| Summary: | 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.
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