The maternal sociodemographic characteristics, reproductive history and periconceptional health status of the study population are listed in Table 1. Both parental age and education level were significantly different between the case and control groups. No family history of CHD was observed among the study subjects.
Table 1. Basic characteristics (sociodemographics, reproductive history, and periconceptional health status) of the study subjects
Characteristics
|
Controls
(N=72)
|
Cases
(N=34)
|
p Value*
|
n (%)
|
n (%)
|
Maternal age (years)
|
|
|
|
<25
|
0 (0)
|
4 (11.8)
|
0.01
|
25–29
|
18 (25)
|
12 (35.3)
|
|
30-34
|
40 (55.6)
|
12 (35.3)
|
|
35+
|
14 (19.4)
|
16 (17.9)
|
|
Paternal age (years)
|
|
|
|
<25
|
0 (0)
|
1 (2.9)
|
0.019
|
25–29
|
11 (15.3)
|
13 (38.2)
|
|
30-34
|
36 (50.0)
|
10 (29.4)
|
|
35+
|
25 (34.7)
|
10 (29.4)
|
|
Maternal education level
|
|
|
|
Low (compulsory only)
|
0 (0)
|
4 (11.8)
|
0.003
|
Medium (completed high school)
|
7 (9.7)
|
7 (20.6)
|
|
High (tertiary or higher)
|
65 (90.3)
|
23 (67.6)
|
|
Paternal education level
|
|
|
|
Low (compulsory only)
|
2 (2.8)
|
5 (14.7)
|
0.023
|
Medium (completed high school)
|
5 (6.9)
|
5 (14.7)
|
|
High (tertiary or higher)
|
65 (90.3)
|
24 (70.6)
|
|
Residence
|
|
|
|
Urban
|
69 (95.8)
|
32 (94.1)
|
0.655
|
Rural
|
3 (4.2)
|
2 (5.9)
|
|
Parity
|
|
|
|
Multiparous
|
27 (37.5)
|
12 (35.3)
|
0.829
|
Primiparous
|
45 (62.5)
|
22 (64.7)
|
|
Folic acid supplementation
|
|
|
|
Never
|
11 (15.3)
|
5 (14.7)
|
0.997
|
Occasionally/irregularly
|
17 (23.6)
|
8 (23.5)
|
|
Frequently/regularly
|
44 (61.1)
|
21 (61.8)
|
|
Multivitamin supplementation
|
|
|
|
Never
|
29 (40.3)
|
19 (55.9)
|
0.277
|
Occasionally/irregularly
|
11 (15.3)
|
5 (14.7)
|
|
Frequently/regularly
|
32 (44.4)
|
10 (29.4)
|
|
Diabetes
|
|
|
|
No
|
65 (90.3)
|
29 (85.3)
|
0.669
|
Yes
|
7 (9.7)
|
5 (14.7)
|
|
Maternal alcohol consumption
|
|
|
|
No
|
54 (75)
|
26 (76.5)
|
0.787
|
Occasionally/irregularly
|
17 (23.6)
|
8 (23.5)
|
|
Frequently/regularly
|
1 (1.4)
|
0
|
|
Maternal smoking
|
|
|
|
No
|
70 (97.2)
|
33 (97.1)
|
1.000
|
Occasionally
|
2 (2.8)
|
1 (2.9)
|
|
*P value was calculated with chi-square or Fisher exact tests.
Table 2. Residential environmental characteristics of the study subjects
Characteristics
|
Controls (N=72)
|
Cases (N=34)
|
p Value
|
n (%) or median (interquartile)
|
n (%) or median (interquartile)
|
|
Gestational weeks at the time of questionnaires (weeks) *
|
24 (6)
|
23.5 (3)
|
0.773
|
Gestational weeks at the time of field investigation (weeks) *
|
26 (6)
|
25 (3)
|
0.235
|
Time spent indoors each day during the first trimester (hours) *
|
16 (5)
|
14 (5)
|
0.637
|
House renovation and ventilation
|
|
|
|
No renovation
|
52 (72.2)
|
22 (64.7)
|
0.002
|
Living in a newly redecorated house with move-in interval<3 months
|
2 (2.8)
|
8 (23.5)
|
|
Living in a newly redecorated house with move-in interval≥3 months
|
18 (25)
|
4 (11.8)
|
|
Indoor floor decoration
|
|
|
|
Wood-base flooring
|
34 (47.2)
|
10 (29.4)
|
0.191
|
Marble and tile paving
|
8 (11.1)
|
8 (23.5)
|
|
Carpet
|
2 (2.8)
|
2 (5.9)
|
|
Mix of various materials
|
28 (38.9)
|
14 (41.2)
|
|
Indoor wall decoration
|
|
|
|
Wallpaper
|
4 (5.6)
|
2 (5.9)
|
0.961
|
Paint
|
32 (44.4)
|
16 (47.1)
|
|
Mix of various materials
|
36 (50)
|
15 (47.1)
|
|
Indoor furniture and ornaments
|
|
|
|
Wood-base furniture
|
34 (47.2)
|
13 (38.2)
|
0.309
|
Wood and leather furniture
|
13 (18.1)
|
4 (11.8)
|
|
Mix of various materials
|
25 (34.7)
|
17 (50)
|
|
Second-hand smoke
|
|
|
|
Not exposed
|
43 (59.7)
|
22 (64.7)
|
0.623
|
Exposed
|
29 (40.3)
|
12 (35.3)
|
|
Exposure to environmental pollutants nearby the residence
|
|
|
|
Cornfields and orchards
|
1
|
3
|
|
Chemical plant
|
1
|
0
|
|
Heavy-traffic road
|
23
|
15
|
|
Incineration plant
|
0
|
1
|
|
More than two facilities concomitantly
|
0
|
2
|
|
Special facilities combined
|
|
|
|
No
|
47 (65.3)
|
13 (38.2)
|
0.005
|
Heavy traffic road
|
23 (31.9)
|
15 (44.1)
|
|
Other special facilities
|
2 (2.8)
|
6 (17.6)
|
|
Smoke ventilators usage when cooking
|
|
|
|
No
|
14 (19.4)
|
18 (52.9)
|
<0.001
|
Yes
|
58 (80.6)
|
16 (47.1)
|
|
Exposure to household chemical products
|
|
|
|
Pesticides
|
7
|
1
|
|
Disinfectants and sanitizers
|
0
|
1
|
|
Paints, dyes and glues
|
1
|
0
|
|
Household cleaning agents
|
5
|
2
|
|
Special chemicals combined
|
|
|
|
None
|
52 (72.2)
|
27 (79.4)
|
0.75
|
One
|
13 (18.1)
|
4 (11.8)
|
|
Multiple
|
7 (9.7)
|
3 (8.8)
|
|
*For abnormally distributed continuous variables, the median (interquartile) was used to describe the distribution, while the P values were calculated by the Mann–Whitney U-test.
Table 2 compares the two groups according to residential environmental characteristics. The two groups spent a similar amount of time indoors each day during the first trimester, with a median of more than 14 hours per day. Significant differences in proportions between the mothers from the case and control groups were detected with respect to maternal exposure to environmental pollutants near the residence, indoor renovations and ventilation time, and smoke ventilator usage when cooking. Eight case women (23.5%) reported exposure to housing renovations with a moving-in interval of less than 3 months, while the same situation occurred in only 2.8% of the control group. A larger proportion of cases than controls lived in residences near heavily trafficked roads (44.1% vs. 31.9%). The rate of ventilator use when cooking was much higher in the control group than in the case group (80.6% vs. 47.1%). There were no between-group differences found in decorative materials of dwelling place, exposure to household chemical products or exposure to second-hand smoke.
Median (interquartile) TVOC [0.430 (2.305) vs. 0.005 (0.250) mg/m3, P < 0.001], PM2.5 [12.00 (8.25) vs. 8.00 (11.00) µg/m3, P=0.037] and PM10 [13.50 (11.25) vs. 8.00 (14.00) µg/m3, P=0.028] levels in cases were significantly higher than those in controls (Table 3). Formaldehyde concentrations were found to exceed the Chinese indoor exposure limit in 6 cases (17.6%) and 12 controls (16.7%), despite no significant difference between the groups. The concentrations of BTX were detected at very low levels in both groups with a median (interquartile) close to zero. Although some studies suggested that temperature and humidity may affect indoor air pollutant concentrations (Meciarova et al. 2017), we did not find any difference in temperature or humidity between the two groups, and most of the subjects were recruited in spring or summer.
Table 4 shows the correlation analysis for these indoor air pollutants. The correlation coefficient between formaldehyde and other pollutants ranged from 0.26-0.45 with statistical significance. BTX concentrations were closely related to each other with moderate correlations ranging from 0.52-0.72 (P < 0.001), suggesting that these three pollutants could have similar or common sources. PM2.5 and PM10 concentrations were highly correlated, with a coefficient of 0.97 (P < 0.001), indicating their common source of pollution. TVOCs, as the total concentrations of formaldehyde, BTX and other VOCs, showed no obvious correlations with PM.
Table 3. Descriptive statistics of indoor air pollutants in the case and control groupsa
Indoor air pollution
|
Reference limit value #
|
Case
|
Control
|
P value*
|
Mean±SD
|
Median (interquartile)
|
Range
(min-max)
|
Number over reference limit (N/%)
|
Mean±SD
|
Median (interquartile)
|
Range
(min-max)
|
Number over reference limit (%)
|
PM10, µg/m3
|
150b
|
15.735±9.202
|
13.500 (11.250)
|
2.000-38.000
|
0
|
15.125±17.671
|
8.000 (14.000)
|
1.000-84.000
|
0
|
0.028
|
PM2.5, µg/m3
|
75c
|
13.294±7.677
|
12.000 (8.250)
|
2.000-32.000
|
0
|
12.931±14.831
|
8.000 (11.000)
|
1.000-73.000
|
6 (8.3)
|
0.037
|
Benzene, mg/m3
|
0.11b
|
0.055±0.190
|
0.005 (0.000)
|
0.005-1.000
|
3 (8.8)
|
0.038±0.148
|
0.005 (0.000)
|
0.005-1.000
|
4 (5.6)
|
0.535
|
Toluene, mg/m3
|
0.2b
|
0.066±0.199
|
0.005 (0.000)
|
0.005-1.000
|
4 (11.8)
|
0.034±0.107
|
0.005 (0.000)
|
0.005-0.600
|
6 (8.3)
|
0.322
|
Xylene, mg/m3
|
0.2b
|
0.066±0.252
|
0.005 (0.000)
|
0.005-1.400
|
3 (8.8)
|
0.039±0.128
|
0.005 (0.000)
|
0.005-0.600
|
5 (6.9)
|
0.734
|
Formaldehyde, mg/m3
|
0.1b
|
0.078±0.142
|
0.010 (0.055)
|
0.005-0.609
|
6 (17.6)
|
0.077±0.142
|
0.022 (0.037)
|
0.005-0.790
|
12 (16.7)
|
0.483
|
TVOC, mg/m3
|
0.6b
|
1.352±1.768
|
0.430 (2.305)
|
0.005-7.027
|
20 (58.8)
|
0.214±0.389
|
0.005 (0.250)
|
0.005-1.850
|
4 (5.6)
|
< 0.001
|
Temperature, ℃
|
/
|
25.741±4.642
|
26.000 (5.250)
|
14.000-34.000
|
/
|
27.008±3.562
|
28.000 (4.000)
|
19.000-34.000
|
/
|
0.186
|
Relative humidity, %
|
/
|
44.319±10.631
|
40.500 (15.250)
|
27.000-69.000
|
/
|
47.193±7.401
|
47.500 (9.750)
|
30.000-63.000
|
/
|
0.054
|
a BTX, formaldehyde and TVOC concentrations below the method of detection limit (MDL) of 0.01 mg/m3 were replaced with 0.005 mg/m3 in all analyses.
b Indoor exposure limits were referenced from Chinese national GB/T 18883-2002.
c Indoor PM2.5 exposure limit was referenced from Chinese national ambient air quality standard GB3095-2012.
* P value was calculated by Mann–Whitney U-test for nonnormally distributed continuous variables.
Table 4. Pearson correlation coefficients for indoor air pollution
|
PM10
|
PM2.5
|
Benzene
|
Toluene
|
Xylene
|
Formaldehyde
|
TVOC
|
PM10
|
1.00
|
|
|
|
|
|
|
PM2.5
|
0.97**
|
1.00
|
|
|
|
|
|
Benzene
|
0.17
|
0.15
|
1.00
|
|
|
|
|
Toluene
|
0.04
|
0.02
|
0.72**
|
1.00
|
|
|
|
Xylene
|
0.06
|
0.06
|
0.55**
|
0.52**
|
1.00
|
|
|
Formaldehyde
|
0.26**
|
0.29**
|
0.48**
|
0.25*
|
0.45**
|
1.00
|
|
TVOC
|
0.15
|
0.15
|
0.19
|
0.20*
|
0.29**
|
0.26**
|
1.00
|
Correlations were calculated with the Spearman rank correlation test; * P<0.05; ** p<0.01
Associations between indoor air pollutant levels and CHDs were investigated using univariate and multivariable single-pollutant regression models. Multivariable models were adjusted for variables considered to be significantly different in bivariate analysis, including both parental age and education level, house renovation and ventilation, exposure to environmental pollutants near the residence, and smoke ventilator usage when cooking. Because BTX concentrations of the majority of subjects in both groups were below the MDLs or were not detected at all, we did not estimate ORs of BTX exposure levels in regression models due to the limited statistical power.
As shown in Table 5, a high level of TVOCs was associated with CHD in univariable analysis (COR 4.46, 95% CI 1.69-11.77) and was enhanced with an elevated AOR of 5.72 (1.6-20.49). Compared with the low level of PM2.5, infants of mothers in the middle and high levels had higher odds for CHDs, with AORs of 11.98 (95% CI: 1.63-88.04) and 10.30 (95% CI: 1.51-70.16), respectively, despite the wide confidence intervals. Similar to its strong correlation with PM2.5, we found that PM10 exposure was similarly associated with CHDs, with a middle-level AOR of 17.59 (95% CI: 1.98-155.96) and a high-level AOR of 18.31 (95% CI: 2.14-156.41) vs. the low level. We did not find any association between formaldehyde exposure level and CHD risk.
Table 5. Associations between indoor air pollutant exposure levels and CHDs
Indoor air pollutant
exposure levels
|
Controls
N (%)
|
Cases
N (%)
|
COR
|
AORa
|
TVOCb
|
|
|
|
|
Low (≤0.005 mg/m3)
|
38 (52.8)
|
9 (26.5)
|
Reference
|
Reference
|
Middle (0.006-0.24 mg/m3)
|
16 (22.2)
|
6 (17.6)
|
1.58 (0.48-5.19)
|
1.34 (0.27-6.52)
|
High (≥0.25 mg/m3)
|
18 (25.0)
|
19 (55.9)
|
4.46** (1.69-11.77)
|
5.72** (1.6-20.49)
|
Formaldehyde
|
|
|
|
|
Low (<0.01 mg/m3)
|
24 (33.3)
|
18 (52.9)
|
Reference
|
Reference
|
Middle (0.01-0.02 mg/m3)
|
24 (33.3)
|
5 (14.7)
|
0.39 (0.12-1.22)
|
0.62 (0.15-2.65)
|
High (≥0.03 mg/m3)
|
24 (33.3)
|
11 (32.4)
|
0.71 (0.28-1.8)
|
0.94 (0.28-3.12)
|
PM2.5
|
|
|
|
|
Low (<4 µg/m3)
|
26 (36.2)
|
3 (8.8)
|
Reference
|
Reference
|
Middle (4-12.9 µg/m3)
|
23 (31.9)
|
17 (50.0)
|
6.41** (1.66-24.7)
|
11.98* (1.63-88.04)
|
High (≥13 µg/m3)
|
23 (31.9)
|
14 (41.2)
|
5.28* (1.34-20.71)
|
10.30* (1.51-70.16)
|
PM10
|
|
|
|
|
Low (<5 µg/m3)
|
22 (30.6)
|
2 (5.9)
|
Reference
|
Reference
|
Middle (5-13.9 µg/m3)
|
24 (33.3)
|
15 (44.1)
|
6.87* (1.41-33.54)
|
17.59** (1.98-155.96)
|
High (≥14 µg/m3)
|
26 (36.1)
|
17 (50.0)
|
7.19* (1.49-34.62)
|
18.31** (2.14-156.41)
|
a Adjusted for maternal and paternal age, maternal and paternal education level, house renovation and ventilation (category), exposure to environmental pollutants near the residence (category), and smoke ventilator usage when cooking.
b As the TVOC concentration was below the MDL in more than one-third of the control population, TVOC exposure levels were divided into low (equal or lesser than the MDL value), middle (below the median detected value of the control distribution), and high (above the median detected value of the control distribution) groups.
* p < 0.05, ** p < 0.01 vs. control.
Due to the limited number of participants in the CHD subgroups, further analysis was performed to compare the cases and controls when these pollutant exposure levels were dichotomized into two levels as described in the aforementioned methods section. The association with high TVOC levels was also present in the subgroups of septal defects and right-sided obstructions in the context of the recategorized low level [AOR 16.73 (95% CI: 2.25-124.65) and 10.68 (95% CI: 1.28-89.43), respectively] but not in subgroup of conotruncal defects (Table 6). Other pollutants, including formaldehyde, PM2.5 and PM10, did not show any statistically significant association with CHD subtypes in the context of this recategorized binary exposure level.
We chose several residential-level environmental factors that were considered to be correlated with indoor air pollutant exposure, referring to the previous literature. Table 7 shows the effects of air pollutants on CHDs in offspring among all participants and stratified by house renovation, smoke ventilator usage, and exposure to environmental pollutants near the residence. Due to the limited sample size, recategorized binary exposure levels of pollutants were used to compare the ORs for CHD in different stratifications.
Table 6. Effect of indoor air pollutant exposure levels on CHD subtypes. a
|
TVOC
|
Formaldehyde
|
PM2.5
|
PM10
|
Low
(<0.25 mg/m3)
|
High
(≥0.25 mg/m3)
|
Low
(<0.03 mg/m3)
|
High
(≥0.03 mg/m3)
|
Low
(<13 µg/m3)
|
High
(≥13 µg/m3)
|
Low
(<14 µg/m3)
|
High
(≥14 µg/m3)
|
N
|
N
|
AOR
(95% CI)
|
N
|
N
|
AOR (95% CI)
|
N
|
N
|
AOR
(95% CI)
|
N
|
N
|
AOR
(95% CI)
|
Controls
|
54
|
18
|
|
48
|
24
|
|
49
|
23
|
|
46
|
26
|
|
Cases
|
|
|
|
|
|
|
|
|
|
|
|
|
Total (n=34)
|
15
|
19
|
5.29**
(1.6-17.47)
|
23
|
11
|
1.09
(0.36-3.36)
|
20
|
14
|
1.82
(0.62-5.33)
|
17
|
17
|
2.11
(0.72-6.18)
|
Septal defects (n=16)
|
6
|
10
|
16.73*
(2.25-124.65)
|
12
|
4
|
0.56
(0.09-3.46)
|
10
|
6
|
1.79
(0.31-10.33)
|
7
|
9
|
3.98
(0.69-22.95)
|
Right-sided obstructions (n=12)
|
5
|
7
|
10.68*
(1.28-89.43)
|
8
|
4
|
0.52
(0.08-3.29)
|
8
|
4
|
0.67
(0.08-5.57)
|
8
|
4
|
0.63
(0.08-5.07)
|
Conotruncal defects (n=12)
|
7
|
5
|
4.22
(0.79-22.56)
|
8
|
4
|
1.98
(0.37-10.53)
|
6
|
6
|
2.88
(0.64-12.92)
|
5
|
7
|
4.19
(0.86-20.53)
|
a Adjusted for maternal and paternal age, maternal and paternal education level, house renovation and ventilation (category), exposure to environmental pollutants near the residence (category), and smoke ventilator usage when cooking. The low-level group served as the reference.
* p < 0.05, ** p < 0.01 vs. control.
Please see the supplementary section for Table 7.
Among participants living in newly redecorated houses, high TVOC exposure was significantly associated with the risk of CHDs (AOR 32.13, 95% CI: 1.48-698.11). The AOR of high TVOC for CHDs was estimated to be 4.44 (95% CI: 1.03-19.18) in houses using smoke ventilators when cooking, while the AOR value tended to be higher in houses without the use of smoke ventilators, but the difference was not statistically significant (AOR 13.1, 95% CI: 0.73-234.81, p=0.08). Associations of high PM2.5 and PM10 exposure levels with the risk of CHDs were found among participants living in residences near heavy-traffic roads (OR 9.16, 95% CI: 1.2-69.93, and OR 8.89, 95% CI: 1.14-69.6, respectively). Nevertheless, the CHD risk associated with air pollutants was not statistically significant among participants with no house renovation, no use of smoke ventilators or no exposure to environmental pollutants near the residence.
We analysed interactions between TVOC and PM2.5 in terms of pairwise combinations modifying the risk for CHDs (Table 8). We observed a joint association AOR of 6.77 (95% CI: 1.50–30.59) for high TVOCs with high PM2.5 compared with low TVOCs and low PM2.5. Moreover, there was a statistically significant multiplicative interaction between TVOCs and PM2.5 (AOR 4.03, 95% CI: 1.09-14.87, p = 0.036), suggesting that high TVOCs and high PM2.5 may interact synergistically to increase the risk of CHDs. Although an RERI value of 2.46 was calculated in the additive model, probably indicating a positive interaction of TVOCs and PM2.5, this evidence was weak, as evidenced by the wide confidence interval crossing 0 (95% CI: −7.01, 11.93).
Table 8. Interaction effects of exposure to TVOCs and PM2.5 on the risks of CHDs
Exposure
|
N, controls/cases
|
AORa (95% CI)
|
p value
|
TVOCs with PM2.5 (dichotomous)
|
Low TVOC and low PM2.5
|
38/11
|
Reference
|
|
High TVOC and low PM2.5
|
11/9
|
4.2 (0.82-21.65)
|
0.086
|
Low TVOC and high PM2.5
|
16/4
|
1.11 (0.21-5.84)
|
0.902
|
High TVOC and high PM2.5
|
7/10
|
6.77 (1.5-30.59)
|
0.013
|
Cross-product for interaction
|
4.03 (1.09-14.87)
|
0.036
|
RERI on the additive scale
|
2.46 (-7.01-11.93)
|
AP on the additive scale
|
0.36 (-0.71-1.43)
|
Low TVOC was defined as a TVOC concentration <0.25 mg/m3, while high TVOC was defined as a TVOC concentration≥0.25 mg/m3; low PM2.5 was defined as a PM2.5 concentration<13 µg/m3, while high PM2.5 was defined as a PM2.5 concentration≥13 µg/m3.
a Adjusted for maternal and paternal age, maternal and paternal education level, house renovation and ventilation (category), exposure to environmental pollutants near the residence (category), and smoke ventilator usage when cooking. The low-level group served as the reference.