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Association Between Anencephaly or Spina Bifida and Dietary Folic Acid Intake Stratified by Supplement Use, a National Birth Defects Prevention Study, 1998-2003
Source publication
Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors' objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the Nati...
Contexts in source publication
Context 1
... odds ratios measuring the association between die- tary folic acid and anencephaly and spina bifida stratified by supplement use are presented in Table 5. Among those who did not use supplements, women who had pregnancies af- fected by anencephaly or spina bifida were no more likely to report consuming dietary folic acid levels in the lowest 50th percentile of intake than were controls. ...
Context 2
... similar to those presented in Table 5 using dietary folic acid were observed when natural folate and total folate expressed as DFE were used to assess the risk of neural tube defects (data not shown). Given concerns that preg- nancy outcomes among cases may impact our findings, we repeated the analyses including participants from only the 5 surveillance programs (Arkansas, California, Iowa, Georgia, and Texas) that have consistently included elec- tively terminated fetuses and stillbirths throughout the study Abbreviation: DFE, dietary folate equivalent. ...
Similar publications
Fortification of select grain products with folic acid and periconceptional supplementation recommendations in Canada and the USA have improved folate status, and have been associated with a reduced risk of neural tube defects. In the present study, we aimed to conduct a comparison of erythrocyte folate concentrations from the 2007-9 Canadian Healt...
Background: Folic acid fortification to reduce NTDs, such as spina bifida and anencephaly as well as congenital heart disease, is considered one of the most successful public health initiatives in the past 50-75 years. No representative data about folate intake are available for Egypt. Despite, if FA guideline is followed, an estimated 50-80% of NT...
To assess the potential contribution of foods fortified with folic acid (FA) to target population intakes when included as part of a healthy breakfast.
Breakfast models aligned with the Spanish Dietary Guidelines were studied using the recommended, average and 95th percentile of serving sizes consumed by women of childbearing age. Food composition...
ABSTRACT. Folates are associated with a variety of human health benefits, while folate deficiency has been identified as a potential risk factor for many health problems and cancers, due to its role in dysregulation of DNA synthesis, repair and methylation. The US Food and Drug Administration adopted requirements for folate fortification in some fo...
Background:- Anemia is a sever public health nutritional problem in pregnant women has a significant impact on the health of the fetus as well as that of the mother and responsible for low birth weight. Objective:- To determine the frequency and morphological types of anemia in anemic pregnant women admitted to the Al-Batool teaching hospital for m...
Citations
... In current postfortification era, there lacks new prospective studies to evaluate the benefits of folic acid supplement among women with pregnancy intention as a public health intervention [7]. Moreover, subsequent observational, case-control studies have not shown a protective association with birth defects such as NTDs [8]. ...
Background
Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting.
Methods
This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses.
Results
Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66–0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39–0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease.
Conclusion
This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.
... Understanding that sufficient folate intake reduces the risk for neural tube defects (NTD) is considered one of the most important health-related discoveries ever made [4] . Folate deficiency, instead, has been linked to several health disorders, such as coronary heart disease, osteoporosis, Alzheime'rs disease, and colorectal cancer [5] . Moreover, folate deficiency causes anemia because it is required for red blood cell production. ...
... The dephosphorylation of dihydroneopterin triphosphate into the monophosphate can occur through an alternative route using pyrophosphohydrolase number EC 3.6.1.-. which is present (Rossi 2011). enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) responsible for DHPPP biosynthesis, as well as the folP gene encoding dihydropteroate synthase, an enzyme involved in the condensation of DHPPP and pABA [5,88] [ Figure 2]. Therefore, it was concluded that animal species, with few exceptions, are auxotrophic for folate, even with the presence of pABA [ Figure 4]. ...
Folate (the general term for all bioactive forms of vitamin B9) plays a crucial role in the evolutionary highly conserved one-carbon (1C) metabolism, a network including central reactions such as DNA and protein synthesis and methylation of macromolecules. Folate delivers 1C units, such as methyl and formyl, between reactants. Plants, algae, fungi, and many bacteria can naturally produce folate, whereas animals, including humans, must obtain folate from external sources. For humans, folate deficiency is, however, a widespread problem. Bifidobacteria constitute an important component of human and many animal microbiomes, providing various health advantages to the host, such as producing folate. This review focuses on bifidobacteria and folate metabolism and the current knowledge of the distribution of genes needed for complete folate biosynthesis across different bifidobacterial species. Biotechnologies based on folate-trophic probiotics aim to create fermented products enriched with folate or design probiotic supplements that can synthesize folate in the colon, improving overall health. Therefore, bifidobacteria (alone or in association with other microorganisms) may, in the future, contribute to reducing widespread folate deficiencies prevalent among vulnerable human population groups, such as older people, women at child-birth age, and people in low-income countries.
... A large randomized controlled trial in China further proved periconceptional intake of folic acid (400 mcg/day) significantly reduced the risk of NTDs [31]. Populationbased case-control studies have provided additional evidence on significant preventive potential of folic acid on NTDs [46,47]. Studies have also examined the interaction between folic acid and other known risk factors for NTDs. ...
Neural tube defects (NTDs) are common birth defects and contribute to life-long disabilities, high medical care costs, and perinatal and child mortality. This review is a primer on prevalence, causes, and evidence-based prevention strategies for NTDs. The estimated average global prevalence of NTDs is two cases per 1000 births, amounting to approximately 214,000-322,000 affected pregnancies worldwide annually. Prevalence and associated adverse outcomes are disproportionately high in developing countries. NTDs have multiple risk factors including genetic and non-genetic (i.e., maternal nutritional status, pre-pregnancy diabetes, early pregnancy exposure to valproic acid (anti-epileptic medication), and a previous pregnancy affected by a NTD) factors. Maternal folate insufficiency before and during early pregnancy is the most common risk factor and is preventable. Folic acid (vitamin B9) is required for formation of the neural tube early in pregnancy, around 28 days after conception, when most women are unaware of their pregnancies. Current guidelines recommend that all women planning or capable of pregnancy take a daily supplement containing 400-800 μg of folic acid. Mandatory folic acid fortification of staple foods (e.g., wheat flour, maize flour, rice) is safe, economical, and the effective intervention for primary prevention of NTDs. Currently, about 60 countries are implementing mandatory folic acid fortification of staple foods, preventing just a quarter of all preventable NTD cases worldwide. There is an urgent need for active champions, including neurosurgeons and other healthcare providers, to generate political will and promote effective mandatory food fortification with folic acid, and reach equitable primary prevention of NTDs in all countries.
... Folate (vitamin B 9 ) and cobalamin (vitamin B 12 ) are essential cofactors in eukaryotic single-carbon metabolism [1,2]. Folate is naturally found in citrus fruits and leafy green vegetables; it is also supplemented in particular grains and synthesized by intestinal commensal bacteria such as Bifidobacterium strains [3][4][5]. In contrast, vitamin B 12 is primarily found in animal products [6,7]. ...
Folate and vitamin B12 deficiency is highly prevalent among Crohn’s disease (CD) patients. Furthermore, CD pathology can be mediated by Mycobacterium avium subsp. paratuberculosis (MAP) infection. However, the direct effect of folate (B9) and cobalamin (B12) deficiency during MAP infection remains uncharacterized. This study investigates how folate and B12 deficiency impedes macrophage apoptosis and exacerbates the inflammation in macrophages infected with MAP isolated from CD patients. Accordingly, we measured folate and B12 in ex vivo plasma samples collected from CD patients with or without MAP infection (N = 35 per group). We also measured the expression of the pro-inflammatory cytokines IL-1β and TNF-α, cellular apoptosis and viability markers, and bacterial viability in MAP-infected macrophages cultured in folate and B12 deficient media. We determined that MAP-positive CD patients have significantly lower plasma folate and B12 in comparison to MAP-negative CD patients [414.48 ± 94.60 pg/mL vs. 512.86 ± 129.12 pg/mL, respectively]. We further show that pro-inflammatory cytokines IL-1β and TNF-α are significantly upregulated during folate and vitamin B12 deprivation following MAP infection by several folds, while supplementation significantly reduces their expression by several folds. Additionally, depletion of folate, B12, and folate/B12 following MAP infection, led to decreased macrophage apoptosis from 1.83 ± 0.40-fold to 1.04 ± 0.08, 0.64 ± 0.12, and 0.45 ± 0.07 in folate-low, B12-low, and folate/B12-low cells, respectively. By contrast, folate and folate/B12 supplementation resulted in 3.38 ± 0.70 and 2.58 ± 0.14-fold increases in infected macrophages. Interestingly, changes in overall macrophage viability were only observed in folate-high, folate/B12-high, and folate/B12-low media, with 0.80 ± 0.05, 0.82 ± 0.02, and 0.91 ± 0.04-fold changes, respectively. Incubation of Caco-2 intestinal epithelial monolayers with supernatant from infected macrophages revealed that folate/B12 deficiency led to increased LDH release independent of oxidative stress. Overall, our results indicate that folate and B12 are key vitamins affecting cell survival and inflammation during MAP infection.
... Folate supplementation soon showed similar effects as yeast and liver extracts in the prevention of megalocytic anemia [2]. Leafy vegetables and citrus fruits are high in natural folates, and the synthetic form of folate, folic acid, has been mandated as a grain supplement by the US Food and Drug Administration since 1998 [1,3,4]. Probiotic intestinal bacteria also have been known to synthesize folate and secrete it into the environment [5]. ...
Vitamin deficiency is well known to contribute to disease development in both humans and other animals. Nonetheless, truly understanding the role of vitamins in human biology requires more than identifying their deficiencies. Discerning the mechanisms by which vitamins participate in health is necessary to assess risk factors, diagnostics, and treatment options for deficiency in a clinical setting. For researchers, the absence of a vitamin may be used as a tool to understand the importance of the metabolic pathways in which it participates. This review aims to explore the current understanding of the complex relationship between the methyl donating vitamins folate and cobalamin (B12), the universal methyl donor S-adenosyl-L-methionine (SAM), and inflammatory processes in human disease. First, it outlines the process of single-carbon metabolism in the generation of first methionine and subsequently SAM. Following this, established relationships between folate, B12, and SAM in varying bodily tissues are discussed, with special attention given to their effects on gut inflammation.
... Moreover, administration of antioxidants such as vitamin E or Glutathione (GSH) ethyl ester can prevent hyperglycemia-induced developmental defects through decreasing oxidative stress, recovering the inhibition of Pax3 [11]. Supplementary folic acid intake during human pregnancy can diminish the fetal rate of defects [12][13][14][15][16][17][18]. However, the antiteratogenic mechanism of folic acid is still unclear. ...
Aimes: This study aimed to determine whether folic acid supplementation could decrease the neural tube defects (NTDs) in embryos caused by hyperglycemia and the mechanism is associated with its antioxidative activity. Study Design: Diabetic pregnancy model were made and folic acid, Vitamin E and control were given to mice. Then the neural tube defects rate, oxidative stress markers and embryos size were measured and were analyzed. Methodology: We injected folic acid to diabetic mice to score NTDs rate, measured embryos size, assayed ROS scavenging enzymes and Pax3 expression and oxidative stress marker including malondiadehyde and H2O2 as well as the vitamin E controls. Results: Injection of folic acid during gestation could diminish neural tube defect rate of diabetic mice and recover the Pax3 expression inhibition which is similar to vitamin E, but no effect was observed on nondiabetic mice. Folic acid supplementation also normalized the embryos size, decreased oxidative stress level including malondiadehyde and H2O2 in diabetic mice and decreased the intracellular ROS of embryonic cells on day 8.5 induced by high glucose incubation in a dose-dependent manner. No effects were observed on ROS scavenging enzymes activity by folic acid supplementation. Conclusion: Overall, the conclusion is that folic acid supplementation could diminish NTDs induced by hyperglycemia, the mechanism is associated with its antioxidant activity which can reduce the oxidative stress and recover the inhibition of Pax3 expression.
... Studies have shown that the mean serum folate concentration increased more than twofold (136%) and the mean erythrocyte folate concentration increased by 57%. The introduction of folic acid-fortified staple foods has effectively decreased the prevalence of NTD in the United States and Canada [53]. It was also observed that fortifying flour with iron and many water-soluble B group vitamins in the United States, Canada, and many other countries has resulted in preventing micronutrient deficiency conditions and is also a very cost-effective prevention of major neural tube defects viz., spina bifida and anencephaly, and also folate deficiency anemia. ...
Folic acid is a B complex water-soluble vitamin that is essential to humans, and its deficiency can cause problems including neural tube defects as well as heart-related diseases. An important feature of such vitamins is that they are generally not synthesized by mammalian cells and therefore must be supplied in sufficient amounts in the diet. Folate is a generic term for compounds, possessing vitamin activity similar to that of pteroylglutamic acid, and is the form of the vitamin, which is naturally present in foods. The main dietary sources of folic acid are dark green and leafy vegetables such as spinach, asparagus, romaine lettuce, broccoli, bok choy, turnip green, beet, dried or fresh beans, and peas. The amount of folate that is absorbed and utilized physiologically varies among different food sources and different chemical forms of the vitamin. About 85% of folic acid is estimated to be bioavailable; however, the bioavailability of food folate is estimated at about 50% of folic acid. Several national health authorities have introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bio-efficacy. Presently, many countries affected by diseases associated with a lack of folic acid have made it mandatory to supplement foods with the vitamin. Considering the need, several analytical procedures were standardized to determine the presence of folic acid in different food matrices. The reported methods are simple, selective, robust, and reproducible and can be used in routine analyses.
... There is compelling evidence that sub-optimal maternal blood folate concentrations can predispose to NTDs and maternal supplementation with folic acid in the periconceptional period, via supplements or food fortification, significantly reduces this risk [103][104][105]. However, FA alone does not provide complete prevention of recurrence or occurrence of NTDs, leading to the description of 'folic acid resistant NTDs' [106]. ...
Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.
... The model developed by Arth et al. (7) first requires estimation of the number of NTD cases preventable by folic acid fortification assuming that the lowest NTD birth prevalence achievable following folic acid fortification is 5 per 10,000 live births, which is the NTD prevalence in the United States after ∼20 y of folic acid fortification (22). Thus, the difference in NTD prevalence between the country of interest and this lower threshold is used to compute the maximum proportion of NTD that can be prevented by folic acid fortification. ...
Several models have been developed to predict the effects of folic acid fortification programs on prevention of neural tube defects (NTDs), but each relies on different assumptions and data inputs. We identified and reviewed 7 models that predict the effects of folic acid intake or status on NTD risk. We applied 4 of these models [the original and a modified version of the Lives Saved Tool (LiST) and models developed by Arth et al. and Wald et al.] to predict the effect of folic acid fortification of wheat flour on reduction of NTDs using national survey data from Cameroon. The estimated percentage of NTDs averted due to fortified wheat flour (5.0 μg folic acid/g flour) varied by predictive model, with a 21-31% reduction in LiST to 83% in Arth's model, and 15% in Wald's model. As the simulated fortification level was increased from 1.0 to 7.0 μg folic acid/g flour, the pattern of change in estimated numbers of NTDs averted differed due to different model assumptions: the number of NTDs averted increased and then reached a plateau in the modified LiST model (as would be expected in real-world conditions), increased sharply in Arth's model, and increased continuously in Wald's model. This wide variation in predicted effects, and implausible results in some cases, undermines the models' utility for users of model outputs. Concurrent collection of dietary and biomarker data, including plasma and RBC folate concentrations, and NTD outcomes, is necessary to validate these models and monitor change in folic acid intake, folate-related biomarkers, and reduced NTD risk due to fortification. In the meantime, models based on erythrocyte folate concentration are recommended, based on biological plausibility and consistency with empirical evidence. Where erythrocyte folate data are unavailable, sensitivity analyses (using several models) could be conducted to examine the range of possible outcomes.
... Second, research has shown that the surgical repair of spina bifida in uterus can improve the prognosis of NTDs (17). However, not all NTDs can be prevented by taking FA, and as the incidence of NTDs remains about 0.1% in Western countries, consideration needs to be given to alternative therapies to treat the NTDs that do not respond to FA (2,18). Additionally, there is growing evidence that components of the immune system may directly affect key morpho-regulatory steps in neurogenesis (11). ...
Background:
Neural tube defects (NTDs) are one of the most common types of birth defects. Oral folic acid (FA) prophylaxis is currently available, but the pathogenesis of NTDs is not fully understood. We conducted this study to examine the role of the immune landscape of NTDs and identify novel diagnostic and therapeutic biomarkers.
Methods:
We downloaded the GSE33111 data set of 12 NTD embryos and 12 healthy embryos in the same period of fetal development from the Gene Expression Omnibus (GEO) database. We compared the healthy embryos and NTD embryos to identify the differentially expressed genes (DEGs). We also performed a functional enrichment analysis of the DEGs using the clusterProfiler package. We extracted the top 10 ranked genes as hub immune-related biomarkers. We then used receiver operating characteristic (ROC) curves to determine the expression levels of the hub immune-related genes and the accuracy of the diagnosis of NTDs. Finally, we analyzed the immune landscape of the NTD embryos and healthy embryos via a single-sample gene set enrichment analysis (ssGSEA).
Results:
A total of 611 DEGs were identified by the differential analysis, including 95 immune genes. The functional enrichment analysis indicated that Epstein-Barr virus infection, antigen processing and presentation, inflammatory bowel disease, and type I diabetes mellitus were associated with NTDs. The results of the expression level analysis showed that the hub immune-related genes were more highly expressed in the NTD embryos than the healthy embryos. Additionally, the ROC curve analysis also indicated that the expression levels of the 10 hub immune-related genes were highly accurate in the diagnosis of NTDs [area under the curve (AUC) range, 0.708-0.812]. The immune infiltration analysis demonstrated that 20 of the 28 immune cell types were more highly infiltrated in the NTD embryos than the healthy embryos.
Conclusions:
Immune-related genes are important regulators of the occurrence and development of NTDs.
