conditions (Dolk et al. 2010; Ritz et al. 2002; Sram et al. 2005). In animal studies, maternal exposure to O3, NO2, and CO has produced embryotoxic effects, as well as teratogenic effects such as skeletal and neuromuscular anomalies (Garvey and Longo 1978; Kavlock et al. 1979; Longo 1977; Singh 1988). Genetic polymorphisms in developmental and detoxification genes have been described as potentially increasing individual susceptibil- ity to the teratogenic effects of maternal smok- ing (e.g., Chevrier et al. 2008; Lammer et al. 2005); evaluation of similar gene–environment interactions may aid mechanistic understand- ing in future studies of air pollution and con- genital anomalies. Interactions between PM and specific micro- and macronutrients in the diet (antioxidants, antiinflammatory fac- tors) have been proposed to play a role in the causation of low birth weight, fetal growth restriction, and preterm birth, through joint oxidative stress and inflammatory mecha- nisms (Jedrychowski et al. 2010; Kannan et al. 2006); such interactions also warrant explora- tion in the causation of congenital anomalies. Recommendations This review of 10 studies finds some evidence of an effect of air pollutants on congenital anomaly risk, so it is worth considering direc- tions for further research in this area. Air pol- lution is a ubiquitous exposure, and small increases in risk may therefore carry a large public health implication; congenital anoma- lies are rare but serious outcomes that have a large impact on infant mortality and morbid- ity and on morbidity in later life. The statisti- cally significant increases in relative risk we observed in meta-analyses were between 3% and 20% per unit of exposure. Exposure units used were of the same order of magnitude as, or well within, the IQRs of these pollutants in most study areas (Table 1). Therefore, relative risk increases of this order of magnitude may be considered important for public health. Existing studies have so far not used some of the recent advances in exposure assessment used in other areas of air pollution research. A case can thus be made for well-designed stud- ies that can make improvements in at least some of the following areas. Exposure assessment. As outlined above, exposure indices with better spatial accuracy (while maintaining an accurate temporal component) should be used to assess exposure to traffic-related air pollution, because this is the main source of air pollution in urban areas. Better identification of the effects of specific exposures and exposure mixtures, and the integration of mobility and time– activity patterns, is recommended for congen- ital anomaly research in the same way as for other birth outcomes. Matching of cases and controls by exposure-related variables such as maternal area of residence should be avoided in future studies. Outcome harmonization. International harmonization of coding and classification of anomalies would greatly aid future systematic evaluations in this field. Any future studies should carefully report the exact classifications and exclusions used and attempt to use the same classifications as previous studies, at least in sensitivity analyses. Other congenital anomalies. Many of the above studies focused on cardiac anoma- lies and orofacial clefts. These are two of the largest anomaly groups, and they have been suspected to be related to other environ- mental exposures (Dolk and Vrijheid 2003). However, studies with sufficient statistical power should also focus on other anomalies for which there may be an environmental eti- ology (e.g., neural tube defects, limb defects, gastroschisis) (EUROCAT 2004). Mechanisms and individual susceptibility. Improved knowledge on potential mecha- nisms of teratogenic action of air pollutants is needed; this may be achieved by the integra- tion of mechanistic biomarkers. Evaluation of interactions with genetic polymorphisms and dietary factors may also provide further insights into mechanisms. Ref Rencs Aguilera I, Guxens M, Garcia-Esteban R, Corbella T, Nieuwenhuijsen MJ, Foradada CM, et al. 2009. Association between GIS-based exposure to urban air pollution during pregnancy and birth weight in the INMA Sabadell Cohort. Environ Health Perspect 117:1322–1327. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, Correa A. 2007. Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A Clin Mol Teratol 79:714–727. Chen L, Bell EM, Caton AR, Druschel CM, Lin S. 2010. Residential mobility during pregnancy and the potential for ambient air pollution exposure misclassification. Environ Res 110:162–168. Chevrier C, Bahuau M, Perret C, Iovannisci DM, Nelva A, Herman C, et al. 2008. Genetic susceptibilities in the asso- ciation between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft. Am J Med Genet A 146A:2396–2406. Cochran WG. 1954. The combination of estimates from different experiments. Biometrics 10:101–129. Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. 2004. Risk of congenital anomalies in the vicin- ity of municipal solid waste incinerators. Occup Environ Med 61:8–15. Dadvand P, Rankin J, Rushton S, Pless-Mulloli T. 2011a. Association between maternal exposure to ambient air pollution and congenital heart disease: a register-based spatio-temporal analysis. Am J Epidemiol 173:171–182. Dadvand P, Rankin J, Rushton S, Pless-Mulloli T. 2011b. Ambient air pollution and congenital heart disease, a reg- istry-based study. Environ Res 111:435–441. DerSimonian R, Laird N. 1986. Meta-analysis in clinical trials. Control Clin Trials 7:177–188. Dolk H, Armstrong B, Lachowycz K, Vrijheid M, Rankin J, Abramsky L, et al. 2010. Ambient air pollution and risk of congenital anomalies in England, 1991–1999. Occup Environ Med 67:223–227. Dolk H, Vrijheid M. 2003. The impact of environmental pollution on congenital anomalies. Br Med Bull 68:25–45. Egger M, Davey SG, Schneider M, Minder C. 1997. Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634. Environmental Health Perspectives • volume 119 | number 5 | May 2011 Air pollution and congenital anomalies EUROCAT (European Surveillance of Congenital Anomalies). 2004. EUROCAT Special Report. A Review of Environmental Risk Factors for Congenital Anomalies. Belfast:University of Ulster. EUROCAT (European Surveillance of Congenital Anomalies). 2009. EUROCAT Guide 1.3. Instructions for the Registration of Congenital Anomalies. Belfast:University of Ulster. EUROCAT (European Surveillance of Congenital Anomalies). 2010. Malformation Coding Guides. Available: http:// www.eurocat-network.eu/ABOUTUS/DataCollection/ GuidelinesforRegistration/MalformationCodingGuides [accessed 30 November 2010]. European Study of Cohorts for Air Pollution Effects Project (ESCAPE). 2009. Homepage. Available: http://www. escapeproject.eu/ [accessed 20 November 2010]. Garvey DJ, Longo LD. 1978. Chronic low level maternal carbon monoxide exposure and fetal growth and development. Biol Reprod 19:8–14. Gilboa SM, Mendola P, Olshan AF, Langlois PH, Savitz DA, Loomis D, et al. 2005. Relation between ambient air quality and selected birth defects, seven county study, Texas, 1997–2000. Am J Epidemiol 162:238–252. Gilliland F, Avol E, Kinney P, Jerrett M, Dvonch T, Lurmann F, et al. 2005. Air pollution exposure assessment for epide- miologic studies of pregnant women and children: lessons learned from the Centers for Children’s Environmental Health and Disease Prevention Research. Environ Health Perspect 113:1447–1454. Glinianaia SV, Rankin J, Bell R, Pless-Mulloli T, Howel D. 2004a. Does particulate air pollution contribute to infant death? A systematic review. Environ Health Perspect 112:1365–1371. Glinianaia SV, Rankin J, Bell R, Pless-Mulloli T, Howel D. 2004b. Particulate air pollution and fetal health: a systematic review of the epidemiologic evidence. Epidemiology 15:36–45. Hansen CA, Barnett AG, Jalaludin BB, Morgan GG. 2009. Ambient air pollution and birth defects in Brisbane, Australia. PLoS One 4:e5408. Hwang B-F, Jaakkola JJK. 2008. Ozone and other air pol- lutants and risk of oral clefts. Environ Health Perspect 116:1411–1415. International Clearinghouse for Birth Defects. 2010. Home page. Available: http://www.icbdsr.org [accessed 30 November 2010]. Jacobs JP, Mavroudis C, Jacobs ML, Maruszewski B, Tchervenkov CI, Lacour-Gayet FG, et al. 2007. Nomenclature and databases—the past, the present, and the future: a primer for the congenital heart surgeon. Pediatr Cardiol 28:105–115. Jedrychowski W, Perera F, Mrozek-Budzyn D, Flak E, Mroz E, Sochacka-Tatara E, et al. 2010. Higher fish consumption in pregnancy may confer protection against the harmful effect of prenatal exposure to fine particulate matter. Ann Nutr Metab 56:119–126. Kannan S, Misra DP, Dvonch JT, Krishnakumar A. 2006. Exposures to airborne particulate matter and adverse perinatal outcomes: a biologically plausible mechanistic framework for exploring potential effect modification by nutrition. Environ Health Perspect 114:1636–1642. Kavlock R, Daston G, Grabowski CT. 1979. Studies on the devel- opmental toxicity of ozone. I. Prenatal effects. Toxicol Appl Pharmacol 48:19–28. Kim OJ, Ha EH, Kim BM, Seo JH, Park HS, Jung WJ, et al. 2007. PM10 and pregnancy outcomes: a hospital-based cohort study of pregnant women in Seoul. J Occup Environ Med 49:1394–1402. Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. 2005. Maternal smoking, genetic variation of glutathione S-transferases, and risk for orofacial clefts. Epidemiology 16:698–701. Lie RT, Wilcox AJ, Taylor J, Gjessing HK, Saugstad OD, Aabyholm F, et al. 2008. Maternal smoking and oral clefts: the role of detoxification pathway genes. Epidemiology 19:606–615. Light RJ, Pillemer DB. 1984. Summing Up: The Science of Reviewing Research. Cambridge, MA:Harvard University Press. Little J, Cardy A, Munger RG. 2004. Tobacco smoking and oral clefts: a meta-analysis. Bull WHO 82:213–218. Longo LD. 1977. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. Am J Obstet Gynecol 129:69–103. Lupo PJ, Symanski E, Chan W, Mitchell LE, Waller DK, Canfield MA, et al. 2010. Differences in exposure assign- ment between conception and delivery: the impact of maternal mobility. Paediatr Perinat Epidemiol 24:200–208. 605