In this prospective Danish cohort study, supplemental folic acid was associated with an increased risk of death. None of the dietary micronutrients investigated were associated with overall mortality and neither was any other supplemental micronutrient. Effect modification was found for smoking and dietary folate, and vitamin E, and for alcohol and dietary vitamin E, whereas no effect modification by BMI was found.
The strengths of the present study include a long follow-up time, allowing accumulation of a large number of cases. The prospective design eliminated the risk of recall bias. We had complete and valid identification of all deaths and comprehensive information on dietary and supplemental micronutrients. This made precise calculations of micronutrient intake with source possible, enabling us to mutually adjust dietary and supplemental consumption of each micronutrient. Comprehensive information was also available on potential confounders.
The estimation of dietary micronutrient intake may be imprecise due to the variation in micronutrient content in different foods, varying with climate, growth, and storage. Also, use of baseline micronutrient consumption as a proxy for consumption during the entire study period may not be accurate, especially so for supplement use. However, possible bias from these factors is expected to be non-differential and should lead to bias towards the null, if any.
This study was conducted in a population with a relatively high dietary micronutrient intake (). Dietary intake of vitamin C and folate in the cohort is above the RDI (37
) for both sexes and vitamin E also for women. For beta-carotene no RDI exists. This suggests a population that is by no means deprived in micronutrient status. For poorly nourished populations, previous studies have suggested beneficial effects of micronutrient supplements in relation to mortality (38
), whereas randomised, controlled trials (RCTs) on micronutrient supplements and overall mortality in well-nourished adult populations have consistently not shown any effects of supplementation on risk of death (41
), or even increased risk (7
), in line with our finding of no beneficial effects of adding micronutrient supplements to the diet.
In contrast, we found a significantly increased risk of death with supplemental folic acid. Folic acid from supplements have, in RCTs, been associated with an increased risk of colorectal adenomas (12
), prostate cancer (11
), lung cancer and mortality (47
), and evidence is accumulating that folate may play a dual role in carcinogenesis with harmful effects among persons harbouring pre-neoplastic lesions (48
). No general tendency towards beneficial or harmful effects of folic acid supplementation has been found in RCTs on cardiovascular disease (13
). However, the detrimental effect of supplemental folic acid could be explained by an increased cancer risk alone. In previous studies examining supplemental folic acid in relation to lung, colorectal, breast, and bladder cancer in the Diet, Cancer and Health cohort, we have, however, not found increased incidence of these (50
). And when considering cause-specific mortality in this study, information that was available for participants deceased up until December 31, 2008, we found no association with cancer (IRR: 1.01; 95% CI: 0.99–1.04) or cardiovascular disease (IRR: 0.96; 95% CI: 0.86–1.07), but an increased risk of endocrine, nutritional, and metabolic disorders (IRR: 1.05; 95% CI: 1.03–1.07), diseases of the respiratory system (IRR: 1.04; 95% CI: 1.01–1.07), and diseases of the digestive system: (IRR: 1.04; 95% CI: 1.01–1.06). The primary source of supplemental folic acid in the Diet, Cancer and Health cohort is multivitamins, followed by vitamin B complexes, or single folic acid supplements, but we did not have comprehensive information regarding folic acid source, allowing consideration of different effects of the diverse supplements. Other vitamin Bs associated with folic acid in vitamin B complexes may therefore be the true active ingredient. Control for intake of vitamin B1
, and B12
did however not materially alter the estimate (IRR: 1.02; 95% CI: 1.00–1.03), suggesting that these could not fully explain the harmful effect.
With regards to effect modification by lifestyle factors, dietary vitamin E was associated with a decreased mortality among current smokers and those with an alcohol intake above 10 g/day ( and ), and dietary folate was associated with an increased mortality among never smokers only (). These findings could be due to limited statistical power in the sub-groups defined by never/former smoking or abstinence/low alcohol intake, as a number of cases in these groups is substantially lower. Apart from the group of abstainers, however, the number of cases should be high enough to show an association if one was present. It is, therefore, also possible that these findings are the result of multiple testing or that they are caused by current smokers who neglect to inform about their true smoking status, leading to differential misclassification of these participants. And as smokers will often also have a lower dietary micronutrient intake (54
), this will skew the association towards being harmful among never smokers and beneficial among smokers. We would, however, then expect to see a similar effect modification by vitamin C and beta-carotene. Smoking and alcohol are also known to lower the bioavailability of micronutrients (56
) and if these do indeed have harmful effects in relation to mortality, it is possible that these are cushioned by current smoking or a high alcohol intake. Another explanation for the findings could also be that only current smokers and those with a high alcohol intake have an additional benefit of a healthy diet. A similar effect of vitamin C and beta-carotene should, however, be expected then. Further studies examining effect modification by these factors are required.
The results of this study suggest that supplements containing the four included micronutrients have no effect in relation to overall mortality in a population of well-nourished Danes. In contrast, the only overall effect seems to be a harmful effect of supplemental folate. This finding, however, needs further scrutinising, as it does not seem to be a strong and consistent finding across different strata in the study where conflicting results are seen.
In conclusion, the results of this prospective observational study in a cohort of middle-aged Danes indicate no beneficial effect of dietary micronutrient intake in relation to mortality, suggesting that if these play a role in health and survival, it may be minor and related to specific outcomes, not generating an effect that can be seen in relation to overall mortality in a generally well-nourished population. A significantly increased risk of death with supplemental folic acid was found, which is in line with studies finding increased cancer incidence of folic acid supplementation. Finally, effect modification by smoking and alcohol was suggested and needs further exploration.