Air Pollution and the Risk of Cardiac Defects: A Population-Based Case-Control Study. Running Head: Air pollution and cardiac defects
Bing-Fang Hwang, Ph.D.,Yungling Leo Lee, MD, Ph.D. Jouni J.K. Jaakkola, MD, Sc.D., Ph.D.
Affiliations
Bing-Fang Hwang professor Department of Occupational Safety and Health, College of Public Health, China Medical University, No 91 Hsueh-Shih Rd, Taichung, 40402, Taiwan Yungling Leo Lee assistant professor Institute of Epidemiology and Preventive Medicine and Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, No.17 Xu-Zhou Road, 516R, Taipei 100,Taipei, Taiwan Jouni J.K. Jaakkola professor Center for Environmental and Respiratory Health Research, Institute of Health Sciences, University of Oulu, Oulu, Finland
ABSTRACT
Previous epidemiologic studies have assessed the role of the exposure to ambient air pollution in the development of cardiac birth defects, but they have provided somewhat inconsistent results. To assess the associations between exposure to ambient air pollutants and the risk of cardiac defects, a population-based case-control study was conducted using 1,087 cases of cardiac defects and a random sample of 10,870 controls from 1,533,748 Taiwanese newborns in 2001-2007.
Logistic regression was performed to calculate odds ratios for 10 ppb increases in O3 and 10
µg/m3 increases in PM
10. In addition, we compared the risk of cardiac defects in four categories
-high exposure (>75th percentile); medium exposure (75th to 50th percentile); low exposure (<50th to 25th percentile); reference (<25th percentile) based on the distribution of each pollutant. The risks of ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA) were associated with 10 ppb increases in O3 exposure during the first 3
gestational months among term and preterm babies. In comparison between high PM10 exposure
and reference category, there were statistically significant elevations in the effect estimates of ASD for all and terms births. In addition, there was a negative or weak association between SO2,
NO2, CO and cardiac defects.
The study proved that exposure to outdoor air O3 and PM10 during the first trimester of
gestation may increase the risk of VSD, ASD and PDA.
ABBREVIATIONS CI = confidence interval CO = carbon monoxide NO2 = nitrogen dioxides O3 = ozone OR = odds ratio
PM10 = particles with an aerodynamic diameter of 10 m or less
ppm= part per million ppb= part per billion SO2= sulfur dioxide
INTRODUCTION
Cardiac birth defects constitute the most common group of birth defects (approximately 50 per 1,000 births),1 and the most common cardiac defects are ventricular septal defect (27.5 /
10,000 births), atrial septal defect (10.6/10,000 births), and patent ductus arteriosus (2.9/10,000 births).2 Epidemiologic studies have provided evidence of the possible effects of air pollutants on
low birth weight, small gestational age, and preterm birth since 1990.3-7 In the past, only twelve
epidemiologic studies elaborated the effects of exposure to ambient air pollution on the risk of cardiac defects during pregnancy,8-19but these studies have provided inconsistent results. One
meta-analysis suggested that NO2 and SO2 exposures were associated with coarctation of the
aorta and tetralogy of Fallot, and PM10 exposure was associated with increased risk of atrial
septal defects.20 But the other one reported that only NO
2 exposure was related to coarctation of
the aorta.21 However, these studies did not adjust for maternal diabetes mellitus, smoking,
alcohol consumption during pregnancy, which are potential sources of confounding. In this study, a nationwide population-based case-control was conducted, and we collected the information on those important potential determinants for cardiac defects in pregnant women.
The exposure assessment in these studies was based on the measurement of monitoring stations nearest to the place of pregnancy during pregnancy which may introduce exposure misclassification. Gilliland et al. suggested that the exposure assessment should rely on the modeling approaches.15 Using a spatial modeling for exposure assessment, we elaborate the
relations between women exposure to ambient air pollution during the first trimester and the risk of cardiac defects. We focused on predominantly traffic-related pollutants such as nitrogen dioxides (NO2), carbon monoxide (CO), and ozone (O3) and air pollutants mainly from other
fossil fuel combustion sources, such as sulfur dioxide (SO2), and particles with an aerodynamic
Study Design
We conducted a population-based case-control study of cardiac defects. The source population comprised of all 1,533,748 births registered by the Taiwanese Birth Registry from January 1, 2001 to December 31, 2007. We identified all the cases of cardiac defects without chromosomal defects in the source population during the study period. Birth records in the registry were sorted by the date of birth. Control subjects were selected randomly from the source population. The study protocol was approved by the Institutional Review Board of China Medical University, and it complied with the principles outlined in the Helsinki Declaration.
Definition and Selection of Cases
All births delivered within 15 days are compulsorily reported to the Taiwan Birth Registration. Taiwanese pregnant women are 99% covered by national health insurance and access to prenatal care is free of charge and there are at least 10 visits during pregnancy. The follow-up time is from the 1st month after conception through 7 days after birth. Birth defects are mostly diagnosed
by physician, most often by cardiologist. A validation study of the Taiwanese birth registration reported a low percentage of missing information (1.6%) and good validity (sensitivity and specificity was 92.8%, and 99.6% respectively) and reliability (Cohen’s k statistics was 0.92) for preterm birth (<37 weeks of gestational age).16
We classified the cardiac defects into 6 categories which were similar with categories used by Gilboa and colleagues.9 The following categories of cardiac defects were applied 1)
ventricular septal defects not included in the conotruncal defects (n=193); 2) atrial septal defects (n=194); 3) patent ductus arteriosus (n=213); 4) endocardial cushion defects (n=23); 5)
pulmonary artery and valve (n=60); and 6) conotruncal defects (n=404) including tetralogy of Fallot (n=111), transposition of the great arteries (n=70), truncus arteriosus communis (n=60), double outlet right ventricle (n=85), and aorticopulmonary window (n=78). All cardiac defects were confirmed by autopsy, echocardiogram or cardiac catheterization. The gestational age was counted from conception through date of birth using ultrasound. A total of 1,087 subjects were identified with ample information on gestational age and air pollutants and 17 cases from the mountainous region were excluded due to missing air pollution data from January 1, 2001 to December 31, 2007.
Selection of Control Subjects
The control subjects were randomly selected from the source population. The eligibility criteria included: born during the study period; no birth defects present; and sufficient information on gestational age and air pollutants. The case-control ratio was approximately 1:10 to meet optimal statistical power. There are 10,870 controls in the final study population.
Ambient air monitoring data for sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), carbon
monoxide (CO), and particles with an aerodynamic diameter of 10 m or less (PM10) are
available for 72 EPA monitoring stations on Taiwan's main island since 1994. Concentrations of each pollutant are measured continuously and reported hourly—CO by non-dispersive infrared absorption, NO2 by chemiluminescence, O3 by ultraviolet absorption, SO2 by ultraviolet
fluorescence, and PM10 by beta-gauge.
We identified the map coordinates of the monitoring stations and air pollution sources. The data were managed by a geographic information system (GIS) (ArcGIS 10.0). The air pollutant measurements from EPA monitoring stations were integrated into monthly point data and interpolated to pollutant surfaces using inverse distance weighting (IDW) method. The
monitoring data was assigned to women individually by zip code. Zip codes typically stand for one block in urban areas (17.00 square kilometer, SD: 8.56) but in rural areas they correspond to larger (154.00 square kilometer, SD: 104.39) districts with lower population density. This method provided high temporal resolution (daily measures for most days) and suitable spatial resolution (100 m). We assigned for each day a concentration from 3 closest monitoring stations within 25 km. We then computed the monthly mean average for each woman during pregnancy. The details of the approach are described elsewhere.17 The air pollutant information for each
woman during pregnancy, corresponding to the zip-code level residence, was extracted from the derived concentration surface maps using ArcGIS Spatial Analyst tool (developed by ESRI).
Exposure parameters were calculated from the monthly 24-hour NO2, CO, SO2, PM10 and
8-hour O3 average concentrations for the duration of pregnancies between 2000 and 2007. Based
on the date of birth and gestational age, we estimated the monthly average concentration corresponding to the first trimester of gestation.
Covariates
The following covariates were available from routine birth registration: sex of infant (male; female), maternal age (<20 years; 20-34 years; >=35 years), plurality (singleton; multiple birth), gestational age (weeks), maternal smoking, alcoholic habit and medication during pregnancy, season of conception (spring; summer; fall; winter), and maternal health status defined as the presence of any of the following diseases or conditions: diabetes mellitus, anemia (HCT< 0.30/HGB<0.10), cardiac disease, acute or chronic lung disease, genital herpes, hydraminios/oligohydramnios, chronic hypertension, pregnancy-associated hypertension, eclampsia, imcompetent cervix, renal disease, Rh sensitization, uterine bleeding (yes; no). The municipal level data was collected from the Department of Household Registration Affairs, Taiwanese Population Data Services, which were used to construct municipal level population density, which is a measure of the proportion of urban population in the municipality. A census-based socio- economic status (SES) was derived from the 2005 national health insurance survey of the average monthly income of approximately 9,700,000 households. All subjects were assigned a SES value, according to their place in residence. All average monthly incomes of households were standardized using Z scores following normal distribution N (μ=0,σ2=1). SES
quintiles were determined from the distribution and assigned to their appropriate quintile: quintile 1 containing the most affluent wards and quintile 5 the most deprived.
We focused on the first three months (first trimester) of pregnancy, because the relevant
embryologic period for cardiac defects is between the 4th and 12th week of gestation.18 We used
odds ratio as a measure of the association between exposure to air pollution and the risk of cardiac defects. We performed logistic regression analysis to adjust for possible confounding factors. The goodness of fit was assessed with likelihood ratio tests (LR) to determine whether a variable contributed significantly to the model. First, we fitted a full model with a complete set of covariates. To elaborate sources of confounding, we fitted models with different combinations of covariates and compared the effect from models with and without the covariate of interest. If the removal of a covariate changed the studied effect estimate more than 10%, the corresponding covariate was kept in the final model.19 We first fitted one-pollutant models, and then considered
two-pollutant models by fitting one traffic-related and one stationary fossil fuel combustion-related pollutant. Finally, we fitted two-pollutant models with O3 and another pollutant (CO, NO2
and SO2). It was not appropriate fit two-pollutant models with O3 and PM10 because of high
collinearity (correlation coefficient r=0.54). The two-pollutant models provide estimates of the independent effects of CO, NO2, SO2, PM10, and O3 on cardiac defects controlling for the second
pollutant in the model. The effect of each pollutant on the risk of cardiac defects was presented as odds ratios (ORs) per 10 ppb changes for NO2, and O3, 100 ppb changes for CO, 10 µg/m3
changes for PM10, and 1 ppb for SO2, along with their 95% confidence intervals (CIs).We also
compared the risk of cardiac defects in four exposure categories based on the distribution of each pollutant representing high (>75th percentile), medium (75th to 50th percentile), low exposure
(<50th to 25th percentile) and <25th percentile as the reference category. Because patent ductus
arteriosus as a congenital malformation is usually only diagnosed in term infants and only after the first few days of life, it may be better to assess patent ductus arteriosus by term births only.
We further performed sensitivity analyses by comparing the effect estimates between all and term births (gestational age >37 weeks).
RESULTS
Characteristics of Control and Case Subjects
A larger proportion of cases than controls had older mothers, maternal diabetes mellitus, lower SES, and shorter gestational age, and were from multiple births (Table 1). We adjusted for these factors in the multivariate analysis.
Air Pollution
The distributions of the monthly mean air pollutant concentrations in different seasons from 72 monitoring stations in Taiwan 2001-2007 are shown in Table 2. The association between NO2
and CO trimester average concentrations during the first trimester was high (r=0.80), which represent the common source of motor vehicles. The concentrations of PM10 and SO2 were also
highly correlated (r=0.53) indicating a common source of stationary fuel combustion, although SO2 concentrations were also associated with both traffic-related pollutants. The concentrations
of O3 were moderately associated with PM10 (r = 0.54), and positively but weakly correlated with
SO2 (r = 0.18). O3 was negatively correlated with the mainly traffic-related pollutants (Table S1).
The adjusted odds ratio for 10 ppb change in O3 for ventricular septal defects in the
single-pollutant model were 1.31 (95% CI: 1.10-1.57) among all births and 1.49 (95% CI: 1.20-1.85) among term births for the first trimester of pregnancy, respectively (Table 3 and 5). Similar ORs were found in the two-pollutant models and the estimates increased a little when added different second pollutants (Table 4). Comparing the adjusted OR for medium and high O3 exposure to
low exposure, the risk of ventricular septal defects was significantly increased (adjusted ORmedium
O3=2.53, 95% CI: 1.55-4.14; adjusted ORhigh O3=2.34, 95% CI: 1.41-3.90) in the single pollutant
model. Furthermore, inclusion of both of the traffic-related pollutants (CO or NO2) and
stationary fossil fuel combustion-related air pollutants (SO2) increased the effect estimate a little
(Table 4). We did not find any association between other air pollutants and the risk of ventricular septal defects.
Air Pollution and the Risk of Atrial Septal Defects
The effect estimates for atrial septal defects were elevated in the first trimester for all births (adjusted OR=1.16, 95% CI: 0.99-1.38), but not statistically increased for term births (adjusted
OR=1.15, 95% CI: 0.94-1.41) for 10 ppb change in O3 (Table 3 and Table 5).
The risk of atrial septal defects was also associated with 10 µg/m3 change in PM
10 in the
first trimester of pregnancy (adjusted OR=1.07, 95% CI: 0.98-1.17) for all births, and inclusion of both of the traffic-related pollutants and O3 did not change the effect estimate substantially
(Table 4). The effect estimates for atrial septal defects for all births with high PM10 exposures
were statistically elevated as compared to low exposures (adjusted ORhigh PM10=2.52, 95% CI:
1.44-4.42) (Table 3). When focusing on term births, the effect estimates were also significantly increased comparing high PM10 exposures to low exposures (adjusted ORhigh PM10=2.26, 95% CI:
Air Pollution and the Risk of Patent Ductus Arteriosus
The risk of patent ductus arteriosus was related to 10 ppb O3 changes in first three months
gestation (adjusted OR=1.19, 95% CI: 1.01-1.40) for all births, but not for term births (adjusted OR=1.04, 95% CI: 0.85-1.28) in the single-pollutant model (Table 3 and Table 5). The effect estimates for patent ductus arteriosus were increased, but not statistically significant in high O3
exposure (adjusted OR=1.41, 95% CI: 0.93-2.13) in single-pollutant model, but inclusion of combustion-related pollutant SO2 changed the effect estimate a little (Table 4). The adjusted
odds ratio for 10 µg/m3 change in PM
10 for patent ductus arteriosus for all births in the
single-pollutant model was 1.07 (95% CI: 0.98-1.16), but did not show statistical significance for term births (adjusted OR=1.02, 95% CI: 0.91-1.13) (Table 5).
In summary, the risks of ventricular septal defects and atrial septal defects for overall and term births were elevated with the continuous O3 exposure, but the risk of patent ductus
arteriosus was increased only for all births. The effect estimates of atrial septal defects for the first trimester with continuous and categorical PM10 exposure was significantly increased when
compared high exposures to low exposures for all and term births. Surprisingly, an inverse association between SO2 exposure and cardiac defects, particular in ventricular septal defects,
atrial septal defects, transposition of the great arteries was found. There were weak or no associations between other air pollutants and pulmonary artery and valve, tetralogy of Fallot, transposition of the great arteries, and conotruncal defects.
DISCUSSION
The results provide evidence that O3 and PM10 exposureduring the first trimester of gestation
may increase the risk of VSD, ASD and PDA. In addition, there was a negative or weak association between SO2, NO2, CO and cardiac defects.
Comparison with other studies
Twelve previous studies, conducted in Southern California,8 San Joaquin Valley of California,15
Texas,9,19 Atlanta,10 Australia,11 and United Kingdom,12-14 Israeli,16 Barcelona,18 and NBDPS
(National Birth Defects Prevention Study ) in nine U.S. States 17 have investigated associations
between cardiac defects and exposure to ambient air pollution. The present study found that per 10 ppb increase in O3 exposure during the first three months of gestation among all births were
associated with the increased risk of ventricular septal defects (31%), atrial septal defects (16%) and patent ductus arteriosus (19%) respectively. The monthly average of O3 varied from 13.8 ppb
to 86.3 ppb. This is different from the results of the Southern Californian study,8 which reported
a CO exposure-related increase response (ORlow=1.62, 95% CI: 1.05, 2.48; ORmedium=2.09, 95%
CI: 1.19, 3.67; ORhigh=2.95, 95% CI: 1.44, 6.05) and the Texan study,9 which showed an
association between SO2 and ventricular septal defects (ORhigh=2.16, 95% CI: 1.51, 3.09). Other
studies in Atlanta, Australia, United Kingdom, San Joaquin Valley of California, Israeli, Barcelona, and NBDPS reported no other or inverse associations between the criteria pollutant levels and ventricular septal defects.12-18 Our study indicated that PM
10 exposure during the first
trimester of gestation has increased risk of atrial septal defects (ORhigh=2.52, 95% CI=1.44, 4.42).
Similar results were reported from the Texan study9 for atrial septal defects (OR
high=2.27, 95%
CI=1.43, 3.60) when high (>75th percentile) was compared with <25th percentile as the reference
category and Atlanta studyfor patent ductus arteriosus (adjusted OR=1.60 per 14.2 µg/m3 95%
Barcelona, NBDPS, Texas.16-19 The other two studies conducted in northeastern England show
weak associations between black smoke and cardiac defects (adjusted OR=1.02 per 1 µg/m3 95%
CI 1.01, 1.03), but they did not find a positive association for patent ductus arteriosus.12,14 In our
study, the risk of patent ductus arteriosus was related to O3 exposure in first three months
gestation for all births, but not for term births. These differences in effect estimates between all births and term births could be explained by information bias related to greater use of ultrasound in term births than in preterm births.
Strengths and limitations of study
The strengths of our study include a comprehensive population based case-control design (all the births in Taiwan), the ability to collect air pollution data from numerous places around the island corresponding to residence of women during pregnancy, and control important risk factors of cardiac defects, such as maternal diabetes mellitus. Our outcomes of interest were based on birth registration rather than clinical examination for the purposes of the study. The cardiac defects might be missed or underreported in Taiwan, because we only include the defects diagnosed up to 7 days of age (1.47/1,000 births),20 compared with the Atlanta 1998-2005 reported rates
(8.14/1,000 births) which were diagnosis through 1 year of age.2 Our case ascertainment taking
place during the first week of life may have introduced both random and systematic error leading to both over diagnosis and under diagnosis. For example, the presence of a patent ductus
arteriosus in the first week of life does not reflect a true congenital anomaly but a neonatal finding that may be normal. Similarly a diagnosis of an atrial defect in this period may be an over reading of a patent foramen ovale or clinically insignificant small atrial defect. This is a possible source of misclassification, which is likely to be random and non-differential between women exposure to high and low levels of ambient air pollution and thus likely to lead to
underestimation of the effect estimates. Although this would depend on whether tertiary care hospitals which might diagnosis more defects are located in the densely populated areas where pollution levels would be higher, we did not find areas of greater pollution in Taiwan. The echocardiograms are commonly performed on infants in Taiwan and the prevalence of certain cardiac defects did not show substantially differences over the study period. In our study, the percentage of premature births was higher among cases than the controls. Even though gestational age (weeks) in the multivariate analysis was adjusted for the potential differences between cases and controls, we still cannot rule out the either a consequence of cardiac defects or a common cause shared between the defects and premature birth.
Because of low occurrence of maternal smoking, alcohol consumption and medication during pregnancy between case and control groups, it’s not meaningful to adjust for these factors (Table 1). It’s not possible to take some confounders such as occupational exposure, maternal work or travel, vitamin use, diet, and folic acid into consideration,21 because there was no such
information available in Taiwanese birth registration data. As these factors may have seasonal and regional variations, we included season of conception and population density to adjust indirectly not only for these factors, but also municipal differences in these behavior factors. However, potential residual confounding might be unmeasured or poorly characterized by other environmental toxicants.
The differences between personal exposure and municipal level exposure could be explained by known or unknown factors such as behavior pattern, living activity, working history, and indoor air pollution. Non-differential errors were assumed between cases and controls. The present and all the previous studies on cardiac defects are adjusted only for covariates based on birth registration information.8-14 Our nationwide population-based
case-control study based on Taiwanese birth registration has the advantage of having larger numbers of births which would reduce the uncertainly due to random error typical for smaller studies that collected detailed information on covariates from pregnant women.22
Our exposure assessment was based on residential zip-code rather than on address during pregnancy, and we applied geographic information system to integrate monthly air pollutant data from 72 EPA monitoring stations which was interpolated to pollutant surfaces using inverse distance weighting method. Two previous studies reported that when using the municipal level exposure obtained from air pollution monitoring stations as a proxy for personal exposure results in smaller effect estimates than when using personal assessment of exposure.23-24 A plausible
explanation of information bias is residential mobility during pregnancy may lead to exposure misclassification. Any random migration in cases and controls might introduce non-differential misclassification and decrease the accuracy of exposure assessment. This would most likely result in underestimation of the air pollution effects rather than a positive bias in the associations.
Since urban air pollution usually consists of a complex mixture of several compounds, evaluating the independent effects of different pollutants and identifying a candidate teratogen is not easy. The results of Pearson's correlation analysis during the first trimester of pregnancy showed a high correlation (r=0.80) between NO2 and CO, since they are both emitted predominantly from motor vehicles. Likewise there exited a moderate correlation (r=0.53) between PM10 and SO2 with important sources from stationary combustion of fossil fuels. O3 is,
a secondary air pollutant produced in the lower atmosphere from precursors of the vehicle emissions (nitrogen dioxide and hydrogen carbon), but the concentrations of O3 are highly
associated with PM10 (r=0.54) and slightly related to NO2 (r=-0.07), CO (r=-0.27) and SO2
effects of O3 on cardiac defects independent from NO2, CO and SO2. Meanwhile it is possible to
control one potential confounder (stationary fossil fuel pollutant) at a time in evaluating the effect of different traffic-related pollutants.
This study investigated a relatively large number of health outcomes, which may influence the interpretation of the results. Since the hypotheses of the effects on a priori defined cardiac defect groups are independent and mutually exclusive, multiple-inference procedures were no longer required.25 According to Greenland and Rothman (1998),26 all the single-inference
procedures with point estimates and confidence intervals were presented in this study. However, selected effect estimates from an unknown number of estimates were not presented. Given 40 associations (8 outcomes × 5 air pollutants) present here, we would expect at least two of the associations to be significant due to chance (if α=0.05). Although our findings suggest the risk of several cardiac defects is related to exposure to O3 andPM10 intime windows that match with our
knowledge about susceptible periods of cardiac development, we cannot rule out the possibility of chance.
Possible mechanisms
How pregnant women’s exposure to airborne particulate matter induces development of cardiac defects is still unknown and needs further investigation. The possible explanation is that aromatic hydrocarbons (PAHs) and heavy metals associated with inhaled particulate may cause DNA damage in male germ cells and changes in humans during development.27-28 An animal
study revealed that high exposure to O3 (>1.26 ppm) during organogenesis had embryocidal
effects in rats.29 As we know, vitamin A deprivation during organogenesis causes several
congenital defects, rats exposed to 0.4 ppm O3 for 1-4 days had an 85% lowering of the serum
retinol concentration,30 supporting the hypothesized adverse effects of O
associated with the e risk of cardiac defects. The most susceptible time to the effects of O3 were
the first three months of gestation. O3 is considered to be a strong oxidizing agent to generate
hydrogen peroxide, hydroxyl radicals, and super oxides. It was related to oxidative stress and the development of cardiac defects.
Our finding of lack of association between the risk of cardiac defects and traffic-related (CO and NO2) and combustion–related (SO2) air pollutant levels is consistent with the results from
Atlanta,10 Australia,11 and United Kingdom.12-14
Conclusions
The present study provides evidence that the effect of exposure to outdoor air O3 and PM10
during the first three month of pregnancy increases the risk of cardiac defects. Given that similar levels are encountered globally by large numbers of pregnant women, O3 and PM10 may be an
important determinant of cardiac defects.
Supporting information
Table S1 Correlations of air pollutants trimester average concentration during the first three months pregnancy.
This study was supported by grant #CMU100-AWARD-07 from China Medical University,
National Science Council (NSC 98-2815-C-039-033-B) and Health Effects Institute through a research agreement (#4790-RFA09-2/10-1). We thank the Taiwan Environmental Protection Agency (EPA) for providing air pollutant monitoring data and the Bureau of Health Promotion, Department of Health for access to the birth registration data. The funding bodies had no role in the design or conduct of this study or in the preparation, review, approval, or decision to submit the manuscript.
The authors have no conflicts of interest to disclosure.
1. Pierpont ME, Basson CT, Benson W, Gelb BD, Giglia TM, Goldmuntz E, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on
Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 3015-3038.
2. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr 2008; 153: 807-13. 3. Ritz B, Yu F. The effect of ambient carbon monoxide on low birth weight among children
born in southern California between 1989 and 1993. Environ Health Perspect 1999; 107: 17-25.
4. Maisonet M, Correa A, Misra D, Jaakkola JJK. A review of the literature on the effects of ambient air pollution on fetal growth. Environ Res 2004; 95: 106-115.
5. Glinianaia SV, Rankin J, Bell R, Pless-Mulloli T, Howel D. Particulate air pollution and fetal health: a systematic review o the epidemiologic evidence. Epidemiology 2004; 15: 36-45.
6. Lacasana M, Esplugues A, Ballester F. Exposure to ambient air pollution and prenatal and early childhood health effects. Eur J Epidemiol 2005; 20: 183-199.
7. Ritz B, Wilhelm M, Hoggatt KJ, Ghosh JK. Ambient air pollution and preterm birth in the environment and pregnancy outcomes study at the University of California, Los Angeles. Am J Epidemiol 2007; 166: 1045-1052.
8. Ritz B, Yu F, Fruin S, Guadalupe C, Shaw GM, Harris JA. Ambient air pollution and risk of birth defects in Southern California. Am J Epidemiol 2002; 155: 17-25.
9. Gilboa SM, Mendola P, Olshan AF, Langlois PH, Savitz DA, Loomis D, et al. Relation between ambient air quality and selected birth defects, seven county study, Texas, 1997-2000. Am J Epidemiol 2005; 162: 238-52.
10. Strickland MJ, Klein M, Correa A, Reller MD, Mahle WT, Riehle-Colarussa TJ, et al. Ambient air pollution and cardiovascular malformation in Atlanta, Georgia, 1986-2003. Am J Eipdemiol 2009; 169: 1004-1041.
11. Hansen CA, Barnett AG, Jalaludin BB, Morgan GG. Ambient air pollution and birth defects in Brisbane, Australia. Plos One 2009; 4:e5408.
12. Rankin J, Chadwich T, Natarajan M, Howel D, Pearce MS, Pless-Mulloli T. Maternal exposure to ambient air pollutants and risk of congenital anomalies. Environ Res 2009; 109: 181-189.
13. Dolk H, Armstrong B, Lachowycz K, Vrijheid M, Rankin J, Abramsky L, et al. Ambient air pollution and risk of congenital anomalies in England, 1991-1999. Occup Environ Med 2010; 67: 223-227.
14. Dadvand P, Rankin J, Rushton S, Pless-Mulloli T. Association between maternal exposure to ambient air pollution and congenital heart disease: a register-based spatio-temporal analysis. Am J Epidemiol 2011; 173:171.
15. Padula AM, Tager IB, Carmichael SL, Hammond SK, Yang W, Lurmann F, Shaw GM. Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California. Paediatr Perinat Epidemiol. 2013; 27:329-39.
16. Agay-Shay K, Friger M, Linn S, Peled A, Amitai Y, Peretz C. Air pollution and congenital heart defects. Environ Res 2013; 124:28-34.
17. Stingone JA, Luben TJ, Daniels JL, Fuentes M, Richardson DB, Aylsworth AS, et al. National Birth Defects Prevention Study. Maternal exposure to criteria air pollutants and congenital heart defects in offspring: results from the national birth defects prevention study. Environ Health Perspect 2014;122: 863-72.
18. Schembari A, Nieuwenhuijsen MJ, Salvador J, de Nazelle A, Cirach M, Dadvand P, et al. Traffic-related air pollution and congenital anomalies in Barcelona. Environ Health Perspect 2014;122: 317-23.
19. Vinikoor-Imler LC, Stewart TG, Luben TJ, Davis JA, Langlois PH. An exploratory analysis of the relationship between ambient ozone and particulate matter concentrations during early pregnancy and selected birth defects in Texas. Environ Pollut 2015; 202:1-6.
20. Vrijheid M, Martinez D, Manzanares S, Dadvand P, Schembari A, Rankin J, et al. Ambiient air pollution and risk of congenital anomalies: a systematic review and meta-analysis. Environ Health Perspect 2011; 119:598-606.
21. Chen EK, Zmirou-Navier D, Padilla C, Deguen S. Effects of air pollution on the risk of congenital anomalies: a systematic review and meta-analysis. Int J Environ Res Public Health 2014;11:7642-68.
22. Gilliland F, Avol E, Kinney P, Jerrett M, Dvonch T, Lurmann F, et al. Air pollution exposure assessment for epidemiologic studies of pregnant women and children: lessons learned from the Centers for Children’s Environmental Health and Disease Prevention Research. Environ Health Perspect 2005; 113: 1447-1454.
23. Lin CM, Lee PC, Teng SW, Lu TH, Mao IF, Li CY. Validation of the Taiwan birth registration using obstetric records. J Formos Med Assoc 2004; 103: 297-301.
24. Hwang BF, Jaakkola JJK. Ozone and the other air pollutants and the risk of oral clefts. Environ Health Perspect 2008; 116:1411-1415.
25. Clark EB. Growth, morphogenesis and function: the dynamics of cardiac development, In: Moller JH, Neal WA, Lack J, eds. Fetal, neonatal and infant heart disease. New York, NY: 1990 Appleton & Lange 3-23.
26. Greenland S. Modelling and variable selection in epidemiologic analysis. Am J Public Health 1989; 79: 340-49.
27. Chen BY, Hwang BF, Guo YL. Epidemiology of congenitial anomalies in a population-based birth registry in Taiwan 2002. J Formos Med Assoc 2009; 108: 460-468.
28. Kuehl KS, Loffredo CA. Genetic and environmental influences on malformations of the cardiac outflow. Expert Rev Cardiovasc Ther 2005; 3: 1125-30.
29. Ritz B, Wilhelm M. Ambient air pollution and adverse birth outcomes: methodological issues in an emerging field. Basic Clin Pharmacol Toxicol 2008; 102:182-190.
30. Navidi W, Lurmann F. Measurement error in air pollution exposure assessment. J Expo Anal Environ Epidemiol 1995; 5: 111-124.
31. Wilhelm M, Ritz B. Local variation in CO and particulate air pollution and adverse birth outcomes in Los Angeles County, California, USA. Environ Health Perspect 2005; 113: 1212-1221.
32. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236-8. 33. Rothman KJ, Greenland S. Modern Epidemiology 2nd ed. 1998 Philadelphina PA:
Lippincott-Raven, 225-229.
34. Samet JM, DeMarini DM, Malling HV. Do airborne particles induce heritable mutations? Science 2004; 304:971-2.
35. Somers CM, McCarry BE, Malek F, Quinn JS. Reduction of particulate air pollution lowers the risk of heritable mutations in mice. Science 2004; 304:1008-10.
36. Kavlock R, Dasston G, Grabowski CT. Studies on the developmental toxicity of ozone. I. Prenatal effects. Toxcol Appl Pharmacol 1979; 48: 19-28.
37. Takahashi Y, Miura T, Kimura S. A decrease in serum retinol by in vivo exposures of rates to ozone. Int J Vitam Nutr Res 1990; 60: 294-295.
38. Lohnes D, Mark M, Mendelsohn C, Dollé P, Decimo D, LeMeur M, et al. Developmental roles of the retinoic acid receptors. J Steroid Biochem Mol Biol 1995; 53: 475-486.
