Folic Acid and the Risk of Congenital Heart Defects

Abstract

Source: Wang D, Jin L, Zhang J, et al. Maternal periconceptional folic acid supplementation and risk for fetal congenital heart defects [published online ahead of print September 8, 2021]. J Pediatr. doi: 10.1016/j.jpeds.2021.09.004.Investigators from Peking University and Tongzhou Maternal and Child Health Hospital, both in Beijing, China, conducted a retrospective study to assess the effectiveness of periconceptional folic acid (FA) supplementation in preventing congenital heart defects (CHD). For the study, they reviewed data contained in the Prenatal Health Care System (PHCS) and Birth Defects Surveillance System (BDSS) databases on singleton deliveries (including live births, stillbirths, and terminated pregnancies) between 2013 and 2018 in the Tongzhou District, Beijing, China. PHCS is a registry that includes data on women during pregnancy and after delivery, including maternal age and educational level, delivery date, and periconceptional FA supplementation. Information about FA supplementation was based on maternal self-report and included type of FA supplementation and when it started (prior to or after conception). In China, women are provided FA in a daily dose of 0.4 mg by the central government. However, some women take micronutrient supplements containing FA (MMFA). The BDSS includes information on birth defects, beginning at 13 weeks of gestation, including CHD.Primary study outcomes were any CHD, ventricular septal defect (VSD), and critical CHD (defined using standardized criteria). Poisson regression was used to compare the risks of these outcomes in women with FA/MMFA supplementation and in those without supplementation. Risk of CHD also was compared in women taking FA vs MMFA, and with FA/MMFA supplementation beginning prior to or after conception. Regression models also included maternal age, education, and year of delivery.Data were analyzed on 63,969 women and their offspring. Women using FA/MMFA supplementation were significantly older and more educated than those who didn’t. There were 308 cases of CHD in the offspring of study women, including 152 live births and 156 stillbirths or terminated pregnancies; the most common CHD was VSD (125 cases). The use of periconceptional FA/MMFA was associated with a reduced risk of any CHD (adjusted risk ratio [ARR], 0.60; 95% CI, 0.44, 0.83), VSD (ARR, 0.47; 95% CI, 0.30, 0.74) and critical CHD (ARR, 0.41; 95% CI, 0.26, 0.67). There were no statistical differences between FA and MMFA supplementation for risk of any CHD (ARR, 0.84; 95% CI, 0.66, 1.09), VSD (ARR, 0.94; 95% CI, 0.63, 1.41) or critical CHD (ARR, 0.64; 95% CI, 0.44, 1.00). Initiation of FA/MMFA supplementation before conception, compared to post-conception, was associated with a reduced risk of any CHD (ARR, 0.68; 95% CI, 0.48, 0.95) and critical CHD (ARR, 0.26; 95% CI, 0.10, 0.71).The authors conclude that maternal periconceptional FA supplementation was associated with a decreased risk of CHD in off-spring, particularly when initiated prior to conception.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.FA, one of the B vitamins, is a micronutrient found in fresh fruit, vegetables, nuts, and eggs.1 FA deficiency has been associated with megaloblastic anemia and neural tube defects in infants, as well as heart disease and cancer in adults.1 Humans are unable to synthesize FA, and thus must rely on ingestion in the form of food or conversion of precursors in the gut microflora.1 FA is an important co-factor in DNA and RNA synthesis, and the formation of the heart neural crest cells are highly sensitive to FA.2 Since 1992, FA and other micronutrient deficiencies have been associated with CHD.3 However, the results of supplementation trials to prevent CHD have been equivocal.4 The results of the current investigation provide convincing evidence to support FA/MMFA supplementation to prevent CHD.The study design was robust, with a governmental registry of more than 63,000 women who were followed prospectively over 5 years. Of note, the investigators evaluated self-report of FA/MMFA supplementation. Although self-report may be imperfect, the study represents a real-world evaluation. Women who took FA/MMFA supplementation were older and better educated. As maternal age is a risk for CHD, and education usually confers better health outcomes, the investigators controlled for these variables.The results of the current study raises several provocative questions that merit future investigation. Pre-conception supplementation was associated with reduced CHD compared to peri-conception supplementation. This suggests that some independent maternal factors may influence CHD formation prior to conception. Also, despite the reduction of CHD due to supplementation, the continued prevalence of CHD suggests other factors such as genetic defects, exogenous toxin, or infection are at play.Maternal periconceptual supplementation with FA may be associated with a reduced risk of CHD, especially when initiated before conception. (See AAP Grand Rounds. 2020;44[6]:68.)5Perhaps the greater protective efficacy of preconceptual FA supplementation is related to the time it takes to achieve effective folate levels during the critical period of heart development.2