Urban Exposome on Birth Weight.

BACKGROUND: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. OBJECTIVE: We evaluated the association of the urban exposome with birth weight. METHODS: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. RESULTS: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. CONCLUSION: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971.

Analysis of multicentre epidemiological studies: contrasting fixed or random effects modelling and meta-analysis.

Multicentre studies are common in epidemiological research aiming at identifying disease risk factors. A major advantage of multicentre over single-centre studies is that, by including a larger number of participants, they allow consideration of rare outcomes and exposures. Their multicentric nature introduces some complexities at the step of data analysis, in particular when it comes to controlling for confounding by centre, which is the focus of this tutorial. Commonly, epidemiologists use one of the following options: pooling all centre-specific data and adjusting for centre using fixed effects; adjusting for centre using random effects; or fitting centre-specific models and combining the results in a meta-analysis. Here, we illustrate the similarities of and differences between these three modelling approaches, explain the reasons why they may provide different conclusions and offer advice on which model to choose depending on the characteristics of the study. Two key issues to examine during the analyses are to distinguish within-centre from between-centre associations, and the possible heterogeneity of the effects (of exposure and/or confounders) by centre. A real epidemiological study is used to illustrate a situation in which these various options yield different results. A synthetic dataset and R and Stata codes are provided to reproduce the results.

Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation.

BACKGROUND: Air pollution exposure represents a major health threat to the developing foetus. DNA methylation is one of the most well-known molecular determinants of the epigenetic status of cells. Blood DNA methylation has been proven sensitive to air pollutants, but the molecular impact of air pollution on new-borns has so far received little attention. OBJECTIVES: We investigated whether nitrogen dioxide (NO2), particulate matter (PM10), temperature and humidity during pregnancy are associated with differences in placental DNA methylation levels. METHODS: Whole-genome DNA-methylation was measured using the Illumina's Infinium HumanMethylation450 BeadChip in the placenta of 668 newborns from the EDEN cohort. We designed an original strategy using a priori biological information to focus on candidate genes with a specific expression pattern in placenta (active or silent) combined with an agnostic epigenome-wide association study (EWAS). We used robust linear regression to identify CpGs and differentially methylated regions (DMR) associated with each exposure during short- and long-term time-windows. RESULTS: The candidate genes approach identified nine CpGs mapping to 9 genes associated with prenatal NO2 and PM10 exposure [false discovery rate (FDR) p < 0.05]. Among these, the methylation level of 2 CpGs located in ADORA2B remained significantly associated with NO2 exposure during the 2nd trimester and whole pregnancy in the EWAS (FDR p < 0.05). EWAS further revealed associations between the environmental exposures under study and variations of DNA methylation of 4 other CpGs. We further identified 27 DMRs significantly (FDR p < 0.05) associated with air pollutants exposure and 13 DMRs with meteorological conditions. CONCLUSIONS: The methylation of ADORA2B, a gene whose expression was previously associated with hypoxia and pre-eclampsia, was consistently found here sensitive to atmospheric pollutants. In addition, air pollutants were associated to DMRs pointing towards genes previously implicated in preeclampsia, hypertensive and metabolic disorders. These findings demonstrate that air pollutants exposure at levels commonly experienced in the European population are associated with placental gene methylation and provide some mechanistic insight into some of the reported effects of air pollutants on preeclampsia.

The Urban Exposome during Pregnancy and Its Socioeconomic Determinants.

BACKGROUND: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development. OBJECTIVE: The authors' goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants. METHODS: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis. RESULTS: Mean±standard deviation (SD) NO2 levels ranged from 13.6±5.1 µg/m3 (in Heraklion, Crete) to 43.2±11 µg/m3 (in Sabadell, Spain), mean±SD walkability score ranged from 0.22±0.04 (Kaunas, Lithuania) to 0.32±0.07 (Valencia, Spain) and mean±SD Normalized Difference Vegetation Index ranged from 0.21±0.05 in Heraklion to 0.51±0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (-0.57 PC1 score, 95% CI: -0.73, -0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (95% CI: 1.21, 1.48). CONCLUSIONS: The urban exposome showed considerable variability across Europe. Pregnant women of low SEP were exposed to higher levels of environmental hazards in some cities, but not others, which may contribute to inequities in child health and development. https://doi.org/10.1289/EHP2862.