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.

B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials.

Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6 . In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research.

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.

BACKGROUND: Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. OBJECTIVE: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. DESIGN, SETTING, AND PARTICIPANTS: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incident PCa and subtype by stage and grade. RESULTS AND LIMITATIONS: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. CONCLUSIONS: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. PATIENT SUMMARY: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

No increase in risk of hip fracture at high serum retinol concentrations in community-dwelling older Norwegians: the Norwegian Epidemiologic Osteoporosis Studies.

BACKGROUND: Norway has the highest hip fracture rates worldwide and a relatively high vitamin A intake. Increased fracture risk at high intakes and serum concentrations of retinol (s-retinol) have been observed in epidemiologic studies. OBJECTIVE: We aimed to study the association between s-retinol and hip fracture and whether high s-retinol may counteract a preventive effect of vitamin D. DESIGN: We conducted the largest prospective analysis of serum retinol and hip fracture to date in 21,774 men and women aged 65-79 y (mean age: 72 y) who attended 4 community-based health studies during 1994-2001. Incident hip fractures occurring up to 10.7 y after baseline were retrieved from electronic hospital discharge registers. Retinol determined by high-pressure liquid chromatography with ultraviolet detection in stored serum was available in 1154 incident hip fracture cases with valid body mass index (BMI) data and in a subcohort defined as a sex-stratified random sample (n = 1418). Cox proportional hazards regression weighted according to the stratified case-cohort design was performed. RESULTS: There was a modest increased risk of hip fracture in the lowest compared with the middle quintile of s-retinol (HR: 1.41; 95% CI: 1.09, 1.82) adjusted for sex and study center. The association was attenuated after adjustment for BMI and serum concentrations of α-tocopherol (HR: 1.16; 95% CI: 0.88, 1.51). We found no increased risk in the upper compared with the middle quintile. No significant interaction between serum concentrations of 25-hydroxyvitamin D and s-retinol on hip fracture was observed (P = 0.68). CONCLUSIONS: We found no evidence of an adverse effect of high serum retinol on hip fracture or any interaction between retinol and 25-hydroxyvitamin D. If anything, there tended to be an increased risk at low retinol concentrations, which was attenuated after control for confounders. We propose that cod liver oil, a commonly used food supplement in Norway, should not be discouraged as a natural source of vitamin D for fracture prevention.

Periconceptional Folic Acid Supplementation and Infant Risk of Congenital Heart Defects in Norway 1999-2009.

BACKGROUND: The birth prevalence of congenital heart defects (CHDs) has decreased in Canada and Europe. Recommended intake of folic acid in pregnancy is a suggestive risk-reducing factor for CHDs. We investigated the association between periconceptional intake of folic acid supplements and infant risk of CHDs. METHODS: Information on maternal intake of folic acid supplements before and during pregnancy in the Medical Birth Registry of Norway 1999-2009 was updated with information on CHD diagnoses from national health registers and the Cardiovascular Diseases in Norway Project. The association between folic acid intake and infant risk of CHD was estimated as relative risk (RR) with binomial log linear regression. RESULTS: Among 517 784 non-chromosomal singleton births, 6200 children were identified with CHD and 1153 with severe CHD. For all births, 18.4% of the mothers initiated folic acid supplements before pregnancy and 31.6% during pregnancy. The adjusted RR for severe CHD was 0.99 [95% confidence interval [CI] 0.86, 1.13] comparing periconceptional intake of folic acid with no intake. Specifically, RR for conotruncal defects was 0.99 [95% CI 0.80, 1.22], atrioventricular septal defects 1.19 [95% CI 0.78, 1.81], left ventricular outflow tract obstructions 1.02 [95% CI 0.78, 1.32], and right ventricular outflow tract obstructions 0.97 [95% CI 0.72, 1.29]. Birth prevalence of septal defects was higher in the group exposed to folic acid supplements with RR 1.19 [95% CI 1.10, 1.30]. CONCLUSIONS: Periconceptional folic acid supplement use showed no association with severe CHDs in the newborn. An unexpected association with an increased risk of septal defects warrants further investigation.

Interactions between plasma concentrations of folate and markers of vitamin B(12) status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study.

A combination of high folate with low vitamin B12 plasma status has been associated with cognitive impairment in a population exposed to mandatory folic acid fortification. The objective of the present study was to examine the interactions between plasma concentrations of folate and vitamin B12 markers in relation to cognitive performance in Norwegian elderly who were unexposed to mandatory or voluntary folic acid fortification. Cognitive performance was assessed by six cognitive tests in 2203 individuals aged 72-74 years. A combined score was calculated using principal component analysis. The associations of folate concentrations, vitamin B12 markers (total vitamin B12, holotranscobalamin (holoTC) and methylmalonic acid (MMA)) and their interactions in relation to cognitive performance were evaluated by quantile regression and least-squares regression, adjusted for sex, education, apo-ɛ4 genotype, history of CVD/hypertension and creatinine. Cross-sectional analyses revealed an interaction (P= 0·009) between plasma concentrations of folate and vitamin B12 in relation to cognitive performance. Plasma vitamin B12 concentrations in the lowest quartile ( < 274 pmol/l) combined with plasma folate concentrations in the highest quartile (>18·5 nmol/l) were associated with a reduced risk of cognitive impairment compared with plasma concentrations in the middle quartiles of both vitamins (OR 0·22, 95 % CI 0·05, 0·92). The interaction between folate and holoTC or MMA in relation to cognitive performance was not significant. In conclusion, this large study population unexposed to mandatory folic acid fortification showed that plasma folate, but not plasma vitamin B12, was associated with cognitive performance. Among the elderly participants with vitamin B12 concentrations in the lower range, the association between plasma folate and cognitive performance was strongest.

Associations between plasma polyunsaturated fatty acids, plasma stearoyl-CoA desaturase indices and body fat.

OBJECTIVE: Stearoyl-CoA desaturase (SCD)-1 deficient mice are resistant to obesity and plasma SCD indices are related to obesity in humans. Both n-3 and n-6 polyunsaturated fatty acids (PUFA) regulate expression of the SCD enzymes. Whether higher plasma PUFA were associated with lower SCD indices in humans was examined. DESIGN AND METHODS: Population-based study of 2,021 elderly subjects from the Hordaland Health Study. Using multivariate linear regression, the cross-sectional associations among plasma PUFA, estimated SCD indices (from fatty acid profiles in plasma total lipids), and fat mass measured by dual-energy X-ray absorptiometry were explored. Two plasma SCD indices were used: SCD-16 (16:1n-7/16:0) and SCD-18 (18:1n-9/18:0). RESULTS: Plasma total, n-6 and n-3 PUFA were inversely associated with both SCD indices (P < 0.001 for all). Among the individual PUFA, 18:2n-6 showed the strongest association with SCD-16 (partial r = -0.59, P < 0.001) followed by 20:5n-3 (partial r = -0.13; P < 0.001). Plasma total, n-6 and n-3 PUFA were inversely associated with body fat (P < 0.001 for all); the associations were markedly attenuated following adjustment for SCD-16. CONCLUSIONS: The epidemiological data are in line with animal studies and suggest that PUFA may decrease SCD1 activity in humans, with possible reduction in body fat.

Cognitive performance among the elderly in relation to the intake of plant foods. The Hordaland Health Study.

Fruits and vegetables are among the most nutritious and healthy of foods, and are related to the prevention of many chronic diseases. The aim of the study was to examine the relationship between intake of different plant foods and cognitive performance in elderly individuals in a cross-sectional study. Two thousand and thirty-one elderly subjects (aged 70-74 years; 55% women) recruited from the general population in Western Norway underwent extensive cognitive testing and completed a comprehensive FFQ. The cognitive test battery covered several domains (Kendrick Object Learning Test, Trail Making Test--part A, modified versions of the Digit Symbol Test, Block Design, Mini-Mental State Examination and Controlled Oral Word Association Test). A validated and self-reported FFQ was used to assess habitual food intake. Subjects with intakes of >10th percentile of fruits, vegetables, grain products and mushrooms performed significantly better in cognitive tests than those with very low or no intake. The associations were strongest between cognition and the combined intake of fruits and vegetables, with a marked dose-dependent relationship up to about 500 g/d. The dose-related increase of intakes of grain products and potatoes reached a plateau at about 100-150 g/d, levelling off or decreasing thereafter, whereas the associations were linear for mushrooms. For individual plant foods, the positive cognitive associations of carrots, cruciferous vegetables, citrus fruits and high-fibre bread were most pronounced. The only negative cognitive association was with increased intake of white bread. In the elderly, a diet rich in plant foods is associated with better performance in several cognitive abilities in a dose-dependent manner.

Dietary intake of n-3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease.

BACKGROUND: Consumption of fish and n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) has been associated with reduced risk of coronary artery disease (CAD) mortality. OBJECTIVE: The aim was to examine the relation between dietary intake of n-3 LCPUFAs or fish and risk of future coronary events or mortality in patients with well-characterized CAD. DESIGN: This was a substudy of 2412 participants in the Western Norway B Vitamin Intervention Trial with a median follow-up time of 57 mo. Patients aged >18 y diagnosed with CAD (81% men) completed a food-frequency questionnaire at baseline, from which daily intakes of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids as well as fish were estimated on the basis of diet and intakes of supplements including fish and cod liver oils. The main endpoint was a composite of coronary events, including coronary death, nonfatal acute myocardial infarction, and unstable angina pectoris. RESULTS: The mean (+/-SD) intakes of n-3 LCPUFAs in quartiles 1-4 were 0.58 +/- 0.29, 0.83 +/- 0.30, 1.36 +/- 0.44, and 2.64 +/- 1.18 g/d, respectively. We found no dose-response relation between quartiles of n-3 LCPUFAs (based on intake as percentage of total energy) or fish and coronary events or separate endpoints. A post hoc additive proportional hazards model showed a slightly increased risk of coronary events at an intake of n-3 LCPUFAs < approximately 0.30 g/d. CONCLUSION: Among Norwegian patients with CAD consuming relatively high amounts of n-3 LCPUFAs and fish, there were no significant trends toward a reduced risk of coronary events or mortality with increasing intakes. This trial was registered at clinicaltrials.gov as NCT00354081.

Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance.

In a cross-sectional study, we examined the relation between intake of 3 common foodstuffs that contain flavonoids (chocolate, wine, and tea) and cognitive performance. 2031 participants (70-74 y, 55% women) recruited from the population-based Hordaland Health Study in Norway underwent cognitive testing. A cognitive test battery included the Kendrick Object Learning Test, Trail Making Test, part A (TMT-A), modified versions of the Digit Symbol Test, Block Design, Mini-Mental State Examination, and Controlled Oral Word Association Test. Poor cognitive performance was defined as a score in the highest decile for the TMT-A and in the lowest decile for all other tests. A self-reported FFQ was used to assess habitual food intake. Participants who consumed chocolate, wine, or tea had significantly better mean test scores and lower prevalence of poor cognitive performance than those who did not. Participants who consumed all 3 studied items had the best test scores and the lowest risks for poor test performance. The associations between intake of these foodstuffs and cognition were dose dependent, with maximum effect at intakes of approximately 10 g/d for chocolate and approximately 75-100 mL/d for wine, but approximately linear for tea. Most cognitive functions tested were influenced by intake of these 3 foodstuffs. The effect was most pronounced for wine and modestly weaker for chocolate intake. Thus, in the elderly, a diet high in some flavonoid-rich foods is associated with better performance in several cognitive abilities in a dose-dependent manner.

Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine in middle-aged and elderly men and women.

BACKGROUND: Choline and betaine are linked to phospholipid and one-carbon metabolism. Blood concentrations or dietary intake of these quaternary amines have been related to the risk of chronic diseases, including cardiovascular disease and the metabolic syndrome. OBJECTIVE: We aimed to determine dietary predictors of plasma choline and betaine among middle-aged and elderly subjects recruited from an area without folic acid fortification. DESIGN: This is a population-based study of 5812 men and women aged 47-49 and 71-74 y, within the Hordaland Health Study cohort. Plasma concentrations per increasing quartile of intake of foods, beverages, and nutrients were assessed by multiple linear regression analysis, and dietary patterns were assessed by factor analysis. RESULTS: Plasma choline was predicted by egg consumption (0.16 micromol/L; P < 0.0001) and cholesterol intake (0.16 micromol/L; P < 0.0001), and betaine was predicted by consumption of high-fiber bread (0.65 micromol/L; P < 0.0001); high-fat dairy products (-0.70 micromol/L; P < 0.0001); complex carbohydrates, fiber, folate, and thiamine (0.66-1.44 micromol/L; P

Dietary fat and plasma total homocysteine concentrations in 2 adult age groups: the Hordaland Homocysteine Study.

BACKGROUND: The intake of n-3 (formerly called omega-3) fatty acids (FAs) may be inversely associated with plasma total homocysteine (tHcy) concentrations, but the epidemiologic data are sparse. OBJECTIVE: We examined the association between dietary fat and tHcy in a Norwegian population. DESIGN: A cross-sectional, population-based study of 5917 subjects in 2 age groups (47-49 and 71-74 y old) was conducted with the use of food-frequency questionnaires and measurement of plasma tHcy concentrations. RESULTS: The intake of saturated FAs (SFAs) was positively and significantly (P for trend < 0.001) associated with tHcy concentrations; the difference in plasma tHcy concentrations between the highest and lowest quartiles of SFAs was 8.8%. The intake of marine very-long-chain n-3 FAs was inversely associated with tHcy concentrations; the difference in plasma tHcy concentrations between the lowest and the highest quartiles was -5.0% (P for trend < 0.001). Intakes of total and monounsaturated fat also were positively associated with plasma tHcy concentrations (P for trend < 0.001 and < 0.005, respectively), whereas the intake of polyunsaturated fat was positively associated with tHcy concentrations only in the younger subjects (P for trend = 0.03). The associations were weakened by additional adjustment for B vitamin intake but remained significant for SFA intake (P < 0.001). When stratified for total B vitamin intake, the inverse association between tHcy concentrations and very-long-chain n-3 FAs was significant only in the highest quartile of B vitamin intake (P for trend = 0.001), regardless of supplement use. CONCLUSIONS: High intakes of SFAs are associated with high plasma concentrations of tHcy. The inverse association between dietary intakes of very-long-chain n-3 FAs and plasma tHcy concentrations is apparent only at high B vitamin intakes.

Dietary predictors of plasma total homocysteine in the Hordaland Homocysteine Study.

Established dietary predictors of plasma total homocysteine (tHcy) include folate, riboflavin, and vitamins B6 and B12, while information is scarce regarding other dietary components. The aim of this study was to examine the relation between a variety of food groups, food items and nutrients, and plasma tHcy in a large population-based study. The study population included 5812 men and women aged 47-49 and 71-74 years who completed a 169-item FFQ. tHcy was examined across quartiles of dietary components by multiple linear regression analyses adjusting for age, sex, energy intake, various risk factors for elevated tHcy, as well as for dietary and plasma B-vitamins. Among 4578 non-users of vitamin supplements, intake of vegetables, fruits, cereals, eggs, fish and milk, as well as chicken and non-processed meats were inversely associated with tHcy level. The estimated mean difference in tHcy per increasing quartile of intake ranged from - 0.11 (95 % CI - 0.21, - 0.01) micromol/l for milk to - 0.32 (95 % CI - 0.42, - 0.22) micromol/l for vegetables. Positive associations were found for sweets and cakes. Whole-grain bread was significantly inversely related to tHcy only after additional adjustment for dietary and plasma B-vitamins. The nutrients folate, vitamin B6, B12, and riboflavin were inversely related to tHcy. Complex carbohydrates were inversely, and fat positively associated with tHcy, also after adjustment for dietary and plasma B-vitamins. In conclusion, food items rich in B-vitamins and with a low content of fat and sugar were related to lower tHcy levels. Eggs, chicken, non-processed meat, fish and milk were inversely associated with tHcy.

Plasma concentration of folate as a biomarker for the intake of fruit and vegetables: the Hordaland Homocysteine Study.

BACKGROUND: Nutritional biomarkers may be used to assess dietary exposure without the errors commonly associated with self-reported dietary data. OBJECTIVE: The objective was to examine the association between plasma folate and intake of folate, fruit, and vegetables in a large cohort of healthy adults consuming foods that had not been fortified with folic acid. DESIGN: The present study population included 5533 middle-aged (47-49 y) and old (71-74 y) subjects from the Hordaland Homocysteine Study. The participants completed a food-frequency questionnaire and provided blood samples for chemical analyses. RESULTS: We observed a significant difference in plasma concentrations of folate across increasing quartiles of fruit, vegetable, and orange juice consumption. The difference in plasma folate between the highest and lowest quartiles was 1.97 (95% CI: 1.86, 2.07) nmol/L for fruit intake, 1.79 (95% CI: 1.69, 1.89) nmol/L for vegetable intake, and 2.69 (95% CI: 2.51, 2.87) nmol/L for orange juice intake. A significant inverse relation was observed across increasing quartiles of milk and bread intakes. The difference between the highest and lowest quartiles was -1.03 (95% CI: -1.13, -0.92) nmol/L for milk and -1.60 (95% CI: -1.69, -1.50) nmol/L for bread. CONCLUSION: Plasma folate concentration may be a useful biomarker for the intake of fruit and vegetables in populations consuming unfortified food products. The association can be attenuated by and should be corrected for individual intake of folic acid supplements.

Changes in lifestyle and plasma total homocysteine: the Hordaland Homocysteine Study.

BACKGROUND: Elevated plasma concentrations of total homocysteine (tHcy) are a risk factor for cardiovascular disease. tHcy is a marker of folate and cobalamin deficiencies and is also related to several lifestyle factors. OBJECTIVE: We examined whether changes in lifestyle influence tHcy over time. DESIGN: A population-based, prospective study was conducted in 7031 subjects from western Norway who constituted 2 age groups (41-42 and 65-67 y) at baseline (1992-1993). The subjects were reinvestigated in 1997-1999 ( follow-up: 6 y). RESULTS: During follow-up, median tHcy concentrations decreased 0.10 (25th and 75th percentiles: -1.24, 1.00) micromol/L in the younger subjects and increased 0.39 (25th and 75th percentiles: -0.99, 1.79) micromol/L in the older subjects. Changes in plasma vitamin status and vitamin supplement use were the strongest determinants of changes in tHcy over time. Each unit increase in plasma folate (nmol/L) and vitamin B-12 (pmol/L) was associated with reductions in tHcy concentrations of 0.2 and 0.1 micromol/L, respectively. Among the younger and older age groups, those who started to take vitamin supplements during follow-up had significant reductions in tHcy concentrations of 0.42 (95% CI: -0.65, -0.20) and 0.41 (-0.78, -0.03) micromol/L, respectively. In the younger subjects who quit smoking, tHcy concentrations decreased 0.54 (-0.91, -0.16) micromol/L. Weight changes were inversely related to tHcy. Both baseline history of cardiovascular disease or hypertension and cardiovascular events during follow-up were significantly associated with changes in tHcy. CONCLUSIONS: Changes in lifestyle factors over time influence tHcy concentrations. These changes are modest when compared with the strong associations between tHcy and lifestyle factors in cross-sectional studies.