PMID 26662928 Effects and safety of periconceptional oral folate supplementation for preventing birth defects Meta-analysis (Cochrane) · Cochrane Database Syst Rev, 2015 5 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s, 7,391 people - periconceptional folic acid lowered fetal neural tube defects by about 69% (RR 0.31, high quality).
Key summary
A CochraneAn international network that rigorously reviews and synthesizes evidence. review pooling 5 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s and 7,391 pregnant women (2,033 with a prior NTD-affected pregnancy). Daily folic acid supplementation (alone or combined with other vitamins and minerals) significantly reduced neural tube defects versus placeboAn inert dummy treatment used as the comparison baseline. or no treatment (RR 0.31, 95% CI 0.17–0.58, high-quality evidence), and also significantly reduced recurrence in women with a history (RR 0.34). Subgroup analysis found the effect held at 400 µg (0.4 mg) a day or higher regardless of dose. By contrast, there was no clear effect on other malformations such as cleft lip, cleft palate, or congenital heart defects.
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BACKGROUND: It has been reported that neural tube defects (NTD) can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear. OBJECTIVES: This review aims to examine whether periconceptional folate supplementation reduces the risk of neural tube and other congenital anomalies (including cleft palate) without causing adverse outcomes in mothers or babies. MAIN RESULTS: Five trials involving 7391 women (2033 with a history of a pregnancy affected by a NTD and 5358 with no history of NTDs) were included. The results of the first comparison involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58); five studies; 6708 births; high quality evidence). Folic acid had a significant protective effect for reoccurrence (RR 0.34, 95% CI 0.18 to 0.64); four studies; 1846 births). Subgroup analyses suggest that the positive effect of folic acid on NTD incidence and recurrence is not affected by the explored daily folic acid dosage (400 µg (0.4 mg) or higher) or whether folic acid is given alone or with other vitamins and minerals. There is no evidence of any preventive or negative effects on cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. AUTHORS' CONCLUSIONS: Folic acid, alone or in combination with vitamins and minerals, prevents NTDs, but does not have a clear effect on other birth defects. ※ The abstract text as collected and stored via the API by the pipeline. The key summary is written based solely on this text.
View original ↗ PMID 1677062 Prevention of neural tube defects: results of the Medical Research Council Vitamin Study RCT · Lancet, 1991 1,817 high-risk women - the landmark trial in which periconceptional folic acid cut recurrence of neural tube defects by 72% (RR 0.28).
Key summary
A randomised, double-blind, factorial-design trial (MRC Vitamin Study) run at 33 centres in seven countries. It randomised 1,817 high-risk women with a prior neural tube defect pregnancy to folic acid, other vitamins, both, or neither. Of 1,195 completed pregnancies with a known outcome, neural tube defects occurred in 6 in the folic acid groups versus 21 in the non-folic-acid groups - a 72% protective effect (relative risk 0.28, 95% CI 0.12–0.71). The other-vitamin mixture had no significant effect. This is the trial that firmly established periconceptional folic acid supplementation.
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A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups--namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid. ※ The abstract text as collected and stored via the API by the pipeline. The key summary is written based solely on this text.
View original ↗ PMID 25771069 Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial RCT · JAMA, 2015 20,702 low-folate Chinese hypertensive adults - adding folic acid cut first stroke by 21% (HR 0.79), with no change in myocardial infarctionA heart attack - death of heart muscle from blocked blood flow..
Key summary
A randomised, double-blind trial (CSPPT) in 20,702 hypertensive adults without a history of stroke or myocardial infarctionA heart attack - death of heart muscle from blocked blood flow., conducted in China, which has no folic acid fortification policy. A single-pill combination of enalapril plus folic acid 0.8 mg significantly reduced first stroke versus enalapril alone over a median 4.5 years (2.7% vs 3.4%, HR 0.79, 95% CI 0.68–0.93). By contrast, there was no difference in myocardial infarction (HR 1.04) or all-cause death (HR 0.94). The authors concluded the finding is consistent with benefit from folate in a population with low baseline folate.
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IMPORTANCE: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS: Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). RESULTS: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93). The risks of myocardial infarction (HR, 1.04; 95% CI, 0.60-1.82) and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. CONCLUSIONS AND RELEVANCE: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. ※ The abstract text as collected and stored via the API by the pipeline. The key summary is written based solely on this text.
View original ↗ PMID 28816346 Homocysteine-lowering interventions for preventing cardiovascular events Meta-analysis (Cochrane) · Cochrane Database Syst Rev, 2017 15 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s, 71,422 people - homocysteineA blood amino acid that rises when folate, B6, or B12 is low; high levels track cardiovascular risk, but lowering it did not reduce cardiac events.-lowering with folic acid did not reduce heart attack or death (high quality); only stroke fell slightly.
Key summary
A CochraneAn international network that rigorously reviews and synthesizes evidence. review pooling 15 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s and 71,422 participants. Lowering homocysteineA blood amino acid that rises when folate, B6, or B12 is low; high levels track cardiovascular risk, but lowering it did not reduce cardiac events. with vitamins B6, B9 (folic acid), or B12 produced no reduction versus placeboAn inert dummy treatment used as the comparison baseline. in myocardial infarctionA heart attack - death of heart muscle from blocked blood flow. (RR 1.02), all-cause death (RR 1.01), or serious adverse events (all high-quality evidence). Only stroke fell slightly (RR 0.90, 95% CI 0.82–0.99, high quality). The result does not support the hypothesis that lowering homocysteine prevents heart disease.
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BACKGROUND: Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. OBJECTIVES: To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety. MAIN RESULTS: In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). AUTHORS' CONCLUSIONS: In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo. ※ The abstract text as collected and stored via the API by the pipeline. The key summary is written based solely on this text.
View original ↗ PMID 23352552 Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals Meta-analysis · Lancet, 2013 13 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s, 49,621 people - high-dose folic acid over 5 years produced no significant change in overall or site-specific cancer (RR 1.06).
Key summary
A meta-analysisA statistical synthesis combining results of multiple studies into one conclusion. of individual-participant data pooling 13 RCTRandomized controlled trial - a high-reliability trial that randomly assigns participants to compare effects.s and 49,621 people. Even though folic acid supplementation at doses far above fortification, used for a weighted-average 5.2 years, quadrupled blood folic acid, there was no significant change in overall cancer incidence (RR 1.06, 95% CI 0.99–1.13). No site-specific cancer of the large intestine, prostate, lung, or breast rose or fell significantly. Because flour fortification uses doses roughly an order of magnitude lower, this is cited as evidence easing the cancer concern about folic acid fortification.
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BACKGROUND: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). FINDINGS: During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99-1·13, p=0·10). There was no trend towards greater effect with longer treatment. Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. ※ The abstract text as collected and stored via the API by the pipeline. The key summary is written based solely on this text.
View original ↗ FDA (openFDA) Folic acid - drug label (warnings, precautions, interactions)
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View original ↗ USDA FoodData Central Edamame, frozen, prepared (FDC 168411)
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View original ↗ USDA FoodData Central Beef, variety meats and by-products, liver, cooked, braised (FDC 168626)
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View original ↗ USDA FoodData Central Lentils, mature seeds, cooked, boiled, with salt (FDC 175254)
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View original ↗ USDA FoodData Central Chickpeas (garbanzo beans, bengal gram), mature seeds, cooked, boiled, with salt (FDC 173799)
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View original ↗ USDA FoodData Central Asparagus, cooked, boiled, drained (FDC 168390)
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View original ↗ USDA FoodData Central Spinach, cooked, boiled, drained, with salt (FDC 170531)
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