Maternal periconceptional environmental exposure and offspring with congenital heart disease: a case–control study in Guangzhou, China

Congenital heart defects (CHDs) constitute the most prevalent congenital anomalies [1], affecting millions of newborns annually [2]. It is estimated that the global birth prevalence of CHDs is 8 to 12 infants per 1000 births [3]. In the United States, CHDs affect approximately 1% of births [4]. In Sweden, the prevalence of CHDs increased steadily from 5.7 to 20 per 1000 live births from 1970 to 2017 [5]. In Western Australia, approximately 11.5‰ of liveborn children were born with CHDs from 1990 to 2016 [6]. In China, according to a large prospective multicenter screening study, the prevalence of CHDs was 8.98‰ [7]. Since CHDs greatly influence children’s quality of life and cause a serious financial burden of families and society as a whole [8], posing a significant global threat to public health [9].

The cause of CHDs is multifactorial [10] and largely unknown [11]. Both environmental and genetic factors contribute to the development of CHDs [11]. Increasing epidemiological evidence have highlighted the importance of the environment in CHDs, with up to 30% of cases being explained by environmental factors [3], such as maternal factors involving maternal diabetes mellitus, obesity, maternal smoking, dietary folate intake, alcohol consumption, certain drug use during pregnancy, exposure to air pollutants and life events, as well as paternal factors (e.g., advanced age) [12‐15]. As CHDs represent a significant public health issue, understanding the causes of CHDs, especially those factors that can be prevented, is crucial for their primary prevention [14].

Household incense burning is a common practice in the Asia-Pacific region [16], and is used for ritual or religious purposes [17]. A cohort study involving 10,563 pregnant women from Guangzhou, China showed that 25.4% of women reported that incense was burnt in their household during early pregnancy [18]. As an important source of indoor air pollution, incense burning produces smoke (fumes) containing numerous hazardous air pollutants [18]. Recently, a study found that maternal incense burning exposure was linked to a higher risk of adverse birth outcomes, such as low birth weight and small for head circumference [19]. Although evidence indicates an association between maternal exposure to incense burning and adverse birth outcomes, little attention has been paid to investigate the potential effect of this exposure on CHDs.

Living near traffic is a multifaceted exposure representing heightened exposure to numerous hazardous air pollutants [e.g., fine particulate matter (PM2.5), nitrogen oxides, heavy metals, ultrafine particles], noise, and other factors, and has been related to elevated risks of lower fecundability [20], preeclampsia [21], and lung cancer [22]. Emerging evidence suggests that a contradictory association between residential proximity to major roads and adverse birth outcomes (preterm birth) [23, 24]. However, limited studies thus far have examined the influence of living near main roads on CHDs in offspring [25]. As hundreds of millions of people live near to major roads around the world [26], we aim to address the potential association between living near main roads and CHDs in offspring, which might provide novel insights into understanding the mechanisms of CHDs.

Additionally, evidence has also shown that acute and chronic stress increase the risk of a variety of adverse pregnancy outcomes, such as low birthweight, preeclampsia, spontaneous preterm birth (PTB), and neonatal morbidity [27‐29]. Recently, Gu et al. [30] reported that maternal stress and stressful life events during pregnancy increased the risk of offspring CHDs. As a stressor, family conflict is a relationship challenge, and little is known about the association between poor relationships with family and CHDs in offspring.

Housing renovations, as a type of indoor air pollution, have been identified as a public health threat, particularly for fetuses and children [1]. Moreover, a previous study suggested that housing renovations during the periconceptional period may be associated with CHDs in offspring [1].

Evidence has demonstrated that the periconceptional period is a critical window of exposure that can influence the growth and development of offspring [31]. The identification of potentially modifiable risk factors in a critical window for CHDs provides opportunities for public health strategies for CHD prevention to improve birth outcomes [18]. Therefore, the present research aimed to explore the associations between maternal periconceptional environmental exposure (family relationships, housing renovation, living near to major roads, and incense burning) and all CHDs, isolated and multiple CHDs as well as isolated CHDs subtypes.

In this study, living near main roads and housing renovation during the periconceptional period were positively associated with all CHDs and isolated CHDs in offspring in addition to multiple CHDs. Additionally, living near main roads was positively associated with secundum ASD/PFO and housing renovation was strongly associated with VSD in further analysis. However, no significant association was found between family relationships and incense burning and all CHDs, similar results were also found in isolated and multiple CHDs as well as three subtypes of CHD.

The univariate analyses found that mothers with higher parity might have lower prevalence of CHDs in offspring. Similarly, Wang et al. [35] found that higher parity groups showed a decreased risk of isolated CHDs. Moreover, we found that mothers who reported having a lack of folic acid use, passive smoking during pregnancy, threatened abortion, maternal history of CHD, take medicine during the first trimester, assisted reproduction, infant with preterm birth have a higher prevalence of CHDs in offspring, these findings were also consistent with previous studies which suggested that mothers with these characteristics had an increased risk of having offspring with CHDs [12, 14, 36‐38]. Furthermore, maternal history of internal diseases and hyperthyroidism were positively associated with higher risk for CHDs in offspring. Considering the host of adverse consequences that are linked with CHDs, recognizing women who are at high risk of having CHDs in offspring is critical. Specifically, we found that females with these characteristics as follows, such as lower parity, infants with preterm birth, maternal passive smoking during pregnancy, lack of maternal folic acid use, assisted reproduction, threatened abortion, as well as have a history of internal diseases, CHD, hyperthyroidism, and reproductive history of birth defects before pregnancy may be more prone to have CHDs in offspring. Hence, we suggest that clinicians should pay more attention to the high-risk women with disadvantageous characteristics mentioned above to reduce the potential risk of CHDs in offspring.

Previous studies have showed that living near major roads might have adverse effects on health [39, 40]. However, limited evidence on its relationship with birth defects has been reported. We reported that living near main roads during the periconceptional period was associated with risk of all CHDs, isolated CHDs and secundum ASD/PFO. Gong et al. [41] found that maternal exposure to loud noise also increased the incidence of CHDs. The increased risk for CHD occurrence from maternal exposure to living near main roads may be due to traffic-related air pollution, such as PM2.5, which has been reported to enhance the risk of CHDs in the offspring of exposed mothers [42]. Another possibility is that living near main roads increases exposure to noise, and it has been found that maternal exposure to loud noise also increases the incidence of CHDs [41]. Further studies could explore the relationship between different distances to the nearest main road and the existence of CHDs in offspring.

Furthermore, the data presented in this study also illustrated that housing renovation during periconceptional period was related to a greater risk of all CHDs, isolated CHDs and VSD. Similarly, previous studies also found that maternal exposure to housing renovation was associated with CHDs in offspring [1, 43, 44]. During or after house renovations, volatile organic compounds (VOCs) as well as heavy metals might be emitted from dyes and paints. In addition, formaldehyde and trichloroethylene (TCE) can be released indoors from air boards and plywood [45‐47]. Hjortebjerg et al. [48] suggested that maternal nonoccupational exposure to paint fumes might be linked with congenital abnormalities. Furthermore, experimental studies have demonstrated that TCE can result in the developmental abnormalities in the hearts of avian embryos and mouse embryos. The mechanism by which housing renovation increases the risk of CHDs is not fully understood. The above evidence may partially account for the mechanism of CHDs caused by house renovation at least, and the biological plausibility and specific toxicological mechanism of different environmental contaminants of housing renovation should be further confirmed.

Living near main roads and housing renovation during the periconceptional period were associated with a higher risk of congenital heart disease in offspring. Additionally, living near main roads was positively associated with secundum ASD/PFO and housing renovation was strongly and positively associated with VSD. Considering the limited sample size, further study is needed to extend the sample size to explore the effects of time and frequency of burning incense and family relationships on CHDs in offspring.