The current study aimed to determine the associations between CHDs in offspring and maternal exposure to indoor air pollution during pregnancy as measured in field-based investigations with a case-control design. Although this was a pilot study with a limited number of subjects, we observed that exposure to indoor TVOCs, PM2.5 and PM10 at high levels during pregnancy could result in increased risks for CHDs and the occurrence of some major subtypes in offspring, probably suggesting a potential dose–response relationship. Some household activities, including house renovation, smoke ventilator usage when cooking, and living near heavy-traffic roads, may affect the risks of CHDs associated with indoor air pollutants. Our results also suggested that maternal exposure to high levels of TVOCs in addition to high levels of PM2.5 may interact synergistically to increase the risk of CHDs. These results provide support for the hypothesis that maternal exposure to indoor air pollution may have adverse effects on foetal cardiac development.
Reports linking environmental exposures to birth defects have steadily increased[11, 18, 20]. However, the inability to routinely identify indoor environmental exposures during pregnancy, difficulty quantifying these exposures and maternal recall biases limit the ability to determine causal relationships. Indoor air pollution, compared to atmospheric pollution, is characterized by its complexity, ubiquity, and persistence, resulting in progressive and cumulative effects on health risk, especially among susceptible pregnant women[28]. Additionally, this research has suggested that most pregnant women spend more time indoors; thus, indoor air quality data are more important for analysing these effects.
VOCs and PM, which are considered to be major indoor air pollutants, have been widely studied for their adverse effects on cardiovascular[12] and pulmonary health[13] in the general population, but limited data among pregnant women and their foetuses have been reported. Some volatile organic solvents (e.g., trichloroethylene (TCE)), which may quickly evaporate and are preserved in the atmosphere, soil and ground water, are sources of indoor pollutant exposure by routes of inhalation, ingestion and skin contact[29]. A study indicated that TCE is likely to be a risk factor for CHD and reported a threefold increased CHD risk among mothers presumably exposed to TCE compared with the risk among non-exposed mothers[30]. Chang et al.[31] indicated that elevated exposure to TVOCs during the prenatal period may adversely influence early postnatal growth. A previous study[18] assessed the effects of ambient air pollutants on CHD and found that effect estimates of cardiac atrial septal defects for the first trimester were significantly increased with continuous and categorical PM10 exposure when comparing high exposures to low exposures. However, it was also reported that at the municipal level, exposure assessed by air pollution monitoring stations as a proxy for personal exposure results in smaller effect estimates than when using individual assessments of exposure[32]. To our knowledge, no prior study has evaluated the effect of indoor air pollution on foetal CHDs using individual maternal exposure data, and most studies were limited by self-reported or occupational exposure assessments.
Indoor air pollutant levels measured among our study participants were generally lower than those reported in previous studies. The mean value of formaldehyde was 0.078 mg/m3 for cases and 0.077 mg/m3 for controls in our study; these values were lower than the reported mean value of 0.175 mg/m3 in general houses in Harbin, China[33] and 81.6 µg/m3 in houses for pregnant women in Korea[31]. BTX concentrations in the majority houses were below the MDLs or were not detected at all. For total VOCs, a reported household mean value of 0.411 mg/m3 (ranging from 0.28–0.48 mg/m3)[33] was close to our median concentration among cases (0.430 mg/m3) but far exceeded the concentration among controls (0.005 mg/m3). The median TVOC concentration among cases was also higher than the prenatal exposure value of 284.2 µg/m3 in Chang’s research[31]. A study in Taipei, China recorded household indoor PM10 and PM2.5 mean concentrations of 41 µg/m3 (ranging from 7.8–99.4 µg/m3) and 25.5 µg/m3 (ranging from 9.5–80.5 µg/m3), both of which were higher than those reported in our control participants (Table 5). According to the Chinese National Air Quality Standards GB/T 18883 and GB3095, the rates of exceeding the current reference value in both groups were below 20% for most indoor air pollutants except for TVOCs in the case group (58.8%).
Although the levels of maternal exposure to indoor air pollutants in our study were generally lower than those in previous studies conducted with the general population and below the Chinese national standard reference values, we did find results indicating that the risk of CHD occurrence in offspring might be associated with maternal high TVOC, PM2.5 and PM10 exposure levels, even at low concentrations. Compared with mothers with low TVOC levels (< 0.25 mg/m3), mothers exposed to high TVOC levels (≥ 0.25 mg/m3) had a 5.29 times higher risk for total CHDs (AOR 5.29, 95% CI: 1.6-17.47), 16.73 times higher risk for septal defects (AOR 16.73, 95% CI: 2.25-124.65) and 10.68 times higher risk for right-sided obstructions (AOR 10.68, 95% CI: 1.28–89.43) after adjusting for confounders. We found that PM2.5 concentrations above 13 µg/m3 and PM10 concentrations above 14 µg/m3 were associated with higher odds for total CHDs than their respective low concentrations levels. However, the target VOCs, such as formaldehyde and BTX, were not observed to be associated with CHD risk in our study, probably because newly presented or complicated organic compounds contributing to the TVOC concentration but not detected in our research played a role in CHD occurrence. Despite the imprecise effect estimates and undefined dose-effect relationships resulting from the small sample size, it is concerning that the current reference values in Chinese indoor air quality standards may lead to underestimation of the risks for CHDs associated with pollutants in pregnant women.
It is difficult to offer a plausible biological mechanism by which developmental toxicity and cardiac teratogenicity could occur as a result of air pollutant exposure. Potential mechanisms underlying air pollutant-induced teratogenicity have been reported, including chromosome and DNA damage (genotoxicity); oxidative stress; altered levels and/or functions of enzymes, hormones and proteins; apoptosis; and toxicogenomic and epigenomic effects (such as DNA methylation)[34, 35]. Some have suggested[36] that maternal exposure to air pollution might influence endothelial function and blood viscosity, which could alter maternal–placental oxygen and nutrient exchanges and thus affect foetal development. More likely, the association that we observed could be attributable to a joint effect of several air pollutants based on various biological mechanisms.
Concentrations of indoor air pollutants display individual variation owing to complex and diverse indoor or outdoor sources, room temperature and humidity, as well as living habits or application of appliances that might reduce or increase the pollutant concentration[27].
TVOCs, consisting of various VOCs such as formaldehyde, trichloroethylene, benzene series, and hydrocarbon compounds, are mainly attributed to indoor sources including building materials, household chemical products, and combustion processes causing smoke[37]. High concentrations of VOCs, which may be emitted from materials such as paints, dyes, adhesives, solvents, boards and plywood, are more often reported in new residential buildings or renovated dwellings[27, 38, 39]. A case-control study in China described that maternal exposure to house renovations increased the risk of CHD, and this relationship was stronger for women who had moved into a newly decorated house[20]. Although there is insufficient evidence of the effects of traditional decorative materials (such as floors, wall decorations and furniture) on CHD risk in our results, we observed a significant TVOC exposure odd for CHDs in newly renovated houses (AOR 32.13, 95CI: 1.48-698.11) but not in houses without renovation. This finding may suggest that people are prone to using traditional decorative materials that are environmentally friendly but that more new-style or complicated ornaments in newly renovated houses that were not reported in our study may contribute to indoor TVOC pollution. Among subjects in newly renovated houses, it seemed that fewer CHDs occurred in subjects living in houses with more than a 3-month moving-in interval, which may indicate that renovation-related volatile air pollutants are time dependent and decrease over time.
Moreover, outdoor sources resulting from the oil and gas industry, transport emissions and biogenic emissions can affect indoor TVOC concentrations through air exchange[40]. In addition, human activities are considered to be significant sources of indoor air pollution. Natural and mechanical ventilation are indicated to improve the levels of chemical pollutants in indoor air[27, 41]. Second-hand smoke was not associated with CHDs in our study, yet smoke ventilator usage during cooking tended to modify the effect of TVOCs on CHDs and implied that the improvement in indoor air quality might have a positive impact on lowering CHD risks. Traffic-related emissions from the outdoors seemed to not interfere in the effect of indoor TVOC on CHDs but increased the PM-associated risk for CHDs. Although some studies indicated that the levels of indoor PM2.5 resulted from pan-frying in kitchens[42], our study did not show that smoke ventilator usage in cooking could modify the effect of PM on CHDs. The results implied that traffic-related outdoor air pollution could be the major contributor of PM2.5 to the indoor environment, which was consistent with Jung’s study[43].
However, in the present study, we could not address the contribution of indoor air pollutants from different sources directly due to their complexities. People's living habits and residential environments also vary individually, affecting the level of exposure to indoor air pollutants. More detailed investigations and comprehensive sampling detections are needed in further studies.
In contrast to a study revealing a negative correlation between indoor TVOC and particulate matter concentrations (PM0.5 and PM1)[27], TVOC concentrations showed no obvious correlations with PM2.5 or PM10 in our study, indicating that they may originate from different sources. Nevertheless, we found that PM exposure had different associations with TVOCs and CHDs. Compared with coexposure to low levels of TVOC (< 0.25 mg/m3) and PM2.5 (< 13 µg/m3), coexposure to high levels of TVOCs (≥ 0.25 mg/m3) and PM2.5 (≥ 13 µg/m3) was associated with a 6.77 times higher risk for CHDs. It could be suggested that coexposure to TVOCs and PM2.5 had a certain synergistic effect on CHD occurrence. An animal experiment suggested that exposure to a combination of PM2.5 and formaldehyde can result in increased lung damage in mice with allergic asthma as a result of oxidative stress, immunogenic response and neurogenic response[44]. The biological mechanisms for the joint effect of indoor air pollutants on foetal cardiac development remain to be further investigated.
Despite constant public concern about indoor air quality, China's national standards, GB/T 18883 − 2002 and GB3095-2012, were put into effect successively and set guideline values for formaldehyde, BTXs, TVOCs, PM10 and PM2.5. However, a specific threshold for susceptible populations, especially pregnant women, is not yet defined in China, probably due to a lack of information on exposure and risk assessment. Our research initially indicated that indoor air pollution was associated with foetal CHDs, yet the exact cut-off value for CHD occurrence still needs to be confirmed in an abundant sample with a sophisticated design. To the best of our knowledge, this study is the first to explore the CHD-related effects of personal maternal air pollution exposure, as opposed to data obtained from air quality monitoring stations in many previous studies[8, 11, 18]. Personal measurements are generally considered a more accurate representation of exposure levels.
The main limitation of our study was the small sample size resulting in limited statistical power—the CIs for less common exposures were wide. The problem of insufficient sample size was especially prominent for some subtypes, such as anomalous pulmonary venous return. The real statistical power may be affected by the small samples for the specific subtypes; thus, we mainly demonstrated associations between maternal exposure to indoor air pollution and total CHDs in our study population. Second, air samples were collected from participants at a median of 25 gestational weeks after the critical period for cardiac development that occurs during the first three months of gestation[14], which may have introduced nondifferential misclassification and decreased the accuracy of the exposure assessment. Although the volatility of indoor air pollution may result in low detection values at sampling time and misclassify exposure level for some participants, the collection of data and air samples in this study were based on unaltered lifestyles and immobile living environments, and the results could reflect the relatively quantifiable exposure within the pregnancy period for the case-control design. In addition, our survey timing was much earlier than most previous reports that usually collected personal exposure air samples during the third trimester of pregnancy[31, 45] or even after delivery[46]. Third, more measured indoor and outdoor pollutant concentrations are needed to calculate indoor/outdoor ratios and confirm the source of pollutants. Although we collected prenatal information on sociodemographics, reproductive history and periconceptional health status based on previous literature[3–7] and adjusted the analysis for several covariates, we cannot rule out potential confounding by unmeasured or unknown factors. More detailed investigations and comprehensive sampling detections are needed in further studies. Due to the small sample size, the number of determinants included in the models was restricted; thus, we did not assess the risks in the multipollutant model.