Review Ambient Air Pollution and Risk of Congenital Anomalies: A Systematic Review and Meta-analysis Martine Vrijheid,1,2,3 David Martinez,1,2,3 Sandra Manzanares,1,2,4 Payam Dadvand,1,2,3 Anna Schembari,1,2 Judith Rankin,5 and Mark Nieuwenhuijsen1,2,3 1Center for Research in Environmental Epidemiology, Barcelona, Spain; 2Hospital del Mar Research Institute (IMIM), Barcelona, Spain; 3CIBER Epidemiología y Salud Pública, Spain; 4Educational Unit of Preventive Medicine and Public Health, Hospital del Mar–Pompeu Fabra University–Agencia de Salut Pública, Barcelona, Spain; 5Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom o Bjectiv d at : We systematically reviewed epidemiologic studies on ambient air pollution and congenital anomalies and conducted meta-analyses for a number of air pollutant–anomaly combinations. source synthei and extracion : From bibliographic searches we extracted 10 original epidemio- logic studies that examined the association between congenital anomaly risk and concentrations of air pollutants. Meta-analyses were conducted if at least four studies published risk estimates for the same pollutant and anomaly group. Summary risk estimates were calculated for a) risk at high versus low exposure level in each study and b) risk per unit increase in continuous pollutant concentration. d at : Each individual study reported statistically significantly increased risks for some combinations of air pollutants and congenital anomalies, among many combinations tested. In meta-analyses, nitrogen dioxide (NO2) and sulfur dioxide (SO2) exposures were related to increases in risk of coarctation of the aorta [odds ratio (OR) per 10 ppb NO2 = 1.17; 95% confidence interval (CI), 1.00–1.36; OR per 1 ppb SO2 = 1.07; 95% CI, 1.01–1.13] and tetralogy of Fallot (OR per 10 ppb NO2 = 1.20; 95% CI, 1.02–1.42; OR per 1 ppb SO2 = 1.03; 95% CI, 1.01–1.05), and PM10 (particulate matter ≤ 10 µm) exposure was related to an increased risk of atrial septal defects (OR per 10 µg/m3 = 1.14; 95% CI, 1.01–1.28). Meta-analyses found no statistically significant increase in risk of other cardiac anomalies and oral clefts. words c onclusi : We found some evidence for an effect of ambient air pollutants on congenital cardiac anomaly risk. Improvements in the areas of exposure assessment, outcome harmonization, assess- ment of other congenital anomalies, and mechanistic knowledge are needed to advance this field. k ey : air pollution, congenital abnormalities, pregnancy. Environ Health Perspect 119:598–606 (2011). doi:10.1289/ehp.1002946 [Online 3 December 2010] There is growing epidemiologic evidence for adverse effects on the fetus and newborn from maternal prenatal exposure to ambient air pol- lution (Glinianaia et al. 2004b; Maisonet et al. 2004; Šrám et al. 2005). Air pollutants such as carbon monoxide (CO), sulfur dioxide (SO2), and particulate matter (PM) have been associ- ated with increased infant mortality, particu- larly postneonatal respiratory mortality, low birth weight, and preterm birth (Glinianaia et al. 2004a, 2004b; Maisonet et al. 2004; Šrám et al. 2005). Inconsistencies and uncer- tainties remain concerning the effects of specific pollutants and pollutant mixtures and criti- cal exposure periods (Ritz and Wilhelm 2008; Woodruff et al. 2009). There are new concerns that air pollution may also play a role in caus- ing congenital anomalies, and such an effect is both biologically plausible and of public health importance (Ritz 2010). Congenital anomalies are a main cause of infant mortality and an important contributor to childhood and adult morbidity. Major congenital anomalies in sur- viving infants often have serious medical and/or cosmetic consequences that commonly require surgery and lead to reduced survival rates into adulthood (Tennant et al. 2010). Major struc- tural congenital anomalies are diagnosed in 2–4% of births, but in most cases their etiology remains unknown (Weinhold 2009). 598 Recently, there has been a steep increase in the number of air pollution studies with congenital anomalies as the primary health outcome. The first publication appeared in 2002 (Ritz et al. 2002), the next in 2005 (Gilboa et al. 2005), and more have followed in the last few years (Dadvand et al. 2011a, 2011b; Dolk et al. 2010; Hansen et al. 2009; Hwang and Jaakkola 2008; Kim et al. 2007; Marshall et al. 2010; Rankin et al. 2009; Strickland et al. 2009). Because the exist- ing studies have few a priori hypotheses and tested many different pollutant–outcome combinations, a systematic assessment of the consistency of associations across studies is needed. Furthermore, in this rapidly evolving field, timely evaluation of methods and results of existing studies can help to inform and improve the design of future research. Here we therefore provide a systematic review of studies on ambient air pollution and congeni- tal anomalies and develop recommendations for future research. There have been few meta-analyses of other environmental exposures and risk of congenital anomalies (e.g., Nieuwenhuijsen et al. 2009) because of great variability in exposure assessment, outcome ascertainment, data analysis, and result reporting. Air pol- lution is one area where exposure estimates appear reasonably comparable. To illustrate the challenges faced by meta-analyses in this field and to offer recommendations for improve- ment, we conducted meta-analyses for a num- ber of air pollutant–anomaly combinations. Materials and Methods Search methods. We followed published guidelines for the reporting of this review and meta-analysis (Moher et al. 2009; Stroup et al. 2000). A bibliographic search was car- ried out in the MEDLINE engine search (National Library of Medicine 2010). The Medical Subject Heading (MeSH) terms “congenital abnormalities,” “pregnancy,” and “air pollution” and non-MeSH terms “birth defect,” “congenital anomalies,” “car- diac anomalies,” “congenital heart disease,” and “oral clefts” were used in the syntax. We also searched references in published articles and reviews on this topic. From this search we selected articles that a) were original epi- demiologic studies; b) were written in the English language; c) defined all or subgroups of congenital anomalies, congenital malfor- mations, or birth defects as outcome; and d) studied human prenatal exposure to ambi- ent air pollution using measured concentra- tions of air pollutants. Studies with purely ecologic exposure assessments (e.g.,maternal residence in a polluted vs. unpolluted area) or studies with quantitative traffic density data but without pollutant data (e.g., Cordier et al. 2004) were not included in the review. We identified one article unpublished at the time of the last MEDLINE search but now published (Dadvand 2011b). We searched Address correspondence to M. Vrijheid, Centre for Research in Environmental Epidemiology, Barcelona Biomedical Research Park, Doctor Aiguader 88, 08003 Barcelona, Spain. Telephone: 34 932 147 346. Fax: 34 932 147 301. E-mail: mvrijheid@creal.cat Supplemental Material is available online (doi:10. 1289/ehp.1002946 via http://dx.doi.org/). We thank the following researchers for provid- ing their unpublished risk estimates for continuous exposure: E. Marshall, D. Wartenberg, P. Mendola, and S. Gilboa. J.R. is funded by a Personal Award Scheme Career Scientist Award from the U.K. National Institute of Health Research. The authors declare they have no actual or potential competing financial interests. Received 7 September 2010; accepted 3 December 2010. ovlume 119 | number 5 | May 2011 • Environmental Health Perspectives