Associations of non-back-extrapolated air pollutants with general cognition and with language development did not differ from the main analysis, whereas the associations with these air pollution measures were slightly attenuated for global psychomotor development (eTable 5, http://links.lww.com/EDE/A802). Restricting the analysis to children with stable residence from birth until the psychomotor development assessment, we found similar effects on global psychomotor development for all pollutants (eTable 6, http://links.lww.com/EDE/A802). Results remained similar when analyses were restricted to children with a good quality psychomotor development test or when scores were restricted to measurements conducted at an earlier age (eTable 6, http://links.lww.com/EDE/A802). Meta-analyses of psychomotor development evaluating early (≤2 years) versus later assessment showed similar results (data not shown). Meta-analyses repeated stratifying for those cohorts where cognitive and psychomotor development test was administered by a psychologist and those based on maternal reports showed materially unchangeable results (data not shown). Meta-analyses for all outcomes restricting to regions with information on both cognitive and psychomotor development showed similar results (data now shown).
We assessed the relationship between exposure to air pollution during pregnancy and childhood cognitive and psychomotor development, based on 6 European birth cohort studies with a total of almost 10,000 children. Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was negatively associated with psychomotor development—but not with cognitive development—in children assessed between 1 and 6 years of age.
The main strengths of our study are the large sample size (almost 10,000 children in 6 European countries), use of a standardized air pollution assessment in all the regions,26,27 assessment at the individual level of a large number of air pollutants (including NO2 and PM), prospective assessment of cognitive and psychomotor development during childhood using standardized and validated neuropsychological tests and questionnaires, and centralized statistical analysis following a consensus protocol. In addition, we adjusted for many socioeconomic and lifestyle variables known to be associated with air pollution exposure during pregnancy and with child cognitive and psychomotor development, although residual confounding (mainly related to socioeconomic position of the families) cannot be completely ruled out.
The main limitation of our study was the heterogeneity of instruments, evaluators, and ages used to assess cognitive and psychomotor functions. Although the selected tests were designed for assessing these functions, they measured in some cases different characteristics of the function or a different level of development. However, we found consistently adverse effects of air pollution exposure during pregnancy, particularly for the effect of NO2 on psychomotor development, regardless of type of instrument, type of evaluator, or age at assessment. Several sensitivity analyses were performed in order to assess the validity of the overall findings. When maternal report was compared with psychologist assessment, results were similar. Psychomotor development tests administered at early ages might be less valid and reliable because they are highly affected by the child’s time of walking. However, results remained after stratifying the analysis based on age (less vs. more than 2 years old). The Dutch cohort is the largest study region (with half of the population included in the meta-analysis) and could have a large influence in the overall results. Nevertheless, the exclusion of this cohort from the global meta-analysis showed similar results. Although associations are quite consistent among regions, we observed some heterogeneity in the association between NO2, NOx, and PM2.5 absorbance and psychomotor development. This heterogeneity was not present for other pollutants, was not related to the type of instrument, type of evaluator, or age of the assessment, and was not related to the levels of air pollution. Air pollution mixtures may be different among the study regions, which could be a potential explanation for the heterogeneity of the effects.
Another limitation of our study is related to exposure assessment. Air pollution levels were back-extrapolated to the pregnancy period using routine background monitoring network sites but monitoring data were not available for all pollutants in all study regions, particularly for PM. Although background monitoring network sites of other pollutants were used in the cases of missing information, this method could lead to a nondifferential misclassification of the exposure, especially for PM because monitoring data were poorer than for NO2. Nevertheless, non-back-extrapolated results were mainly unchanged. Associations between air pollutants and global psychomotor development were found only for NO2. This finding could be due to the fact that back-extrapolated levels of NO2 were more robust or that PM data were not available in all study regions. When we restricted the analysis of NO2 to the regions with available PM data, results were attenuated, indicating that the lack of association between PM and global psychomotor development could be driven by the selection of the regions. Finally, road traffic noise exposure was not measured in this study and might be a potential confounder because it is related to motor vehicle traffic and could be associated (as has been shown for airport noise) with impaired cognitive development among school-aged children.35,36
We observed an adverse association of air pollution exposure during pregnancy, particularly for NO2 and childhood psychomotor development. Some animal studies have found that diesel exhaust particles, black carbon, or NO2 exposure during pregnancy decreased the motor function in the offspring mice.6–9 One study suggested that the observed impairment of the motor activity was more likely due to an indirect effect caused by maternal inflammation during pregnancy.8 Some others suggested that spontaneous motor function impairment could be due to a facilitated release of dopamine in the prefrontal cortex7 or in the striatum,6,7 triggered by the diesel exhaust particle exposure during pregnancy. Dopamine and noradrenaline systems in the prefrontal cortex have an important role in the control of motor activity.37 In humans, a double-blind randomized crossover study was carried out, in which volunteers were exposed to dilute diesel exhaust or filtered air for 1 hour.38 There was increased activity of the frontal cortex during and after diesel exhaust exposure.38 The frontal cortex controls the actions of the body through its motor areas such as the primary motor or the premotor cortex.
Previous epidemiologic studies assessing exposure to air pollution during pregnancy and childhood psychomotor development are scarce and have contradictory results.10,13 Levels of PAHs were collected in a small sample of nonsmoking pregnancy women from New York City during 2 days in the third trimester of pregnancy.10 No association was found with childhood psychomotor development assessed at the ages of 1, 2, and 3 years.10
In another study carried out in Tongliang (China) where a seasonal coal-fired power plant was operating, prenatal PAH exposure measured by PAH–DNA adducts in umbilical cord blood was associated with an impairment in childhood psychomotor development at the age of 2 years.13 It is difficult to compare directly the magnitude of our findings with those previous studies, mainly due to the different treatment of the exposure variables in the statistical analyses (ie, increase of 10 μg/m3 in NO2 levels in our study; high/low PAH levels dichotomized at the 4th quartile in Perera et al10; high/low PAH levels dichotomized at the median in Perera et al11 and Edward et al12). Previous epidemiologic studies adjusted their models for several potential confounding variables similarly to our study. Moreover, the tests applied to assess psychomotor development were comparable with those applied in our study, and the assignment of the exposure was done mainly at the individual level. However, exposure mixtures may vary among study regions.
Two other studies assessed the relation between postnatal air pollution exposure and child psychomotor development with a cross-sectional approach, showing inconsistent results.39,40 A tendency toward an adverse association was found between postnatal NO2 exposure and psychomotor development at 4 years of age in the Granada region of the Spanish cohort included in the present study—in which we instead observed a positive association between prenatal NO2 exposure and psychomotor development.39 Possible reasons for these varying findings may be the assessment of exposure in a different period of child development (prenatal vs. postnatal), the various adjustments of the association models, or the different NO2 exposure assessment including different number of measurement sites (14 in our study vs. 70 in the previous study), different duration of the air pollution measurement periods (three 2-week measurements in our study vs. two 1-week measurements in the previous study), or different land-use regression models (R2 = 0.77 in our study vs. R2 = 0.45 for urban area and R2 = 0.75 for nonurban area in the previous study). In another study, children who attended a school in a highly polluted area of the Fujian province (China) showed worse performance in a psychomotor test at 8–10 years of age compared with children who attended a school in a less polluted area of the same province.40
We found no association between exposure during pregnancy to NO2 and PM and childhood cognitive development. A possible explanation is that children were assessed at an early stage of development, before 2 years of age in most of the centers. Cognitive development continues until young adulthood,41 and its assessment in early life might indicate an intermediate stage of development, when the measurement has more variability. Studies at older ages are warranted because children develop more cognitive abilities over the years, and these abilities can be assessed with more specific instruments at older ages. However, although previous epidemiologic studies carried out in children showed mixed results,10–15 some of them have found an association between air pollution exposure during pregnancy, especially PAH exposure, and childhood cognitive development at very young ages.10–14 Some other studies assessed postnatal exposure to air pollutants and child cognitive development with a cross-sectional design.39,40,42,43 Some of these studies found an association.42,43 Similar to previous studies on psychomotor development, these studies were adjusted for several potential confounders and applied cognitive tests comparable with those in our study. However, the 2 studies that found an association between postnatal exposure to air pollution and cognitive development assessed children at older ages. In our study, when we restricted the analysis to those children who did not change residence from birth until the cognitive development assessment, our results were unchanged. Further analyses are warranted to disentangle the effect of prenatal versus postnatal air pollutants, as well as to follow children to older ages.
Air pollution is a complex mixture that includes PM and NOx. Based on experimental models, it has been hypothesized that among the major contributors to the neurological effects of air pollution are PM-soluble components, very small particulate fragments, or ultrafine PM (PM with diameter of <0.1 μm) because they may translocate from the respiratory tract into the systemic circulation and reach the brain.1 In a postmortem study, presence of PM in the human brain and early disruption of the blood–brain barrier were observed in subjects from a large polluted city.44 PM is rich in organic carbon content, as well as in prooxidative PAH that promotes oxidative stress and inflammation.1 In our study, although all measures of PM were negatively associated with childhood psychomotor development, only NO2 exposure showed a strong relationship. This difference in the findings may be due to the fact that PM was measured only in 5 of the 11 regions, and thus we had low power to detect associations with PM. Also, back-extrapolation of PM to the pregnancy period was limited because routine background monitoring network sites for PM were not always available in all the regions, which increases the chances of an underestimation and also decreases the statistical power. In our study, NO2 and PM are markers of traffic air pollution, but also sources such as space heating, because small-scale traffic and population/household density variables were the most frequently used predictors in the land-use regression models.26,27 Moreover, due to the high correlation between pollutants, it is difficult to acertain which set of pollutants is responsible for the observed effects. However, because the trace-metal content of PM (such as lead and manganese, as well as PAH) has been found to be among the most neurotoxic components of air pollution,1 further studies on the relationship of these components with child cognitive and motor development are warranted.
In the present study, we found a decrease of 0.7 points on a psychomotor development scale for each 10 μg/m3 increase in pregnancy average NO2 levels. There is a large literature on the public impact of a 1-point loss of a neuropsychological scale, most are based on effects of lead exposure on intelligence quotient.3 Although a seemingly small change of a 1-point decrease in intelligence quotient score might not be relevant at the individual level, at the population level, this will shift the distribution of intelligence quotient to the left and increase the number of persons below the normal range.45 Further research is needed on long-term consequences of decreased psychomotor development score in childhood, as well as whether air pollution effects on psychomotor development are persistent at older ages.46
In sum, we found an association between air pollution exposure during pregnancy (particularly NO2, for which motorized traffic is a major source) and psychomotor development assessed between 1 and 6 years of age. Cognitive development measured at similar ages was not related to air pollution exposure during pregnancy.
We thank all participants for their generous collaboration.
GENERATION R. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The Generation R Study is supported by the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organization for Scientific Research (NWO), and the Ministry of Health, Welfare and Sport. TNO received funding from the Netherlands Ministry of Infrastructure and the Environment to support exposure assessment. V.W.V. J. received an additional grant from the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). The work by A.G. was supported by a research grant from the European Community’s 7th Framework Programme (FP7/2008-2013) under grant agreement 212652 (NUTRIMENTHE project, “The Effect of Diet on the Mental Performance of Children”).
DUISBURG. The Duisburg cohort study was financially supported and coordinated by the North Rhine-Westphalia State Agency for Nature, Environment and Consumer Protection (LANUV NRW), Germany. Additional financial support was given by the Federal Ministry of Environment, Nature Conservation, and Radioprotection (Bonn).
EDEN. Funding sources for the EDEN study are Fondation pour la Recherche Médicale (FRM), French Ministry of Research: IFR and Cohort program, INSERM Nutrition Research Program, French Ministry of Health Perinatality Program, French Agency for Environment Security (ANSES), French National Institute for Population Health Surveillance (INVS), Paris–Sud University, French National Institute for Health Education (INPES), Nestlé, Mutuelle Générale de l’Education Nationale (MGEN), French-speaking association for the study of diabetes and metabolism (Alfediam), National Agency for Research (ANR nonthematic program), National Institute for Research in Public Health (IRESP: TGIR cohorte santé 2008 program).
A list of the main EDEN investigators can be found at http://eden.vjf.inserm.fr/index.php/fr/organisation-d-eden.
GASPII. This study was funded by a grant from the Italian Ministry of Health (ex art.12, 2001).
RHEA. Rhea project was supported by European projects (EU FP6-2003-Food-3-A NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-188.8.131.52 Envirogenomarkers, EU FP7-HEALTH-2009- single-stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO) and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014). We thank Vicky Patelarou and Mina Iakovides who participated in the exposure assessment, and Katerina Koutra for her contribution in the neurodevelopment assessment.
INMA. This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041 FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647 FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FIS-PI06/0867 FIS-PS09/00090, and FIS-07/0252), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), Consejería de Salud de la Junta de Andalucía (grant number 183/07), and Fundación Roger Torné. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/en_listado-investigadores.html.
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