First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring.

This study aimed to examine effect modification of maternal risk factor exposures and congenital heart disease (CHD) by maternal folic acid supplementation (FAS)/non-FAS. We included 8379 CHD cases and 6918 CHD-free controls from 40 clinical centers in Guangdong Province, Southern China, 2004-2016. Controls were randomly chosen from malformation-free fetuses and infants and frequency matched to the echocardiogram-confirmed cases by enrollment hospital and year of birth. We used multiple regression models to evaluate interactions between FAS/non-FAS and risk factors on CHDs and major CHD categories, adjusted for confounding variables. We detected statistically significant additive and multiplicative interactions between maternal FAS/non-FAS and first-trimester fever, viral infection, and threatened abortion on CHDs. An additive interaction on CHDs was also identified between non-FAS and living in a newly renovated home. We observed a statistically significant dose-response relationship between non-FAS and a greater number of maternal risk factors on CHDs. Non-FAS and maternal risk factors interacted additively on multiple critical CHDs, conotruncal defects, and right ventricular outflow tract obstruction. Maternal risk factor exposures may have differential associations with CHD risk in offspring, according to FAS. These findings may inform the design of targeted interventions to prevent CHDs in highly susceptible population groups.

Maternal folic acid supplementation mediates the associations between maternal socioeconomic status and congenital heart diseases in offspring.

Low maternal socioeconomic status (SES) is considered as a risk factor of congenital heart diseases (CHDs) in offspring. However, the pathways underpinning the SES-CHDs associations are unclear. We assessed if first trimester maternal folic acid supplementation (FAS) is a mediator of the SES-CHDs associations. This case-control study included 8379 CHD cases and 6918 CHD-free controls from 40 participating centers in Guangdong, Southern China, 2004-2016. All fetuses were screened for CHDs using ultrasound and cases were confirmed by echocardiogram. We collected SES and FAS information during face-to-face interview by obstetricians using a structured questionnaire. Low SES was defined as education attainment <12 years, household individual income <3000 Chinese Yuan/person/month or unemployment. FAS referred to at least 0.4 mg of daily folic acid intake over 5 days/week continuously. We used causal mediation analysis to estimate the direct, indirect and proportion mediated by FAS on the SES-CHDs associations adjusted for confounders. Both low maternal income and education were significantly associated with increased risks of CHDs and lower prevalence of FAS. Low maternal FAS prevalence mediated 10% [95%CI:5%,13%] and 3% [95%CI:1%,5%] of the maternal low income-CHDs and the maternal low education-CHDs associations, respectively. In addition, FAS mediated the highest proportion of the associations between income and multiple critical CHDs [46.9%, 95%CI:24.7%,77%] and conotruncal defects [31.5%, 95%CI:17.1%,52.0%], respectively. Maternal FAS partially mediated the SES-CHDs associations, especially among the most critical and common CHDs. Promoting FAS in low SES women of childbearing age may be a feasible intervention to help prevent CHDs.

First-Trimester Maternal Folic Acid Supplementation Reduced Risks of Severe and Most Congenital Heart Diseases in Offspring: A Large Case-Control Study.

Background Maternal folic acid supplementation (FAS) reduces the risk of neural tube defects in offspring. However, its effect on congenital heart disease (CHDs), especially on the severe ones remains uncertain. This study aimed to assess the individual and joint effect of first-trimester maternal FAS and multivitamin use on CHDs in offspring. Methods and Results This is a case-control study including 8379 confirmed CHD cases and 6918 controls from 40 healthcare centers of 21 cities in Guangdong Province, China. Adjusted odds ratios (aORs) of FAS and multivitamin use between CHD cases (overall and specific CHD phenotypes) and controls were calculated by controlling for parental confounders. The multiplicative interaction effect of FAS and multivitamin use on CHDs was estimated. A significantly protective association was detected between first-trimester maternal FAS and CHDs among offspring (aOR, 0.69; 95% CI, 0.62-0.76), but not for multivitamin use alone (aOR, 1.42; 95% CI, 0.73-2.78). There was no interaction between FAS and multivitamin use on CHDs (P=0.292). Most CHD phenotypes benefited from FAS (aORs ranged from 0.03-0.85), especially the most severe categories (ie, multiple critical CHDs [aOR, 0.16; 95% CI, 0.12-0.22]) and phenotypes (ie, single ventricle [aOR, 0.03; 95% CI, 0.004-0.21]). Conclusions First-trimester maternal FAS, but not multivitamin use, was substantially associated with lower risk of CHDs, and the association was strongest for the most severe CHD phenotypes. We recommend that women of childbearing age should supplement with folic acid as early as possible, ensuring coverage of the critical window for fetal heart development to prevent CHDs.