Background
Congenital heart disease (CHD) has been the most prevalent birth defect [
1], and it remains to be an important cause of neonatal and infant deaths [
2,
3]. It was reported that the global incidence of CHD had increased nearly 15 times over the past approximately 60 years, from 0.6‰ in 1930–1934 to 9.1‰ in 1995 [
1]. In China, the rising trend similarly existed, and the prevalence of CHD among newborns had reached up to 11.1‰ [
4]. Therefore, CHD has become a severe public health challenge all around the world.
The exact cause of CHD is still unclear. Generally, only 10–15% of CHD could be explained by gene defects and chromosome abnormalities, and the majority should be caused by the interaction of genetic factors and environmental exposures [
5]. Early pregnancy is a key period for the development of fetal cardiovascular system, especially 14–60 days of gestation is the vulnerable window for CHD [
6]. Upon the perspective of prevention, it is critically important to explore and identify CHD-related risk factors, especially those factors that can be intervened.
Upper respiratory tract infection and influenza always outbreak seasonally, in which season pregnant women are susceptible to the infection [
7‐
9]. Previous studies have explored the relationship between maternal upper respiratory tract infection during pregnancy and the risk of CHD [
10‐
25]. A number of evidence seemed to support the association [
11,
16,
19,
20,
22,
23], however, a few other studies did not establish the relationship [
12,
13]. Similarly, findings on the association between influenza during pregnancy and CHD was also controversial [
11,
13‐
15,
18‐
21,
24,
25]. Almost all these studies took all CHD types as a whole. If the role of maternal upper respiratory tract infection/influenza varies in different type of CHD, then the possible different CHD type constitution may, at least partly, explains the inconsistent finding.
The present study aimed at exploring the associations of maternal upper respiratory tract infection/influenza during early pregnancy with CHD through a case-control study and a further meta-analysis. We observed if the associations were different between simple and complex CHD. Meanwhile, we paid particular attention to ventricular septal defects (VSD) and tetralogy of fallot (TOF), the most prevalent type of simple and complex CHD, respectively.
Discussion
Up to now, this is the largest population-based epidemiology study (n = 86,269) exploring the relationship between maternal upper respiratory tract infection/influenza and the risk of CHD in offspring. In this study, we examined the associations through a case-control study and a further meta-analysis based on previous evidences and our findings. Our examinations were performed not only in all CHD as a whole group but also in subgroups of CHD, simple CHD and complex CHD. Meanwhile, for the first time, we particularly examined the associations in VSD and TOF, the most prevalent single type of simple and complex CHD, respectively. The very consistent associations were established among different groups of CHD and even single types of CHD in our case-control study. In the subsequent meta-analysis, except for TOF, the similar consistent associations still existed. Generally, our study proposed enriched evidence that maternal upper respiratory tract infection/influenza during early pregnancy was implicated in CHD, although more studies are still needed to verify the association in each single type of CHD.
A number of previous studies have explored the impact of upper respiratory tract infection or influenza on CHD [
11‐
17,
21‐
25]. There is considerable overlap in etiology and symptomatology between upper respiratory tract infection and influenza [
33], and the symptoms of influenza are similar to the symptoms of upper respiratory tract infection, including fever, cough, sneezing, runny nose, sore throat, and etc. [
33,
34]. For the common population and even medical professional, it is difficult to distinguish the two [
34]. Therefore, we merged upper respiratory tract infection and influenza in the present study. A number of previous studies were conducted to explore the associations between upper respiratory tract infection or influenza and CHD [
11‐
17,
21‐
25]. Usually, the studies observed the associations in CHD as a whole, without considering the possible difference among different type of CHD [
11‐
17,
21‐
25]. However, although the information is still somewhat limited, the available evidence demonstrated that the impacts of upper respiratory tract infection/influenza varied among subtypes of CHD [
10,
18‐
20]. In our hospital-based case-control study, we set up two case groups as simple CHD and complex CHD, respectively. To the best of our knowledge, this is the first study exploring the associations of maternal upper respiratory tract infection/influenza with simple CHD and complex CHD separately. Furthermore, we also observed the associations in VSD and TOF, the most prevalent single type of simple and complex CHD, respectively. Our case-control study showed that maternal upper respiratory tract infection/influenza could increase the risk of CHD, and the adverse impacts were consistent either in subgroups of CHD or single types of CHD. The subsequent meta-analysis, except for TOF, overally confirmed our findings, which verified our findings and further enforced the evidence between upper respiratory tract infection/ influenza and CHD.
In the present study, upper respiratory tract infection/ influenza was found to be a risk factor for TOF. As far as we know, to date only three previous studies specifically examine the associations, however, by contrast to our study, none of them got the similar findings [
13,
17,
25]. The initial study to explore the correlation was a population-based case-control study conducted in Atlanta, the USA, in which 49 TOF cases vs. controls were analyzed, and among 49 cases, only one reported influenza exposure during pregnancy [
13]. The limited case sample size may make the statistical model unstable and would affect the precision of the predictive value of the model. In addition, early pregnancy is the critical period for fetal cardiovascular development and, therefore, the susceptible window for CHD [
6], however, the study collected information on influenza exposure without considering the stage of gestation. Similarly, another case-control study did not consider the susceptible period of influenza exposure during pregnancy for the risk of TOF [
17]. A very recent study among 193 Chinese children with TOF examined the effects of influenza infection during different periods of pregnancy on the risk of TOF based on a 1:1 matched case-control study [
25]. It seemed that maternal influenza exposure could increase the risk of TOF (OR ranged from 1.30 to 3.51 for influenza exposure during the first, second, and third trimester of pregnancy), although these results were not statistically significant. However, it is reasonable to deduce that the adverse effects would reach up to statistical significance with increasing sample size. Even so, it should be noticed that the value of OR in the second/third trimester was greater than that of the first trimester, which suggested that recalling bias should be a major limitation to be taken into account when explaining the results. Presently, it was difficult to clearly explain why our results were different from these previous studies. We hope more studies will be performed in the future to verify these results.
European surveillance of congenital anomalies (EUROCAT) study recorded a total prevalence of major congenital anomalies of 23.9 per 1000 births for 2003–2007, in which that CHD was the most common non-chromosomal subgroup, at 6.5 per 1000 births [
35]. CHD is the most common cause of major congenital anomalies, forming a major global health burden [
1]. In the present study, we detected maternal upper respiratory tract infection/influenza during first trimester perinatal period as an independent risk factor of CHD, even after a meta-analysis. Although the mechanism by which maternal upper respiratory tract infection/influenza may result in CHD is still unclear, several potential explanations are feasible in theory to support the relationship. The majority of upper respiratory tract infection is caused by viruses and bacteria, and influenza is always caused by viruses [
36]. It was revealed that upper respiratory tract infection viruses such as respiratory syncytial virus could cause a cytokine related immunological or inflammatory response [
37,
38]. Upper respiratory tract infection/influenza is often accompanied by fever, the mechanism may be same to which fever influence CHD. Previous studies have suggested that both fever [
39,
40] and influenza virus infection [
41‐
43] could induce the apoptotic death of cells. Apoptosis is known to be involved in cardiac morphogenesis, and altered apoptosis has been suggested to cause birth defect [
40]. Another possible pathway is a direct effect of influenza virus inducing cell death [
44].
Several limitations should be acknowledged in interpreting the results. First, although the diagnosis of CHD is more accurate in hospital-based case-control studies than in population-based case-control studies, selection bias cannot be inevitable. To reduce the potential selection bias between cases and controls, propensity score matching was used, however, the method is usually used in clinical intervention study. Secondly, our exposure data were collected by retrospective maternal self-reported information, thus recall bias is a concern. Thirdly, there was publication bias in CHD group, and it may have some effect on the outcome of meta-analysis.
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