Congenital heart disease (CHD) is the most common birth defect, affecting approximately 1% of all live births [1]. Despite significant advances in early detection and management over the past five decades, CHD remains a leading cause of infant morbidity and mortality, both in the United States and globally [2,3]. In 2017, CHD was the underlying cause of 261,247 deaths globally (95% confidence interval (CI) 216,567–308,159), with 72% of these fatalities occurring in infants under one year old [4]. While the proportion of CHD associated with external exposures and modifiable risk factors is unknown, prior epidemiologic studies attribute modifiable risk factors with up to 30% of certain congenital heart defects [5]. External maternal exposures such as infection, medications, alcohol, and illicit drugs are traditionally associated with CHD, especially during the first trimester when cardiac embryogenesis occurs [6,7].

Climate change and its associated exposures pose an emerging threat to worldwide health gains achieved over the past century. Over 150 years of fossil fuel combustion elevate atmospheric concentrations of pollutants, including greenhouse gases, and lead to increasing global temperature, long-term shifts in weather patterns, ecosystem disruptions, and rising sea levels. An expanding body of research suggests that air pollution, global warming, and associated environmental stressors contribute to cardiovascular morbidity and mortality [8–10]. Polygenic abnormalities are linked to many forms of CHD development, but the environmental contribution and interaction with genetics is less well understood [6]. This review explores the mechanisms—both direct and indirect—through which CHD may be influenced by a changing climate (Fig. 1).

As global temperatures continue to rise, heatwaves—defined as prolonged periods of extreme heat—will become more frequent and intense [12]. Although the health implications are undeniable, the thresholds and definitions of extreme heat and heatwaves differ by location. In a study assessing 107 communities in the United States over a fourteen-year period, adult cardiovascular hospitalizations increased at thresholds 20°F higher in the southwestern U.S. compared to the traditionally cooler Pacific Northwest [13].

Maternal exposure to extreme heat and heatwaves during pregnancy is linked to negative effects on birth outcomes, with increased incidence of preterm birth, low birth weight, and stillbirths [14]. However, the relationship between extreme heat and CHD development is less clear. Animal studies suggest that extreme heat exposure leads to fetal cell death and heat shock responses with subsequent disruptions in normal protein synthesis [15,16]. Cardiac neural crest cells express temperature activated ion channels. Disruption of these channels is associated with errors in rotation and septation that lead to a constellation of conotruncal abnormalities such as double outlet right ventricle and Tetralogy of Fallot (ToF) [17]. Despite the pathophysiologic pathway noted above, no existing research in humans has shown a definitive increase in these birth defects after maternal extreme heat exposure [16].

Retrospective studies find an association between maternal heat exposure during first trimester and overall incidence of fetal septal defects. Auger et al. [16] examined extreme heat exposure during weeks 2–8 of pregnancy and found that 15 or more days of extreme heat exposure compared to 0 days of exposure was associated with increased risk of atrial septal defects (ASD) (prevalence ratio 1.32; 95% CI: 1.10 to 1.70). There was also an increase in non-critical CHD, defined as endocardial cushion defects, septal defects, valvular defects, aortic/pulmonic defects, and heterotaxy (prevalence ratio 1.54; 95% CI: 1.20 to 1.97). The researchers noted that higher temperature thresholds (i.e., 95th percentile vs. 90th percentile for extreme heat) were associated with higher odds of ventricular septal defect (VSD) development. Lin et al. [18] assessed extreme heat exposure during weeks 3–8 of pregnancy and noted a similar trend of increasing prevalence of CHD with increasing extreme heat exposure and intensity. Three to five days of cumulative extreme heat exposure with temperatures >90th percentile was associated with increased odds of VSD development, with odds ratio (OR) ranging 2.17 to 2.57 (all p < 0.05), while higher cumulative exposure was associated with even higher odds (OR 3.24; 95% CI: 1.01 to 10.40) [18].

Using models based on the data from Lin et al. [18], Zhang et al. [19] projected an increase in early pregnancy maternal heat exposure by 2035 and consequently significant increases in CHD incidence. Their modelling suggests different increases in CHD subset incidence in different regions of the United States, with projected increase in conotruncal CHD in the south and increased ASDs in the Northeast. While it is unclear what drives this geographic heterogeneity, differences in ambient temperature/temperature ranges along with differences in heat acclimatization may contribute.

Air pollution is the leading cause of reversible premature morbidity and mortality worldwide, with 99% of the global population breathing levels of air pollution above World Health Organization guideline limits [20,21]. Air pollution consists of myriad particles, from anthropogenic sources such as cars or factories, to natural phenomena like wildfires. These anthropogenic particles include particulate matter less than 2.5 µM (PM_2.5), as well as the greenhouse gasses nitrogen dioxide (NO₂), sulfur dioxide (SO₂), carbon monoxide (CO), and ozone (O₃). These pollutants are inhaled and can enter the bloodstream, where they can exert systemic effects. Wildfires, which are increasing in frequency and intensity, lead to acute heat and air pollution exposure [22]. However, there are no currently published studies addressing the impact of wildfires on CHD.

In adults, inhalation of air pollution leads to increased morbidity and mortality through increases in systemic inflammation, prothrombotic pathways, autonomic imbalance, metabolic derangements, and epigenomic changes [23–27]. It appears that active pregnancy modifies the effect of air pollution on the body at a cellular level. In one study PM_2.5 exposure during pregnancy was associated with differential modulation of histone post-translational modifications compared to non-pregnant, age-matched controls [28]. While impacts on maternal health may secondarily affect the fetus, there is additional evidence that the fetus itself is directly affected. Studies associate air pollution with changes in DNA methylation patterns of placental genes involved in fetal development, with implications before and after delivery [29].

As with extreme heat, evidence connects air pollution exposure and cardiac septal defects [30,31]. In a Canadian cohort of approximately 1.3 million newborns, maternal exposure to PM_2.5 and NO₂ during the first trimester was associated with increased risk of ASD development. These risks increased in mothers with pre-existing comorbidities [32]. In a Chinese case-control study of 1.4 million newborns, each 10 μg/m³ increase in maternal PM_2.5 exposure during the first trimester was associated with a 2% increase in risk of CHD (OR 1.02; 95% CI 1.00–1.04). This effect was most evident with septal defects (OR 1.04; 95% CI 1.01–1.08) [33]. Notably, these effects were also evident during the three months prior to conception, implying a long-term effect of air pollution beyond the acute exposure.

Unlike with extreme heat, air pollution has a stronger association with fetal prevalence of more complex, wide-ranging forms of CHD in humans. Zhang et al. [30] found that O₃ exposure was associated with increased risk of total CHD, VSD, and ToF; with the greatest risk for ToF at exposure during the third month of pregnancy (OR 1.31; 95% CI 1.13–1.51). A meta-analysis of 10 studies also noted an association between air pollution and ToF, this time with exposure to NO₂ (OR 1.20; 95% CI, 1.02–1.42) and SO₂ (OR 1.03; 95% CI, 1.01–1.05) [34]. This same meta-analysis found that NO₂ and SO₂ exposure during early pregnancy was associated with coarctation of the aorta (CoA), a finding corroborated in a separate study of children born via in vitro fertilization [35]. A meta-analysis of 26 epidemiologic studies noted an association between PM_2.5 exposure and ToF (OR 1.52; 95% CI 1.44–1.60) [36]. Additionally, both PM_2.5 and NO₂ were associated with pulmonary stenosis (OR 1.42; 95% CI 1.36–1.48 and OR 1.74; 95% CI, 1.68–1.81, respectively). Although other, more recent meta-analyses confirmed these findings, an analysis of 32 studies by Wan et al. [37,38] noted a small but statistically significant negative association between SO₂ and transposition of the great arteries, ToF, VSD, and pulmonary artery and valve defects. There may also be synergy between air pollution and other exposures, such as tobacco use. In a retrospective study of almost 28,000 women at high risk for CHD according to the American Heart Association, paternal tobacco amplified the effect of O₃ exposure on CHD incidence [39,40].

Extreme heat and air pollution do not exist in isolation, and appear to have compounding effects on cardiovascular health [10,41]. Limited evidence suggests persistence of this effect in regard to maternal exposure and CHD, but further research is needed better clarify this interaction [42,43].

Environmental air pollution and extreme heat are linked to increased prevalence of extreme weather events, such as hurricanes and tropical storms. Studies show these major events lead to increased mortality rates that persist for over a decade after a storm makes landfall [44]. Storms additionally cause physical damage, disruption of health care and economic systems, and population displacement. An increased incidence of CHD associated with these events may be due to maternal stress and the healthcare disruptions from these events, rather than direct maternal/fetal exposure to heat and/or air pollution. However, there is currently no published data assessing CHD development with extreme weather events.

Exposure to extreme temperatures and air pollution is associated with an increased incidence of CHD. However, there are significant limitations in the largely retrospective and population-based literature that must be considered before confirming causality.

There remain areas for further research to better assess the intersection between climate exposure and CHD. First, as noted above, there are no studies assessing the effects of extreme weather events on CHD incidence. Second, wildfire seasons are also becoming longer and more intense, leading to smoke inhalation by pregnant women hundreds of miles from the source. We found no studies assessing this interaction. Third, there is no data on paternal pre-conception heat and air pollution exposure on CHD incidence. Evaluating the role of paternal exposure will be important for optimal pre-conception counseling. Fourth, there is no research on the impact of climate change related stressors on adults with CHD. Ninety-seven percent of all children born with CHD will survive into adulthood and will require specialized care that is individualized to their condition [45]. This is a diverse population in which close follow-up is critical, but often challenging [46]. There is evidence that short disruptions of care have long term impacts on the general population, but data on adults with CHD is lacking [44,47]. Data indicate that these patients had increased difficulty accessing necessary healthcare during the COVID-19 pandemic, but the long-term health implications of these disruptions is unknown [48]. Finally, 90% of CHD occurs in low- and middle-income countries [49]. There is a paucity of data assessing environmental exposures to CHD in these regions despite the high burden and greater expected impacts from climate change [50]. Further research in these countries will necessetate investing in surveillance systems and data collection. As an example, only 24 of the 54 countries in Africa currently have the capacity to monitor air pollution [51].

Clinicians should be aware that maternal exposure to extreme temperature and air pollution in the weeks preceding and following conception carries an increased risk for the development of CHD. Prospective mothers should be counseled on the risks of extreme heat and air pollution exposure and should be aware that air pollution prior to conception may be relevant as well. Further research on environmental exposures in pregnant women and adult CHD patients will be critical to help inform practice and policy.