The Association of Folic Acid, Iron Nutrition during Pregnancy and Congenital Heart Disease in Northwestern China: A Matched Case-Control Study.

Background: The purpose of this study was to investigate the relationship between folic acid and iron nutrition during pregnancy and congenital heart disease (CHD) in the offspring. Methods: Conditional logistic regression models and nonlinear mixed-effects models were used to analyze the effects of folic acid and iron nutrition during pregnancy on CHD in offspring. Results: After adjusting for confounders, folic acid or iron supplementation during pregnancy reduced the risk for fetal CHD (OR = 0.60 (0.45, 0.82) or 0.36 (0.27, 0.48)). Similarly, dietary iron intake during pregnancy (≥29 mg/d) was associated with a reduced risk of fetal CHD (OR = 0.64 (0.46, 0.88)). Additionally, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or iron (OR = 0.32 (0.16, 0.60)), women who supplemented both folic acid and iron had lower risk for newborns with CHD (OR = 0.22 (0.15, 0.34)). Similarly, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or higher dietary iron intake (≥29 mg/d) (OR = 0.60 (0.33, 1.09)), women who supplemented both folic acid and higher dietary iron intake (≥29 mg/d) had lower risk for the newborn with CHD (OR = 0.41 (0.28, 0.62)). The combined effects were significant in the multiplication model (OR = 0.35 (0.26, 0.48) or 0.66 (0.50, 0.85)) but not in the additive model. Conclusions: Our study found that folic acid and iron nutrition during pregnancy were associated with a reduced risk of CHD in the offspring and confirmed a statistically significant multiplicative interaction between folic acid and iron nutrition on the reduced risk of CHD in offspring.

Synergistic protective effects of folic acid and resveratrol against fine particulate matter-induced heart malformations in zebrafish embryos.

Ambient fine particulate matter (PM2.5) is a major environmental health problem worldwide, and recent studies indicate that maternal PM2.5 exposure is closely associated with congenital heart diseases (CHDs) in offspring. We previously found that supplementation with folic acid (FA) or Resveratrol (RSV) could protect against heart defects in zebrafish embryos exposed to extractable organic matter (EOM) from PM2.5 by targeting aryl hydrocarbon receptor (AHR) signaling and reactive oxygen species (ROS) production respectively. Thus, we hypothesized that FA combined with RSV may have a synergistic protective effect against PM2.5-induced heart defects. To test our hypothesis, we treated zebrafish embryos with EOM in the presence or absence of FA, RSV or a combination of both. We found that RSV and FA showed a clear synergistic protection against EOM-induced heart defects in zebrafish embryos. Further studies showed that FA and RSV suppressed EOM-induced AHR activity and ROS generation respectively. Although only RSV inhibited EOM-induced apoptosis, FA enhanced the inhibitory effect of RSV. Moreover, vitamin C (VC), a typical antioxidant, also exhibits a synergistic inhibitory effect with FA on EOM-induced apoptosis and heart defects. In conclusion, supplementation with FA and RSV have a synergistic protective effect against PM2.5-induced heart defects in zebrafish embryos by targeting AHR activity and ROS production respectively. Our results indicate that, in the presence of antioxidants, FA even at a low concentration level could protect against the high risk of CHDs caused by air pollution.

Multivitamin intake and the risk of congenital heart defects: A cohort study.

OBJECTIVE: Congenital heart disease (CHD) is the most common type of congenital birth defect, but little is known about possible modifiable behavioral risk factors. The study aimed to assess whether intake of periconceptional or postconceptional multivitamin was associated with a decreased risk of CHD in the offspring. STUDY DESIGN: The study population comprised 15,567 women from the Copenhagen Pregnancy Cohort with complete data on multivitamin intake before and during pregnancy, who gave birth to live-born singletons from October 2012 to October 2016. Main outcome measure was CHD defined according to the International Classification of Diseases (ICD), 10th revision. Cases of CHD were classified into five subgroups based on the clinical phenotype: 1) Conotruncal defects, 2) Left ventricular outflow tract obstruction, 3) Right ventricular outflow tract obstruction, 4) Septal defects, and 5) Other CHD. Multivariate logistic regression analyses were performed with adjustment for maternal age, chronic disease, assisted reproductive technology, smoking status, and alcohol consumption. RESULTS: Of the 15,567 included women, 31.9 % reported a daily multivitamin intake in the periconceptional period, 53.7 % in the postconceptional period, and 14.4 % women did not report a daily multivitamin intake. The prevalence of CHD in the population was 0.7 % (n = 112). Periconceptional and postconceptional multivitamin intake was not associated with risk of overall CHD in offspring: Adjusted OR was 0.64 (95 % CI 0.36-1.13) and 0.77 (95 % CI 0.47-1.30), respectively. CONCLUSION: The current large cohort study did not show a preventive effect of multivitamin intake in the periconceptional or postconceptional period on the risk of CHD in the offspring.

Periconception Red Blood Cell Folate and Offspring Congenital Heart Disease : Nested Case-Control and Mendelian Randomization Studies.

BACKGROUND: Periconception folic acid supplementation has been suggested to protect against congenital heart disease (CHD), but the association between maternal red blood cell (RBC) folate, the gold-standard biomarker of folate exposure, and subsequent offspring CHD risk is lacking. OBJECTIVE: To quantify the association between periconception maternal RBC folate and offspring CHD risk. DESIGN: Prospective, nested, case-control study and 1-sample Mendelian randomization. (ClinicalTrials.gov: NCT02737644). SETTING: 29 maternity institutions in 12 districts of Greater Shanghai, China. PARTICIPANTS: All 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort). MEASUREMENTS: Maternal RBC folate was measured before or at early pregnancy. Odds ratios [ORs] were estimated using conditional logistic regression after adjustment for covariates. Mendelian randomization was done using the methylenetetrahydrofolate reductase (MTHFR) C677T as the genetic instrument. RESULTS: Case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482 to 1008 nmol/L] vs. 788 nmol/L [557 to 1094 nmol/L]). Maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted OR per 100 nmol/L, 0.93 [95% CI, 0.89 to 0.99]). The adjusted OR for mothers with periconception RBC folate of 906 nmol/L or more (vs. <906 nmol/L) was 0.61 (CI, 0.40 to 0.93). Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75 [CI, 0.61 to 0.92]). LIMITATION: Potential confounding due to unmeasured covariates in the nested case-control study. CONCLUSION: Higher maternal RBC folate is associated with reduced offspring CHD risk. For primary CHD prevention, higher target RBC folate levels than currently recommended for neural tube defect prevention may be needed and warrant further study. PRIMARY FUNDING SOURCE: National Key Research and Development Program of China, National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis.

BACKGROUND: Folic acid (FA), as a synthetic form of folate, has been widely used for dietary supplementation in pregnant women. The preventive effect of FA supplementation on the occurrence and recurrence of fetal neural tube defects (NTD) has been confirmed. Incidence of congenital heart diseases (CHD), however, has been parallelly increasing worldwide. The present study aimed to evaluate whether FA supplementation is associated with a decreased risk of CHD. METHODS: We searched the literature using PubMed, Web of Science and Google Scholar, for the peer-reviewed studies which reported CHD and FA and followed with a meta-analysis. The study-specific relative risks were used as summary statistics for the association between maternal FA supplementation and CHD risk. Cochran's Q and I2 statistics were used to test for the heterogeneity. RESULTS: Maternal FA supplementation was found to be associated with a decreased risk of CHD (OR = 0.82, 95% CI: 0.72-0.94). However, the heterogeneity of the association was high (P < 0.001, I2 = 92.7%). FA supplementation within 1 month before and after pregnancy correlated positively with CHD (OR 1.10, 95%CI 0.99-1.23), and high-dose FA intake is positively associated with atrial septal defect (OR 1.23, 95%CI 0.64-2.34). Pregnant women with irrational FA use may be at increased risk for CHD. CONCLUSIONS: Data from the present study indicate that the heterogeneity of the association between maternal FA supplementation and CHD is high and suggest that the real relationship between maternal FA supplementation and CHD may need to be further investigated with well-designed clinical studies and biological experiments.

Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart Defects.

OBJECTIVE: To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). STUDY DESIGN: Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63 969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). RESULTS: For folic acid or multiple micronutrients containing folic acid users compared with nonusers, the adjusted RRs (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% CI, 0.44-0.83), 0.41 (95% CI, 0.26-0.67), and 0.47 (95% CI, 0.30-0.74), respectively. When we compared multiple micronutrients containing folic acid users with folic acid users, the ARRs were 0.84 (95% CI, 0.66-1.09), 0.64 (95% CI, 0.41-1.00), and 0.94 (95% CI, 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that, compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95% CI, 0.48-0.95) for total CHDs and 0.26 (95% CI, 0.10-0.71) for critical CHD, but 1.08 (95% CI, 0.63-1.83) for VSD. CONCLUSIONS: Maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid seems to decrease the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between folic acid and multiple micronutrients containing folic acid in terms of preventing CHDs.

AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol.

Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an aryl hydrocarbon receptor (AHR) inhibitor, or N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.

Maternal B-vitamin intake and B-vitamin supplementation during pregnancy in relation to neonatal congenital heart defects: a case-control study with propensity score matching.

BACKGROUND/OBJECTIVES: The effect of dietary folate intake or folic acid (FA) supplementation during pregnancy on neonatal congenital heart defects (CHDs) remains inconclusive. There are limited data about non-folate-B-vitamin intake and the risk of CHDs. Furthermore, few studies have investigated dietary B-vitamin intake and B-vitamin supplement use simultaneously in relation to the risk of CHDs. This study aimed to explore the associations between maternal folate, vitamin B6, and vitamin B12 intake (dietary intake, total intake from diet and supplements); B-vitamin supplement use during pregnancy; and the risk of CHDs using the propensity score matching (PSM) method. METHODS: We conducted a case-control study and included 760 cases and 1600 controls in Shaanxi Province, China. Diet, supplement use and other information were collected through a questionnaire interview. By using the 1:2 ratio PSM method, 396 cases were matched with 792 controls. Conditional logistic regression was used to investigate the associations between maternal B-vitamin intake and supplement use during pregnancy and CHDs. RESULTS: Higher maternal dietary and total intake of folate and vitamin B12 were associated with reduced risk of CHDs, and the tests for linear trend were significant. Compared with non-users, maternal FA + VB6 + VB12 containing supplement use during pregnancy (OR 0.61, 95%CI 0.40-0.94), FA supplement use during pregnancy (OR 0.70, 95%CI 0.50-0.98) and in the first trimester (OR 0.62, 95%CI 0.46-0.85) were associated with a lower risk of CHDs. CONCLUSIONS: The findings of this study suggest that a higher intake of folate and vitamin B12 during pregnancy reduces the risk of CHDs.

Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2 H5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant." METHODS/RESULTS: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts. CONCLUSIONS: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

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.

Research into the intervention effect of folic acid on arsenic-induced heart abnormalities in fetal rats during the periconception period.

BACKGROUND: The incidence of CHD is the highest among birth defects and is increasing year to year. CHD seriously harms the health of infants and young children and presents a large economic burden to families and society. The pathogenesis of CHD and preventive measures are the focus of current research. Our research aimed to explore the intervention effect of folic acid on heart abnormalities resulting from sodium arsenic (NaAsO2) exposure during the periconception period. METHODS: Sixty 35-day-old female SD rats were randomly divided into 5 groups with 12 rats in each group. Group A was the control group. The rats were given distilled water and ordinary chow. The rats in group B were given distilled water containing 75 mg/L NaAsO2 and ordinary chow. The rats in groups C, D, and E were given distilled water containing 75 mg/L NaAsO2 and chow containing 0.53 mg/kg, 5.3 mg/kg, and 10.6 mg/kg folic acid, respectively. The general condition of the embryos and the histopathology of the embryonic hearts were examined. The acetylation levels of histone H3K9 in heart tissues and the expression levels of Mef2C (which is related to heart development) were observed. RESULTS: The embryo weight and placental weight of groups B-E were significantly lower than those of group A (P < 0.05). The heart malformation rate of the fetal rats in groups B-E was significantly higher than that of the fetal rats in group A (P < 0.05). We found that the level of H3K9 acetylation in fetal rat cardiomyocytes in groups B-E was significantly higher than that in group A (P < 0.05) and that the level of H3K9 acetylation in groups C-E was lower than that in group B (P < 0.05). The mRNA level of Mef2C in fetal rat cardiomyocytes in group B-E was significantly higher than that in group A (P < 0.05), and the mRNA level of Mef2C in groups C-E was significantly lower than that in group B (P < 0.05). CONCLUSION: Supplementation with folic acid during the periconception period can interfere with the toxic effects of arsenic on the heart. The mechanism may be that lowering the acetylation levels of histone H3K9 in heart tissues leads to decreased expression levels of Mef2C, which may play a protective role in heart development in fetal rats.

AHR-mediated oxidative stress contributes to the cardiac developmental toxicity of trichloroethylene in zebrafish embryos.

Trichloroethylene (TCE), a widely used chlorinated solvent, is a common environmental pollutant. Current evidence shows that TCE could induce heart defects during embryonic development, but the underlining mechanism(s) remain unclear. Since activation of the aryl hydrocarbon receptor (AHR) could induce oxidative stress, we hypothesized that AHR-mediated oxidative stress may play a role in the cardiac developmental toxicity of TCE. In this study, we found that the reactive oxygen species (ROS) scavenger, N-Acetyl-L-cysteine (NAC), and AHR inhibitors, CH223191 (CH) and StemRegenin 1, significantly counteracted the TCE-induced heart malformations in zebrafish embryos. Moreover, both CH and NAC suppressed TCE-induced ROS and 8-OHdG (8-hydroxy-2' -deoxyguanosine). TCE did not affect ahr2 and cyp1a expression, but increased cyp1b1 expression, which was restored by CH supplementation. CH also attenuated the TCE-induced mRNA expression changes of Nrf2 signalling genes (nrf2b, gstp2, sod2, ho1, nqo1) and cardiac differentiation genes (gata4, hand2, c-fos, sox9b). In addition, the TCE enhanced SOD activity was attenuated by CH. Morpholino knockdown confirmed that AHR mediated the TCE-induced ROS and 8-OHdG generation in the heart of zebrafish embryos. In conclusion, our results suggest that AHR mediates TCE-induced oxidative stress, leading to DNA damage and heart malformations in zebrafish embryos.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

Maternal and neonatal micronutrient levels in newborns with CHD.

OBJECTIVE: It is suggested that folic acid and/or multivitamins, taken periconceptionally, have a role in the prevention of many congenital anomalies. The aim of this study was to determine the serum micronutrient levels in mother-infant pairs with CHD compared with those with healthy newborns and their mothers. METHODS: Serum levels of folic acid, homocysteine, zinc, vitamin A, vitamin D, and vitamin B12 were measured from 108 newborns with CHD (study group) and 103 healthy newborns (control group). The mothers' micronutrient levels were also measured simultaneously. RESULTS: When compared with healthy newborns, for both maternal and neonatal data, homocysteine and zinc levels were higher and vitamin D levels were lower in the study group. In multivariate analysis, only maternal high zinc levels were associated with CHD in the newborns (p=0.02, OR: 0.9, 95% CI 0.8-0.9). The results did not change when analysed for truncal anomalies including truncus arteriosus, tetralogy of Fallot, and d-transposition of great arteries. There were positive correlations between maternal and neonatal levels of micronutrients, except vitamin B12. CONCLUSION: We thought that high homocysteine and zinc levels and low vitamin D levels in mother-infant pairs might have a role in the aetiopathogenesis of CHD. Large-scale, prospective studies are needed to clarify the role of micronutrients in CHDs.

Maternal folic acid supplementation and dietary folate intake and congenital heart defects.

BACKGROUND: It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs). However, the results from limited epidemiologic studies have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs. METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations. RESULTS: Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025) after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect). A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004). Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (<149.88 µg/day) during pregnancy were associated with increased risk of overall CHDs (OR: 1.63, 95% CI: 1.01-2.62) and patent ductus arteriosus (OR: 1.85, 95% CI: 1.03-3.32). Women who were non-user folic acid supplement and lower dietary folate intake have almost 2-fold increased CHDs risk in their offspring. CONCLUSIONS: Our study suggested that folic acid supplementation before pregnancy was associated with a reduced risk of CHDs, lower dietary folate intake during pregnancy was associated with increased risk. The observed associations varied by CHD subtypes. A synergistic effect of dietary folate intake and folic acid supplementation was also observed.

Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure.

BACKGROUND: Despite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown. METHODS: Previously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 µM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine. RESULTS: Compared to EtOH-exposed embryos, betaine-supplemented embryos had higher late-stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5-methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine. CONCLUSIONS: This is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).

Instituto Pediátrico del Corazón / Pediatric Health Institute

En el año 2001, se constituye el Instituto Pediátrico del Corazón (IPC) con el fin de integrar a cardiólogos pediátricos y cirujanos cardiacos en una unidad multidisciplinar dedicada a la atención integral del paciente con cardiopatía congénita. Esto incluye la atención a pacientes desde el periodo fetal hasta la edad adulta y requiere de una estrecha colaboración con intensivistas pediátricos, anestesiólogos, obstetras y cardiólogos de adultos. El crecimiento y la calidad de la actividad asistencial, investigadora y docente de esta unidad en los últimos años, la ha llevado a ser designada como unidad de referencia a nivel nacional (CSUR) para el tratamiento de neonatos y niños con cardiopatías congénitas así como para el tratamiento de la hipertensión pulmonar compleja (AU)

In the year 2001, the Pediatric Heart Institute (PHI) was formed in order to integrate pediatric cardiologists and heart surgeons into a multidisciplinary unit dedicated to the comprehensive care of the patient with congenital heart disease. This includes patient care from the fetal period up to the adult age and requires close collaboration by the pediatric intensive care physicians, anesthesiologists, adult cardiologist and obstetricians. The growth and quality of the care, investigator and teaching activity of this unit in recent years has led it to being designated as Reference Centers, Services and Units (CSUR by its acronym in Spanish) on the national level for the treatment of newborn and children with congenital heart disease and for the treatment of complex pulmonary hypertension (AU)

El Área del Corazón Infantil del Hospital General Universitario Gregorio Marañón / Area of Pediatric Cardiology of the Hospital General Universitario Gregorio Marañón

La atención integral de las enfermedades cardiovasculares de la infancia y de las cardiopatías congénitas del feto al adulto, se realiza desde hace más de 40 años en el Hospital General Universitario Gregorio Marañón de Madrid, siendo centro nacional de referencia (CSUR) de trasplante cardíaco infantil, cardiopatías congénitas complejas y neonatales, cardiopatías familiares y cardiopatías congénitas del adulto. El Área del Corazón Infantil es la estructura organizativa que engloba Cardiología Pediátrica y Cirugía Cardíaca Infantil, en colaboración con otros servicios del Hospital Infantil y de Adultos. Se incluyen en la cartera de servicios todos los programas asistenciales específicos relacionados, incluso algunos novedosos, como la rehabilitación cardíaca infantil y la telemedicina. Destacar que es el centro con mayor actividad en trasplante cardíaco infantil (serie de 160 pacientes, un 40% del total nacional). En el período 2013 y 2014, con el nuevo equipo quirúrgico se realizaron 645 intervenciones en menores de l 8 años, con alta complejidad (surgical performance de 7) y bajada de la mortalidad del 3,2 al 1,5 %. Entre 2011 y 2014 se realizaron 1.146 cateterismos intervencionistas en menores de 18 años, cerca de 1/3 en menores de 1 año, con una mortalidad menor del 1 por 1.000; se evaluaron en cardiopatías familiares 725 nuevos pacientes (1/4 casos pediátricos) y se realizaron 758 test genéticos. La actividad docente incluye el pregrado de Medicina, Enfermería e Ingeniería Biomédica, residentes de pediatría y cardiología, post MIR y fellows en cardiología pediátrica tanto de España como de otros países, especialmente de Latinoamérica. Destacan los cursos internacionales anuales de actualización en enfermería y medicina (23 ediciones) así como el preceptorship in pediatric cardiology. La actividad investigadora se estructura como grupo dentro del área cardiovascular del Instituto de Investigación Sanitaria Gregorio Marañón, con participación en la red de investigación cardiovascular (RIC), colaboración con el centro nacional de investigaciones cardiológicas (CNIC). Contamos con investigadores de forma continuada así como proyectos de Financiación pública competitiva desde 2010. Las líneas de investigación incluyen la genética de las miocardiopatías, los ensayos clínicos con células madre en Fontan, el uso de vasodilatadores pulmonares y otros fármacos cardiovasculares, así como el impacto de las infecciones respiratorias en niños con cardiopatía y síndrome de Down. Se han iniciado líneas de innovación en el campo de los dispositivos para intervencionismo cardíaco así como en aspectos organizativos y en cooperación internacional al desarrollo con un centro en Nicaragua. La colaboración con los pacientes y sus familias a través de organizaciones como Menudos Corazones han sido claves para obtener los objetivos ñnales del programa: la obtención de la mayor esperanza y calidad de vida de los niños que tienen una condición cardiovascular (AU)

Comprehensive care of pediatric cardiovascular disease and congenital heart disease from fetus to adult, has been performed at the Hospital General Universitario Gregorio Marañon de Madrid for the last 40 years. Our hospital is national reference centre (CSUR) for pediatric heart transplant, complex and neonatal congenital heart disease and familia] and adult congenital heart disease. The Children's Heart Area is the organizing structure encompassing pediatric cardiology and pediatric cardiac surgery, in collaboration with the other pediatric and adult hospital services. Our service offers all related specific healthcare including novelties such as pediatric cardiac rehabilitation and telemedicine. Our centre has the highest activity as regards pediatric heart transplant (series of 160 patients, 40% of the national total). During the period from 2013 to 2014, with the new surgical team, 645 interventions were performed in under 185, with high complex surgical interventions (surgical performace 7) with low mortality, from 3.2 to 1.5%. 1,146 interventional catheterism were performed in under 185, between 2011 to 2014, near 1/3 under 1 year of age, with mortality rates less tan 1 per 1,000; 725 new patients were evaluated in the familial cardiopathy clinic (1/4 pediatric cases) and 758 genetic tests were carried out. Teaching activity includes undergraduare medicine, nursing and biomedical engineering, residency in pediatrics and cardiology, post MIR and fellowships in pediatric cardiology in Spain as well as in other countries, especially Latin America. Of interest, are the yearly international courses in updates in nursing and medicine (23 editions) as well as the preceptorship in pediatric cardiology. Research activity is encompassed as the group within the cardiovascular area of the Instituto de Investigación Sanitaria Gregorio Marañón, participating in the Cardiovascular Research Network (RIC), collaboration with the National Centre for Cardiological Research (CNIC). Our research is continuous with competitive publicly funded projects since 2010. Research topics include the genetics of cardiomyopathics, clinical trials with stem cells in Fontan, use of pulmonary vasodilators and other cardiovascular drugs, as well as the impact of respiratory infections in children with heart disease and Down's Syndrome. Innovations in the field of devices in cardiac interventionism have been implemented and also in organizational aspects as well as international cooperation for development with a centre in Nicaragua. Collaboration with patients and families through organizations like ‘Menudos Corazones’ have been key in achieving the goals of our program: the longest life-expectancy and highest quality of life in children who have a cardiovascular condition (AU)

A Meta-Analysis of the Relationship Between Maternal Folic Acid Supplementation and the Risk of Congenital Heart Defects.

Controversial opinions exist with respect to the relationship between maternal folic acid (FA) supplementation and birth prevalence of congenital heart defects (CHDs).Eligible articles were retrieved by searching databases, including PubMed, Cochrane library, EMBASE, CNKI, and WanFang up to September 2015. A meta-analysis was performed to evaluate the effects of FA on CHDs. Odds ratios (ORs) and 95% confidence interval (CIs) were merged using STATA 12.0. Meta-regression analysis was used to explore the possible sources of heterogeneity. Subgroup analysis according to the selected sources was also performed. Publication bias was assessed by Egger's test.Twenty studies were included in the meta-analysis. The overall analysis showed that FA supplementation was significantly associated with decreased risk of CHDs. The meta-regression analysis showed that geographical area could be an important source of heterogeneity. The subgroup analysis based on the geographical area revealed that FA supplementation during pregnancy was a protective factor against CHDs in Chinese and European patients, but not in American patients. Subgroup analysis according to literature quality also displayed positive associations between FA supplementation and the decreased risk of CHDs of China.FA supplementation during pregnancy significantly decreases the risk of CHDs in newborns in China and Europe.