Vrijheid et al. Discussion Figure 1A–E). p-Values for heterogeneity in 4 vs. quartile 1 = 1.6; 95% CI, 1.1–2.2 these analyses showed limited evidence for (Marshall et al. 2010)]. None of the studies The evidence base for an effect of exposure to heterogeneity (p-values between 0.1 and 0.9). reported increased risks of cleft palate alone. ambient air pollutants on congenital anom- Sensitivity analyses excluding the study with Meta-analyses summarizing risk estimates for aly risk is small. Individual studies reported the largest weight from each meta-analysis exposure to five pollutants and risk of cleft increased risks for some combinations of air showed that results for NO2 and tetralogy of lip with or without cleft palate and cleft pal- pollutants and congenital anomalies, mostly Fallot and for SO2 and coarctation of the aorta ate alone were all close to one, and none cardiac anomalies, but these occurred among were robust to this exclusion. The results for reached statistical significance (Table 3). We many associations tested in each study. Meta- SO2 were not robust to the inclusion of the found evidence for significant heterogeneity analyses suggest that NO2 and SO2 expo- first Dadvand study (Dadvand et al. 2011a) (p < 0.1) in the CO and SO2 analyses. O3 sures were related to statistically significant instead of the second (Dadvand et al. 2011b) exposure and cleft lip with or without cleft increases in risk of coarctation of the aorta (Table 2); the first study by Dadvand et al. palate showed an association of borderline and tetralogy of Fallot, and PM10 exposure (2011a) also introduced significant heterogene- statistical significance (OR per 10 ppb = 1.10; to an increase in risk of ASDs; we based sum- ity. High versus low comparisons did not show 95% CI, 0.99–1.21) (Table 3, Figure 1F). mary risk estimates on few studies (n = 4), evidence for increased risks for any anomaly– Other congenital anomalies. Two studies but the total numbers of cases included were pollutant combinations. The summary OR examined a range of anomalies other than car- relatively large (between 655 and 951). Meta- for high compared with low CO exposure and diac anomalies and orofacial clefts (Dolk et al. analyses found no statistically significant risk of ASDs was significantly reduced (OR per 2010; Rankin et al. 2009). They observed sta- increase in risk of other cardiac anomalies 1 ppm = 0.86; 95% CI, 0.75–0.99). tistically significantly increased risks of ompha- and orofacial clefts in relation to air pollution Orofacial clefts. Seven studies examined locele in relation to PM10 concentrations exposure. This review and its meta-analysis the association between air pollutants and [90th vs. 10th percentile: OR = 2.17; 95% CI, raise important issues that may guide both the risk of cleft lip with or without cleft palate 1.00–4.71 (Dolk et al. 2010)] and of nervous design and presentation of future studies. (Table 1). Statistically significantly increased system anomalies in relation to black smoke A common feature of all the reviewed concentration [OR = 1.10/mg/m3; 95% CI, risks of cleft lip with or without cleft pal- studies was the use of routine monitoring ate were observed in relation to SO2 in two 1.03–1.18 (Rankin et al. 2009)]. No other stations as the basis for exposure assessment. studies [OR per 0.6 ppb = 1.27; 95% CI, anomaly groups/subtypes were at an increased Exposure indices were usually calculated from 1.01–1.62 (Hansen et al. 2009); OR quartile risk in relation to the pollutants studied. pollutant measurements at the nearest moni- toring station or as a distance-weighted aver- Table 2. Summary of meta-analysis of studies on air pollutant exposures and cardiac anomalies. age of measurements of all stations in the area; Continuous exposurec High versus low exposure these methods apply a similar exposure to a Total Pollutant and anomaly Studies number Heterogeneity Summary OR Heterogeneity Summary OR relatively large geographic area and thereby includeda of casesb (95% CI)d (95% CI)d combination p-value p-value measure predominantly community-wide vari- CO per 1 ppm ations in air pollution. This approach will be ASDs 1, 2, 5, 6, 9 1,337 0.10 0.87 (0.72–1.05) 0.17 0.86 (0.75–0.99) more appropriate for pollutants that vary at VSDs 1, 2, 5, 6, 9 3,710 < 0.001 1.14 (0.70–1.85) < 0.001 1.18 (0.82–1.69) large geographic scale (e.g., SO2, O3) than for Conotruncal defects 1, 2, 5, 6 1,156 0.02 0.95 (0.57–1.58) 0.01 0.95 (0.62–1.44) those that may have a much finer spatial dis- NO2 per 10 ppb tribution/resolution (e.g., CO, NO2). Traffic ASDs 2, 5, 6, 9 952 0.81 1.10 (0.91–1.33) 0.28 1.07 (0.90–1.26) exhaust fumes are the main source of air pol- VSDs 2, 5, 6, 9 3,460 0.002 1.12 (0.87–1.44) 0.03 0.92 (0.77–1.12) lutants such as NO2 and PM2.5 in urban areas, Coarctation of the aorta 2, 5, 7, 9 756 0.31 1.17 (1.00–1.36) 0.13 1.04 (0.86–1.26) Tetralogy of Fallot 2, 5, 7, 9 704 0.22 1.20 (1.02–1.42) 0.06 1.04 (0.70–1.55) as well as a main source of suspected caus- O per 10 ppb ative agents for adverse birth outcomes, such 3 ASDs 1, 2, 5, 6, 9 1,307 0.08 1.10 (0.92–1.32) 0.31 0.99 (0.83–1.19) as polycyclic aromatic hydrocarbons (PAHs) VSDs 1, 2, 5, 6, 9 3,557 0.02 0.95 (0.83–1.08) 0.02 0.93 (0.73–1.18) (Perera et al. 2003; Ritz and Wilhelm 2008). Conotruncal defects 1, 2, 5, 6 1,164 0.64 1.07 (0.96–1.19) 0.45 1.13 (0.89–1.42) More precise spatial models, based on disper- PM10 per 10 μg/m3 sion or land-use regression models that take ASDs 2, 5, 6, 9 951 0.10 1.14 (1.01–1.28) 0.02 1.23 (0.91–1.67) into account local road networks and other VSDs 2, 5, 6, 9 3,410 0.12 1.03 (0.96–1.10) 0.70 0.93 (0.84–1.02) Coarctation of the aorta 2, 5, 7, 9 761 0.02 1.10 (0.88–1.39) 0.48 1.00 (0.79–1.26) predictive variables, are therefore increasingly Tetralogy of Fallot 2, 5, 7, 9 546 0.37 1.00 (0.87–1.15) 0.02 0.91 (0.53–1.56) being recommended and used in research on SO2 per 1 ppb adverse birth outcomes (Aguilera et al. 2009; ASDs 2, 5, 6, 9 909 0.01 0.96 (0.86–1.07) 0.005 1.21 (0.82–1.79) Gilliland et al. 2005; Madsen et al. 2010; 2, 5, 6, 10e 914 0.01 0.97 (0.88–1.07) 0.02 1.27 (0.91–1.77) Nethery et al. 2008; Ritz and Wilhelm 2008; VSDs 2, 5, 6, 9 3,217 0.002 1.04 (0.95–1.15) < 0.001 0.96 (0.63–1.46) Slama et al. 2007, 2008; Wu et al. 2009). 2, 5, 6, 10e 3,056 < 0.001 1.02 (0.91–1.14) < 0.001 1.08 (0.81–1.44) 2, 4, 5, 6f < 0.001 1.05 (0.76–1.46) Only one of the reviewed studies (Dadvand Coarctation of the aorta 2, 5, 7, 9 682 0.90 1.07 (1.01–1.13) 0.29 1.06 (0.89–1.27) et al. 2011a) used a spatiotemporal model 2, 5, 7, 10e 687 0.02 1.02 (0.91–1.15) 0.01 0.89 (0.61–1.32) for black smoke and SO2 exposure in which 2, 4, 5, 7f 0.95 1.10 (0.92–1.31) concentrations of these pollutants were pre- Tetralogy of Fallot 2, 5, 7, 9 655 0.23 1.03 (1.01–1.05) < 0.001 0.80 (0.45–1.41) dicted from monitoring data combined with 2, 5, 7, 10e 670 0.05 1.01 (0.99–1.04) 0.06 1.02 (0.75–1.39) data from traffic, meteorology, and land use. 2, 4, 5, 7f 0.13 1.13 (0.93–1.36) Application of these types of models to future aStudies included are different in each pollutant-anomaly meta-analysis depending on the data they published. studies of congenital anomalies would be a References are as follows: 1, Ritz et al. (2002); 2, Gilboa et al. (2005); 4, Rankin et al. (2009); 5, Strickland et al. (2009); 6, Hansen et al. (2009); 7, Dolk et al. (2010); 9, Dadvand et al. (2011b); 10, Dadvand et al. (2011a). bNumber of cases included step toward more accurate exposure assess- in the continuous exposure analysis. cConversion factors: CO, 1 ppb = 1.15 μg/m3; NO2, 1 ppb = 1.88 μg/m3; O3, 1 ppb = ment for some of the pollutants of interest. 1.96 μg/m3; SO2, 1 ppb = 2.62 μg/m3. dWhen heterogeneity p-value is < 0.10, the OR from random effect model is shown; Characterization and quantification of errors otherwise, the OR from the fixed-effects model is shown. eSensitivity analysis using Dadvand 2011a instead of Dadvand 2011b. f Sensitivity analysis including Rankin 2009 instead of Dadvand 2011b. in exposure estimates from these models will 602 119 | number 5 | May 2011 • Environmental Health Perspectives ovlume