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Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.
Li, M, Zhang, Y, Chen, X, Wang, D, Ji, M, Jiang, Y, Dou, Y, Ma, X, Sheng, W, Yan, W, et al
BMC pregnancy and childbirth. 2020;(1):475
Abstract
BACKGROUND Birth defects are the main cause of fetal death, infant mortality and morbidity worldwide. However, the etiology of birth defects remains largely unknown. Maternal folate status during periconception plays an important role in organogenesis and folic acid supplement reduces the risk of neural tube defects, congenital heart diseases, and several other birth defects. This trial seeks to evaluate the effectiveness of folate-oriented tertiary interventions during periconception on the incidence of fetus and birth defects. METHODS This is a single-blind, two-arm cluster randomized controlled trial in Shanghai, China. Eligible women from 22 clusters are recruited at pre-pregnancy physical examinations clinical settings. Compared to the routine perinatal care group (control arm), folate-oriented tertiary interventions will be provided to the intervention arm. The core interventions consist of assessments of folate status and metabolism, folate intake guidance, and re-evaluation of folate status to ensure red blood cell folate level above 400 ng/ml (906 nmol/L) before pregnancy. Screening and consulting of fetus and birth defects, and treatments of birth defects during pregnancy and afterward will be provided to both arms. The primary outcome is a composite incidence of fetus defects, stillbirth, and neonatal birth defects identified from the confirmation of pregnancy to 28 days after birth. Secondary outcomes include maternal and offspring adverse complications and cost-effectiveness of folate-oriented tertiary interventions. This protocol adheres to the SPIRIT Checklist. DISCUSSION To achieve the recommended folate status before or during pregnancy is still a challenge worldwide. This community-based cluster-randomized controlled intervention trial will evaluate the effectiveness of a package of interventions aiming at achieving recommended maternal folate status covering pre- and during pregnancy in reducing fetus and birth defects. Our study has the potential to improve the community-based practice of reducing modifiable risk factors of disease and improving primary prevention of the defects in China. The procedures would formulate the policy on folic acid supplementation during periconception against birth defects in primary care settings. TRIAL REGISTRATION Clinical Trial Registry, NCT03725878 . Prospectively registered on 31 October 2018.
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Platelet Count Affects Efficacy of Folic Acid in Preventing First Stroke.
Kong, X, Huang, X, Zhao, M, Xu, B, Xu, R, Song, Y, Yu, Y, Yang, W, Zhang, J, Liu, L, et al
Journal of the American College of Cardiology. 2018;(19):2136-2146
Abstract
BACKGROUND The role of platelets and important effect modifiers on the risk of first stroke is unknown. OBJECTIVES This study examined whether low platelet count (PLT) and elevated total homocysteine (tHcy) levels jointly increase the risk of first stroke, and, if so, whether folic acid treatment is particularly effective in stroke prevention in such a setting. METHODS A total of 10,789 Chinese hypertensive adults (mean age 59.5 years; 38% male, with no history of stroke and myocardial infarction) were analyzed from the China Stroke Primary Prevention Trial, where participants were randomly assigned to daily treatments of 10 mg enalapril and 0.8 mg folic acid (n = 5,408) or 10 mg enalapril alone (n = 5,381). The primary endpoint was first stroke. RESULTS During 4.2 years of follow-up, a total of 371 first strokes occurred. In the enalapril-alone group, the lowest rate of first stroke (3.3%) was found in patients with high PLT (quartiles 2 to 4) and low tHcy (<15 μmol/l); and the highest rate (5.6%) was in patients with low PLT (quartile 1) and high tHcy (≥15 μmol/l) levels. Following folic acid treatment, the high-risk group had a 73% reduction in stroke (hazard ratio: 0.27; 95% confidence interval: 0.11 to 0.64; p = 0.003), whereas there was no significant effect among the low-risk group. CONCLUSIONS Among Chinese hypertensive adults, the subgroup with low PLT and high tHcy had the highest risk of first stroke, and this risk was reduced by 73% with folic acid treatment. If confirmed, PLT and tHcy could serve as biomarkers to identify high-risk individuals who would particularly benefit from folic acid treatment. (China Stroke Primary Prevention Trial [CSPPT]; NCT00794885).
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Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.
Huo, Y, Li, J, Qin, X, Huang, Y, Wang, X, Gottesman, RF, Tang, G, Wang, B, Chen, D, He, M, et al
JAMA. 2015;(13):1325-35
Abstract
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). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. 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), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (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. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00794885.
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Relationship Between Myo-Inositol Supplementary and Gestational Diabetes Mellitus: A Meta-Analysis.
Zheng, X, Liu, Z, Zhang, Y, Lin, Y, Song, J, Zheng, L, Lin, S
Medicine. 2015;(42):e1604
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Abstract
To determine whether myo-inositol supplement will increase the action of endogenous insulin, which is mainly measured by markers of insulin resistance such as homeostasis model assessment of insulin resistance.PubMed, Cochrane Library, Embase, and web of science were comprehensively searched using "gestational diabetes mellitus" and "myo-inositol" to identify relevant studies. Both subject headings and free texts were adopted. The methodological quality of the included studies were assessed and pooled analyzed by the methods recommended by the Cochrane collaboration.A total of 5 trials containing 513 participants were included. There was a significant reduction in aspects of gestational diabetes incidence (risk ratio [RR], 0.29; 95% confidence interval (95% CI), 0.19-0.44), birth weight (mean difference [MD], -116.98; 95% CI, -208.87 to -25.09), fasting glucose oral glucose tolerance test (OGTT) (MD, -0.36; 95% CI, -0.51 to -0.21), 1-h glucose OGTT (MD, -0.63; 95% CI, -1.01 to -0.26), 2-h glucose OGTT (MD, -0.45; 95% CI, -0.75 to -0.16), and related complications (odds ratio [OR], 0.28; 95% CI 0.14-0.58).On the basis of current evidence, myo-inositol supplementation reduces the development of gestational diabetes mellitus (GDM), although this conclusion requires further evaluation in large-scale, multicenter, blinded randomized controlled trials.
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Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants.
Yang, Z, Yang, X, Wu, Y, Wang, J, Zhang, Y, Xiong, H, Jiang, Y, Qin, J
PloS one. 2014;(3):e92803
Abstract
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis.
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Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials.
Qin, X, Xu, M, Zhang, Y, Li, J, Xu, X, Wang, X, Xu, X, Huo, Y
Atherosclerosis. 2012;(2):307-13
Abstract
OBJECTIVES We conducted a meta-analysis of relevant randomized trials to assess whether folic acid supplementation reduces the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT). METHODS This analysis included 2052 subjects from ten folic acid randomized trials with the change in CIMT reported as one of the end points. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effect models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS Our analysis showed that folic acid supplementation significantly reduces the progression of CIMT (WMD: -0.04 mm; 95%CI: -0.07, -0.02; P<0.001), particularly in subjects with chronic kidney disease (CKD) (WMD: -0.16 mm; 95%CI: -0.26, -0.07; P=0.0006) or high cardiovascular disease (CVD) risk (WMD: -0.05 mm; 95%CI: -0.11, 0.00; P=0.06) but not in subjects who were generally healthy with only elevated homocysteine concentrations (WMD:0.00 mm; 95%CI: -0.01, 0.01; P=0.35). Furthermore, meta-regression analysis of the data showed that the baseline CIMT levels (P=0.011) and the percent reduction of homocysteine (P<0.001) were positively related to the effect size. Consistently, a greater beneficial effect was seen in those trials with baseline CIMT levels ≥0.8 mm (WMD: -0.14 mm; 95%CI: -0.19, -0.08; P<0.0001), and a reduction in the homocysteine concentration ≥30% (WMD: -0.22 mm; 95%CI: -0.38, -0.06; P=0.009). In the corresponding comparison groups, the effect sizes were attenuated and insignificant. CONCLUSIONS Our findings indicate that folic acid supplementation is effective in reducing the progression of CIMT, particularly in subjects with CKD or high CVD risk and among trials with higher baseline CIMT levels or a larger homocysteine reduction.