Study population and data collection
This case-control study was conducted at West China Second University Hospital from January 2014 to December 2016. The hospital serves all of southwest China and Tibet, and ranks among the top ten in obstetrics, gynecology and pediatrics in China.31. The inclusion criteria for the study were singleton pregnancy, and for non-syndromic coronary artery disease (ICD-10 code Q20-26), which referred to cases with coronary heart disease only and no other non-cardiac abnormalities. , and for the witnesses, no coronary heart disease or other congenital malformations. Cases and controls with extra-cardiac abnormalities, syndromic diseases and chromosomal aberrations, or whose mothers were active smokers were excluded.
After providing signed informed consent, all participants were interviewed face-to-face at the first, second, third trimester, and one month postpartum.32. Information from the questionnaires included parental socioeconomic characteristics, family history of birth defects, maternal folic acid supplementation, exposure to ETS or HNS at home or work, etc.
The study was approved by the Ethics Committee of West China Second University Hospital and was based on the principles of the Declaration of Helsinki.
Classification of cases
Coronary heart disease was diagnosed by systematic prenatal echocardiography. Live births were confirmed by routine examination, which included cardiac auscultation and neonatal echocardiography within a week of birth. Stillbirths diagnosed with CHD were aborted according to the standard process. Each CHD medical record has been reviewed by specialists, neonatal cardiologists to confirm the diagnostic results. All cases of coronary heart disease were coded according to the International Classification of Diseases-10 (ICD-10).
CHD cases were divided into five subtypes based on anatomical lesion as follows: (1) septal defects (SPD), including atrial septal defects, ventricular septal defects, and endocardial cushion defects; (2) conotruncal defects (CTD), including transposition of the great arteries, tetralogy of Fallot, arterial trunk, and double outlet right ventricle; (3) left ventricular outflow tract obstruction (LVOTO), including aortic valve stenosis, hypoplastic left heart syndrome and its variants, aortic coarctation, and interrupted aortic arch; (4) right ventricular outflow tract obstruction (RVOTO), including pulmonary valve stenosis, pulmonary atresia, tricuspid atresia, and Ebstein’s anomalies; (5) other coronary artery disease, including abnormal venous return (total and partial abnormal pulmonary or systematic venous return), heterotaxy, and other heart structural abnormalities.
Maternal environmental tobacco smoke (ETS) was measured by maternal self-report and was defined as exposure to tobacco smoke, at least an average of 15 min/day at home or on the workplace during the 12th before pregnancy until the first trimester33. There were three different exposure periods: (a) 3rd to 12th month before pregnancy, (b) 0 to 3rd month before pregnancy, and (c) first trimester. We further created a categorical variable capturing the duration of ETS exposure as (A) equals the interval (a) above; (B) Cumulative exposure of intervals (a) and (b); and (C) cumulative exposure of intervals (a), (b) and (c) (Fig. 1). The mean maternal exposure dose to ETS during the first trimester of pregnancy has been classified into three groups: (1) less than one hour per day; (2) 1-2 hours per day; 3) 2 hours or more per day.
Maternal exposure to HNS during the 3 months before conception through the first trimester was measured by self-report, including lead, cadmium, mercury, oil paint, solder, pesticides, insecticides, formaldehyde or other chemical materials.
Maternal folate intake means mothers take a folic acid supplement for 90 days or more for the 3 months before conception through the first trimester32.34.
We estimated the association between maternal ETS and fetal coronary artery disease, including the dose-response relationship, by calculating odds ratios (ORs) and two-sided Wald-type 95% confidence intervals from logistic regression. unconditional.35. First, we fit a model including only a categorical covariate for maternal ETS and nested categorical covariates for exposure interval and exposure dose. Second, we examined confounding by additionally adjusting for potential confounders, such as mother’s age (36. The excess relative risk due to the interaction (RERI), the proportion attributable to the interaction (AP) and the synergy index (SI) with the corresponding 95% CIs were derived from the regression coefficients and from the the covariance matrix from multivariate logistic regression analyzes using an R function for additive interaction measures37or the epiR package and InteractionR38. 95% CI of RERI or AP equal to 0 and that of SI equal to 1 were defined as no additive interaction.
Finally, we performed several sensitivity and subgroup analyzes to assess the robustness of the interactive effects. (a) We compared the results of models including exposure to ETS as a multicategorical variable with those of models including ETS as a binary variable. (b) To assess the effects of potential confounders, we adjusted different covariates in the models (i.e. without any adjustment, adjusted for the two of the three exposures when assessing the interactive effect on the other, fully adjusted by all the aforementioned covariates in models). (c) Subgroup analyzes were performed on different groups stratified by maternal age ( 12 years), residence (urban vs. rural), and family history of birth defects (Yes vs. No).
The level of statistical significance for α was set at 0.05. And all analyzes were performed using the R 4.1.2 program.