0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation | Health Care Reform

Dietary Supplements and Mortality Rate in Older Women:  The Iowa Women's Health Study FREE

Jaakko Mursu, PhD; Kim Robien, PhD; Lisa J. Harnack, DrPH, MPH; Kyong Park, PhD; David R. Jacobs, PhD
[+] Author Affiliations

Author Affiliations: Department of Health Sciences, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland (Dr Mursu); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (Drs Mursu, Robien, Harnack, and Jacobs); Department of Food and Nutrition, Yeungnam University, Gyeongbuk, Republic of Korea (Dr Park); and Department of Nutrition, School of Medicine, University of Oslo, Oslo, Norway (Dr Jacobs).


Arch Intern Med. 2011;171(18):1625-1633. doi:10.1001/archinternmed.2011.445.
Text Size: A A A
Published online

Background Although dietary supplements are commonly taken to prevent chronic disease, the long-term health consequences of many compounds are unknown.

Methods We assessed the use of vitamin and mineral supplements in relation to total mortality in 38 772 older women in the Iowa Women's Health Study; mean age was 61.6 years at baseline in 1986. Supplement use was self-reported in 1986, 1997, and 2004. Through December 31, 2008, a total of 15 594 deaths (40.2%) were identified through the State Health Registry of Iowa and the National Death Index.

Results In multivariable adjusted proportional hazards regression models, the use of multivitamins (hazard ratio, 1.06; 95% CI, 1.02-1.10; absolute risk increase, 2.4%), vitamin B6 (1.10; 1.01-1.21; 4.1%), folic acid (1.15; 1.00-1.32; 5.9%), iron (1.10; 1.03-1.17; 3.9%), magnesium (1.08; 1.01-1.15; 3.6%), zinc (1.08; 1.01-1.15; 3.0%), and copper (1.45; 1.20-1.75; 18.0%) were associated with increased risk of total mortality when compared with corresponding nonuse. Use of calcium was inversely related (hazard ratio, 0.91; 95% confidence interval, 0.88-0.94; absolute risk reduction, 3.8%). Findings for iron and calcium were replicated in separate, shorter-term analyses (10-year, 6-year, and 4-year follow-up), each with approximately 15% of the original participants having died, starting in 1986, 1997, and 2004.

Conclusions In older women, several commonly used dietary vitamin and mineral supplements may be associated with increased total mortality risk; this association is strongest with supplemental iron. In contrast to the findings of many studies, calcium is associated with decreased risk.

Figures in this Article

In the United States, the use of dietary supplements has increased substantially during the past several decades,13 reaching approximately one-half of adults in 2000, with annual sales of more than $20 billion.1,3 Sixty-six percent of women participating in the Iowa Women's Health Study2 used at least 1 dietary supplement daily in 1986 at an average age of 62 years; in 2004, the proportion increased to 85%. Moreover, 27% of women reported using 4 or more supplemental products in 2004.2 At the population level, dietary supplements contributed substantially to the total intake of several nutrients, particularly in elderly individuals.1,2

Supplemental nutrient intake clearly is beneficial in deficiency conditions.4 However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic diseases. Results of epidemiologic studies59 assessing supplement use and total mortality risk have been inconsistent. Several randomized controlled trials (RCTs),10,11 concentrating mainly on calcium and vitamins B, C, D, and E, have not shown beneficial effects of dietary supplements on total mortality rate; in contrast, some12,13 have suggested the possibility of harm. Meta-analyses14,15 concur in finding no decreased risk and potential harm. Supplements are widely used, and further studies regarding their health effects are needed. Also, little is known about the long-term effects of multivitamin use and less commonly used supplements, such as iron and other minerals.

The aim of the present study was to assess the relationship between supplement use and total mortality rate in older women in the Iowa Women's Health Study. Our hypothesis, based on the findings of a previous study by some of us,2 was that the use of dietary supplements would not be associated with a reduced rate of total mortality.

The Iowa Women's Health Study16 was designed to examine associations between several host, dietary, and lifestyle factors and the incidence of cancer in postmenopausal women. At the study baseline in 1986, a total of 41 836 women aged 55 to 69 years completed a 16-page self-administered questionnaire. Of these women, 99.2% were white and 98.6% were postmenopausal. Respondents were slightly younger, had lower body mass index (calculated as weight in kilograms divided by height in meters squared), and were more likely to live in rural areas compared with nonrespondents.17 The Iowa Women's Health Study was approved by the University of Minnesota Institutional Review Board; return of the questionnaire was considered to indicate informed consent, concordant with prevailing practice in 1986.

We included 38 772 women, excluding from all analyses those who did not adequately complete a questionnaire including food frequency and supplement use at baseline in 1986.2 For the analyses starting in 1997, a total of 29 230 women who filled out the supplement use questionnaire (diet data were not assessed) were included. In the 2004 starting analysis, 19 124 women were included. The study flow is shown in the Figure.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Flowchart for the Iowa Women's Health Study. FFQ indicates Food Frequency Questionnaire.

SUPPLEMENT USE AND DIETARY INFORMATION

Food intake was assessed at baseline and in the 2004 follow-up, using 2 nearly identical versions of the validated 127-food item Harvard Service Food Frequency Questionnaire.18,19 Food composition values were obtained from the Harvard University Food Composition Database derived from US Department of Agriculture sources, supplemented with manufacturer information, and updated to reflect marketplace changes.

Supplement use was queried in 1986, 1997, and 2004 and included the 15 supplements assessed at all 3 surveys: multivitamins; vitamins A, beta-carotene, B6, folic acid, B complex, C, D, and E; and minerals iron, calcium, copper, magnesium, selenium, and zinc. Different forms of vitamin D, cholecalciferol (D3) or ergocalciferol (D2), were not distinguished. At the baseline and 2004 follow-up surveys, the supplement-related questions were part of the Food Frequency Questionnaire. In the 1997 follow-up survey, the supplement questions were asked without querying regarding diet. Dose was assessed uniformly across 3 surveys for vitamins A, B6, C, D, and E and for minerals calcium, iron, selenium, and zinc with 5 supplement-specific response options (no dose information was collected for vitamin B6 at baseline or for vitamin D in 2004). Although the dietary supplement portion of the Food Frequency Questionnaire used in the study was not validated separately,19 an evaluation20 with similar instruments has reported validity correlations of approximately 0.8.

ASCERTAINMENT AND CLASSIFICATION OF MORTALITY

Deaths through December 31, 2008, were identified annually through the State Health Registry of Iowa or the National Death Index for participants who did not respond to the follow-up questionnaires or who had emigrated from Iowa. Underlying cause of death was assigned by state vital registries via the International Classification of Diseases (ICD). We defined all cardiovascular disease (CVD) by ICD-9 codes 390-459 or ICD-10 codes I00-I99, cancer by codes 140-239 or C00-D48, and “other cause of death” for all other deaths, excluding 231 of those related to injury, accident, and suicide, because it is unlikely that supplement use would be causally related to these outcomes. Follow-up duration was calculated as the time from the baseline date to the date of death or to the last follow-up contact or December 31, 2008, whichever came first.

OTHER MEASUREMENTS

The baseline questionnaire included questions concerning potential confounders including age, height, educational level, place of residence (farm, rural area other than a farm, or city), diabetes mellitus, high blood pressure, weight, hormone replacement therapy, physical activity, and smoking status. As previously described,2 physical activity was characterized as participating in moderate or vigorous activities less than a few times per month, a few times per month or once per week, or 2 or more times per week. Waist and hip circumferences were measured by each participant using a fixed protocol.20

The 1986 and 2004 questionnaires included the same questions and in a similar form except that educational level, place of residence, and waist and hip circumferences were not reassessed. The only questions that the 1997 questionnaire included in common with the 1986 and 2004 questionnaires were those regarding diabetes mellitus, weight, high blood pressure, hormone replacement therapy, and smoking status. Neither blood lipid levels nor blood pressure were measured in any survey.

DATA ANALYSES

Analyses were performed using statistical software (PC-SAS, version 9.2; SAS Institute, Inc, Cary, North Carolina). Continuous variables were compared using analysis of variance and categorical variables using χ2 tests. Cumulative mortality rates by supplement use were examined. Absolute risk increase (ARI) and absolute risk reduction (ARR) were calculated by multiplying the absolute risk in the reference group by the multivariable-adjusted hazard ratio (HR) change in the comparison group. Cox proportional hazards regression analyses were used to explore the relationship between supplement use and outcomes. In the minimally adjusted model, we adjusted the association for age and energy intake; in multivariable adjusted model, version 1, we additionally adjusted for educational level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone replacement therapy, physical activity, and smoking status. For multivariable adjusted model, version 2, we added intake of alcohol, saturated fatty acids, whole grain products, fruits, and vegetables.

Additional analyses were performed for shorter follow-up intervals; in each of the following periods, approximately 15% of deaths occurred: from 1986 until the end of 1996, from 1997 until the end of 2003, and from 2004 until the end of 2008. Data including supplement use from the corresponding interval questionnaire were used whenever available. Covariate adjustment was performed, as described in the previous paragraph. For analyses starting in 1997, current covariate data were available for diabetes mellitus, high blood pressure, body mass index, hormone replacement therapy, and smoking status. For analyses starting in 2004, current data were available for all covariates except educational level, place of residence, and waist to hip ratio. When current data were unavailable, information from 1986 was used.

Among the 38 772 women (mean [SD] age, 61.6 [4.2] years) followed up from the 1986 questionnaire data, 15 594 deaths (40.2%) occurred during the mean follow-up time of 19.0 years. Mean body mass index was 27.0 (5.1); 36.8% of the respondents reported high blood pressure; 6.8%, diabetes mellitus; and 15.1%, current smoking status. At baseline, compared with nonusers, supplement users had a lower prevalence of diabetes mellitus, high blood pressure, and smoking status; a lower BMI and waist to hip ratio; and were less likely to live on a farm. Supplement users had a higher educational level, were more physically active, and were more likely to use estrogen replacement therapy (Table 1). Also, supplement users were more likely to have lower intake of energy, total fat, and monounsaturated fatty acids, saturated fatty acids and to have higher intake of protein, carbohydrates, polyunsaturated fatty acids, alcohol, whole grain products, fruits, and vegetables. Similar patterns were seen in the 2004 questionnaire among 19 124 women (Table 1) and for individual supplements (eg, iron and calcium) (eTable 1).

Table Graphic Jump LocationTable 1. Characteristics of Women From the Iowa Women's Health Study Who Completed Questionnairesa

Self-reported use of dietary supplements increased substantially between 1986 and 2004.2 In 1986, 1997, and 2004, 62.7%, 75.1%, and 85.1% of the women, respectively, reported using at least 1 supplement daily. The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E (eTable 2); the most common supplement combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

At baseline, in Cox proportional hazards regression models with full follow-up time and adjusted for age and energy intake, self-reported use of vitamin B complex; vitamins C, D, and E; and calcium had significantly lower risk of total mortality compared with nonuse; copper was associated with higher risk (Table 2). With further adjustment (dose in multivariable adjusted model version 1), only the use of calcium retained a significantly lower risk of mortality (HR, 0.92; ARR, 3.5%); the other inverse associations were attenuated to nonsignificance. In contrast, further adjustment for nonnutritional factors strengthened several associations to significance that had HR higher than 1 in the minimal model: multivitamins (HR, 1.06; ARI, 2.2%), vitamin B6 (1.09; 3.5%), and iron (1.09; 3.8%). Further adjustment for nutritional factors (version 2) affected the associations further: multivitamins (HR, 1.06; ARI, 2.4%), vitamin B6 (1.10; 4.1%), folic acid (1.15; 5.9%), calcium (0.91; 3.8%), copper (1.45; 18.0%), iron (1.10; 3.9%), magnesium (1.08; 3.6%), and zinc (1.08; 3.0%).

Table Graphic Jump LocationTable 2. Adjusted HR (95% CI) for the Use of Supplements and Risk of Total Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Studya

In sensitivity analyses excluding women who had CVD or diabetes mellitus (n = 5772) or cancer (n = 3523) at baseline, the results were not materially changed. For example, for iron, the multivariable adjusted HR for total mortality was 1.13 (95% CI, 1.05-1.22). Parallel to the situation with total mortality rate, most supplements were unrelated to or showed higher cause-specific mortality rate in multivariable adjusted model version 2, although risk patterns varied across causes (Table 3).

Table Graphic Jump LocationTable 3. Adjusted HR (95% CI) for the Use of Supplements and Risk of Disease-Specific Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Study

In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire (Table 4), the most consistent findings in multivariable adjusted model version 2 were for supplemental iron (HR, 1.20, 1.43, and 1.56; ARI, 2.2%, 5.5%, and 6.6%, respectively) and calcium (0.89, 0.90, and 0.88; ARR, 1.4%, 1.5%, and 1.8%, respectively). Supplemental folic acid tended toward higher risk, significant only in the last interval (HR, 1.28, 1.19, and 1.27; ARI, 3.0%, 2.6%, and 3.4%, respectively).

Table Graphic Jump LocationTable 4. Adjusted HR (95% CI) for the Use of Supplements and Risk of Total Mortality Across 3 Separate Follow-up Periods in Women Aged 55-69 Years at Baseline From the Iowa Women's Health Study

Dose-response associations could be computed for selected supplements. The inverse association with calcium was lost at its highest dose (Table 5). For supplemental iron, a dose-response relationship was observed in the full follow-up cohort starting in 1986. In the dose-response interval analyses, significantly increased risk was seen at progressively lower doses as the women aged through baseline in 1986, to baseline in 1997, to baseline in 2004. For vitamins A, C, D, and E, as well as minerals selenium and zinc, no dose-response association was found. These dose-response associations persisted after women with a history of CVD, diabetes mellitus, or cancer at baseline were excluded.

Table Graphic Jump LocationTable 5. Multivariable Adjusted HR (95% CI) for the Dose of Calcium and Iron Supplements and Risk of Total Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Studya

For supplemental iron, we also studied the consistency of reported use across surveys and total mortality among 16 841 women who completed all 3 questionnaires. Compared with measures for nonusers, the multivariable adjusted HRs for users were 1.35 (95% CI, 1.20-1.52) for use reported at 1 survey, 1.62 (1.30-2.01) for use reported at 2 surveys, and 1.60 (1.04-2.46) for use reported at all 3 surveys.

In agreement with our hypothesis, most of the supplements studied were not associated with a reduced total mortality rate in older women. In contrast, we found that several commonly used dietary vitamin and mineral supplements, including multivitamins, vitamins B6, and folic acid, as well as minerals iron, magnesium, zinc, and copper, were associated with a higher risk of total mortality. Of particular concern, supplemental iron was strongly and dose dependently associated with increased total mortality risk. Also, the association was consistent across shorter intervals, strengthened with multiple use reports and with increasing age at reported use. Supplemental calcium was consistently inversely related to total mortality rate; however, no clear dose-response relationship was observed.

Previous studies summarized in a systematic review21 provide little support for our findings, suggesting beneficial effects of calcium on total mortality rate; in prospective cohorts and RCTs, vitamin D supplementation, but not calcium, was found to be associated with a nonsignificant reduction in CVD mortality. The pooled HR for the CVD risk in RCTs was 0.90 (95% CI, 0.77-1.05) for vitamin D and 1.14 (0.92-1.41) for calcium. We found no evidence for a benefit of vitamin D against total mortality.

The evidence regarding a possible harmful effect of supplemental iron is limited. Pocobelli et al6 found that men in the highest category of average 10-year dose of supplemental iron had a 27% increased risk of total mortality compared with nonusers in age- and sex-adjusted models. The association was, however, attenuated after multivariable adjustment. High iron stores, measured as serum ferritin, have been found to be related to increased risk of CVD in 2 studies22,23 but not in another.24 Although we did not evaluate the possible mechanism, iron is suggested25 to catalyze reactions that produce oxidants and thus promote oxidative stress. However, we cannot rule out the possibility that the increase in total mortality rate was caused by illnesses for which use of iron supplements is indicated. Chronic disease, major injury, and/or operations may cause anemia, which is then treated with supplemental iron. However, we could find no evidence for such reverse causality. Iron supplementation was related to future mortality rate even 19 years later in women free of CVD, diabetes mellitus, and cancer; baseline covariates of iron use were not greatly different from those of other supplements; and progressively lower doses were associated with excess risk as the women aged.

Increased blood homocysteine concentrations are considered to be a modifiable risk factor for CVD.26 In RCTs,14,27 folic acid, vitamin B6, and vitamin B12 or their combinations have decreased blood homocysteine concentrations but failed to reduce the risk of CVD. In contrast, use of B vitamins has been found to be related to an increased risk of CVD in one study. Ebbing et al13 found that the combination of folic acid and B12 supplementation increased the risk of mortality from all causes and from cancer in an RCT setting.

We are not aware of any long-term RCTs studying the effects of daily multivitamins on total mortality rate; epidemiologic studies5,79 have not provided evidence of benefit. Observational findings regarding the antioxidant supplements selenium, beta-carotene, and vitamins A, C, and E and total mortality have been inconsistent,5,6,9 although the use of vitamins C and E has been found to be related with reduced risk of all-cause mortality in 2 studies.5,9 For supplemental vitamin A and beta-carotene, an observational study6 has not provided evidence of benefit for total mortality rate. In RCTs,10,11 supplementation with selenium, beta-carotene, or vitamins A, C, or E has not been found to be beneficial relative to total mortality rate in well-nourished populations, and some studies12,13 have suggested this practice yields harm.

Strengths of the current study include the large sample size and longitudinal design. Also, the use of dietary supplements was queried 3 times: at baseline in 1986, 1997, and 2004. The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified.

Our study also has limitations. An intermediate event, such as CVD or cancer, can induce a change in supplement use and confound the exposure-outcome association. In our data, the use of supplements was not modified by a prebaseline diagnosis of CVD, diabetes mellitus, or cancer. Furthermore, intermediate cancer did not alter the supplement-taking pattern. It is possible that despite extensive adjustment, residual confounding remained. The use of dietary supplements is related to healthier lifestyle,1,2 thus leading to apparently inverse associations with total mortality rate. The associations found after adjustment for lifestyle factors are more accurate from a perspective of a causal relationship. However, we cannot exclude the possibility that some supplements were taken for reasonable cause in response to symptoms or clinical disease. We did not have data regarding nutritional status or detailed information of supplements used. Also, the study population consisted only of white women; thus, generalization to other populations, ethnic groups, or men could be questioned. Because our primary hypothesis concerning supplement use and total mortality rate with covariate adjustment included 15 separate tests, a conservative Bonferroni approach would require a P value of .05/15.00 = .003. However, many of the additional statistical tests were confirmatory, strengthening confidence that findings were not explainable by chance.

Among the elderly population, the use of dietary supplements is widespread,13 and supplements often are used with the intention of attaining health benefits by preventing chronic diseases. Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety. Also, cumulative effects of widespread supplement use, together with food fortification, have raised concern regarding exceeding upper recommended levels and, thus, regarding long-term safety.1 It is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous RCT testing, and observational studies are often the best-available method for assessing the safety of long-term use. Based on existing evidence, we see little justification for the general and widespread use of dietary supplements. We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease.

In conclusion, in this large prospective cohort of older women, we found that most dietary supplements were unrelated to total mortality rate. However, several commonly used dietary vitamin and mineral supplements were associated with increased total mortality rate, most strongly supplemental iron; calcium showed some evidence of lower risk.

Correspondence: Jaakko Mursu, PhD, Department of Health Sciences, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, PO Box 1627, 70211 Kuopio, Finland (jaakko.mursu@uef.fi).

Accepted for Publication: June 6, 2011.

Author Contributions: Dr Mursu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jacobs. Acquisition of data: Robien, Harnack, and Jacobs. Analysis and interpretation of data: Mursu and Jacobs. Drafting of the manuscript: Mursu and Jacobs. Critical revision of the manuscript for important intellectual content: Mursu, Robien, Harnack, Park, and Jacobs. Statistical analysis: Mursu and Jacobs. Obtained funding: Robien, Harnack, and Jacobs. Administrative, technical, and material support: Robien, Harnack, and Jacobs.

Financial Disclosure: Dr Jacobs is an unpaid member of the Scientific Advisory Board of the California Walnut Commission.

Funding/Support: This study was partially supported by grant R01 CA39742 from the National Cancer Institute and by grant 131209 from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program's Research Grant for a Junior Scholar (the last 2 of which were granted to Dr Mursu).

Role of the Sponsors: The sponsors did not play a role in the conception, design, or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.

National Institutes of Health State-of-the-Science Panel.  National Institutes of Health State-of-the-Science conference statement: multivitamin/mineral supplements and chronic disease prevention.  Ann Intern Med. 2006;145(5):364-371
PubMed
Park K, Harnack L, Jacobs DR Jr. Trends in dietary supplement use in a cohort of postmenopausal women from Iowa.  Am J Epidemiol. 2009;169(7):887-892
PubMed   |  Link to Article
Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000.  Am J Epidemiol. 2004;160(4):339-349
PubMed   |  Link to Article
Silver HJ. Oral strategies to supplement older adults' dietary intakes: comparing the evidence.  Nutr Rev. 2009;67(1):21-31
PubMed   |  Link to Article
Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW Jr. Multivitamin use and mortality in a large prospective study.  Am J Epidemiol. 2000;152(2):149-162
PubMed   |  Link to Article
Pocobelli G, Kristal AR, Patterson RE,  et al.  Total mortality risk in relation to use of less-common dietary supplements.  Am J Clin Nutr. 2010;91(6):1791-1800
PubMed   |  Link to Article
Neuhouser ML, Wassertheil-Smoller S, Thomson C,  et al.  Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts.  Arch Intern Med. 2009;169(3):294-304
PubMed   |  Link to Article
Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality and cancer incidence: the Multiethnic Cohort Study.  Am J Epidemiol. 2011;173(8):906-914
PubMed   |  Link to Article
Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality.  Am J Epidemiol. 2009;170(4):472-483
PubMed   |  Link to Article
Sesso HD, Buring JE, Christen WG,  et al.  Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.  JAMA. 2008;300(18):2123-2133
PubMed   |  Link to Article
Lee I-M, Cook NR, Manson JE, Buring JE, Hennekens CH. β-Carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.  J Natl Cancer Inst. 1999;91(24):2102-2106
PubMed   |  Link to Article
Albanes D, Heinonen OP, Huttunen JK,  et al.  Effects of α-tocopherol and β-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.  Am J Clin Nutr. 1995;62(6):(suppl)  1427S-1430S
PubMed
Ebbing M, Bønaa KH, Nygård O,  et al.  Cancer incidence and mortality after treatment with folic acid and vitamin B12 JAMA. 2009;302(19):2119-2126
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.  JAMA. 2007;297(8):842-857
PubMed   |  Link to Article
Folsom AR, Kushi LH, Anderson KE,  et al.  Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study.  Arch Intern Med. 2000;160(14):2117-2128
PubMed   |  Link to Article
Bisgard KM, Folsom AR, Hong CP, Sellers TA. Mortality and cancer rates in nonrespondents to a prospective study of older women: 5-year follow-up.  Am J Epidemiol. 1994;139(10):990-1000
PubMed
Willett WC, Sampson L, Browne ML,  et al.  The use of a self-administered questionnaire to assess diet four years in the past.  Am J Epidemiol. 1988;127(1):188-199
PubMed
Munger RG, Folsom AR, Kushi LH, Kaye SA, Sellers TA. Dietary assessment of older Iowa women with a food frequency questionnaire: nutrient intake, reproducibility, and comparison with 24-hour dietary recall interviews.  Am J Epidemiol. 1992;136(2):192-200
PubMed
Murphy SP, Wilkens LR, Hankin JH,  et al.  Comparison of two instruments for quantifying intake of vitamin and mineral supplements: a brief questionnaire versus three 24-hour recalls.  Am J Epidemiol. 2002;156(7):669-675
PubMed   |  Link to Article
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events.  Ann Intern Med. 2010;152(5):315-323
PubMed
Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.  Circulation. 1992;86(3):803-811
PubMed   |  Link to Article
Salonen JT, Nyyssönen K, Salonen R. Body iron stores and the risk of coronary heart disease.  N Engl J Med. 1994;331(17):1159-1160
PubMed   |  Link to Article
Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies.  Circulation. 1999;99(7):852-854
PubMed   |  Link to Article
Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease.  Toxicology. 2011;283(2-3):65-87
PubMed   |  Link to Article
Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis.  Mayo Clin Proc. 2008;83(11):1203-1212
PubMed   |  Link to Article
Clarke R, Halsey J, Lewington S,  et al; B-Vitamin Treatment Trialists' Collaboration.  Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals.  Arch Intern Med. 2010;170(18):1622-1631
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. Flowchart for the Iowa Women's Health Study. FFQ indicates Food Frequency Questionnaire.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Women From the Iowa Women's Health Study Who Completed Questionnairesa
Table Graphic Jump LocationTable 2. Adjusted HR (95% CI) for the Use of Supplements and Risk of Total Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Studya
Table Graphic Jump LocationTable 3. Adjusted HR (95% CI) for the Use of Supplements and Risk of Disease-Specific Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Study
Table Graphic Jump LocationTable 4. Adjusted HR (95% CI) for the Use of Supplements and Risk of Total Mortality Across 3 Separate Follow-up Periods in Women Aged 55-69 Years at Baseline From the Iowa Women's Health Study
Table Graphic Jump LocationTable 5. Multivariable Adjusted HR (95% CI) for the Dose of Calcium and Iron Supplements and Risk of Total Mortality in Women Aged 55-69 y at Baseline From the Iowa Women's Health Studya

References

National Institutes of Health State-of-the-Science Panel.  National Institutes of Health State-of-the-Science conference statement: multivitamin/mineral supplements and chronic disease prevention.  Ann Intern Med. 2006;145(5):364-371
PubMed
Park K, Harnack L, Jacobs DR Jr. Trends in dietary supplement use in a cohort of postmenopausal women from Iowa.  Am J Epidemiol. 2009;169(7):887-892
PubMed   |  Link to Article
Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000.  Am J Epidemiol. 2004;160(4):339-349
PubMed   |  Link to Article
Silver HJ. Oral strategies to supplement older adults' dietary intakes: comparing the evidence.  Nutr Rev. 2009;67(1):21-31
PubMed   |  Link to Article
Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW Jr. Multivitamin use and mortality in a large prospective study.  Am J Epidemiol. 2000;152(2):149-162
PubMed   |  Link to Article
Pocobelli G, Kristal AR, Patterson RE,  et al.  Total mortality risk in relation to use of less-common dietary supplements.  Am J Clin Nutr. 2010;91(6):1791-1800
PubMed   |  Link to Article
Neuhouser ML, Wassertheil-Smoller S, Thomson C,  et al.  Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts.  Arch Intern Med. 2009;169(3):294-304
PubMed   |  Link to Article
Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality and cancer incidence: the Multiethnic Cohort Study.  Am J Epidemiol. 2011;173(8):906-914
PubMed   |  Link to Article
Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality.  Am J Epidemiol. 2009;170(4):472-483
PubMed   |  Link to Article
Sesso HD, Buring JE, Christen WG,  et al.  Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.  JAMA. 2008;300(18):2123-2133
PubMed   |  Link to Article
Lee I-M, Cook NR, Manson JE, Buring JE, Hennekens CH. β-Carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.  J Natl Cancer Inst. 1999;91(24):2102-2106
PubMed   |  Link to Article
Albanes D, Heinonen OP, Huttunen JK,  et al.  Effects of α-tocopherol and β-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.  Am J Clin Nutr. 1995;62(6):(suppl)  1427S-1430S
PubMed
Ebbing M, Bønaa KH, Nygård O,  et al.  Cancer incidence and mortality after treatment with folic acid and vitamin B12 JAMA. 2009;302(19):2119-2126
PubMed   |  Link to Article
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA. 2006;296(22):2720-2726
PubMed   |  Link to Article
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.  JAMA. 2007;297(8):842-857
PubMed   |  Link to Article
Folsom AR, Kushi LH, Anderson KE,  et al.  Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study.  Arch Intern Med. 2000;160(14):2117-2128
PubMed   |  Link to Article
Bisgard KM, Folsom AR, Hong CP, Sellers TA. Mortality and cancer rates in nonrespondents to a prospective study of older women: 5-year follow-up.  Am J Epidemiol. 1994;139(10):990-1000
PubMed
Willett WC, Sampson L, Browne ML,  et al.  The use of a self-administered questionnaire to assess diet four years in the past.  Am J Epidemiol. 1988;127(1):188-199
PubMed
Munger RG, Folsom AR, Kushi LH, Kaye SA, Sellers TA. Dietary assessment of older Iowa women with a food frequency questionnaire: nutrient intake, reproducibility, and comparison with 24-hour dietary recall interviews.  Am J Epidemiol. 1992;136(2):192-200
PubMed
Murphy SP, Wilkens LR, Hankin JH,  et al.  Comparison of two instruments for quantifying intake of vitamin and mineral supplements: a brief questionnaire versus three 24-hour recalls.  Am J Epidemiol. 2002;156(7):669-675
PubMed   |  Link to Article
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events.  Ann Intern Med. 2010;152(5):315-323
PubMed
Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men.  Circulation. 1992;86(3):803-811
PubMed   |  Link to Article
Salonen JT, Nyyssönen K, Salonen R. Body iron stores and the risk of coronary heart disease.  N Engl J Med. 1994;331(17):1159-1160
PubMed   |  Link to Article
Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies.  Circulation. 1999;99(7):852-854
PubMed   |  Link to Article
Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease.  Toxicology. 2011;283(2-3):65-87
PubMed   |  Link to Article
Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis.  Mayo Clin Proc. 2008;83(11):1203-1212
PubMed   |  Link to Article
Clarke R, Halsey J, Lewington S,  et al; B-Vitamin Treatment Trialists' Collaboration.  Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals.  Arch Intern Med. 2010;170(18):1622-1631
PubMed   |  Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment
Posted on October 12, 2011
Marcia K Roark, BSN
retired nurse
Conflict of Interest: None Declared
My question is: what other health issues were going on with these subjects(not mentioned in the abstract) that may have contributed to the mortality rates, and how does it differ from the general death rate of this population? This assumption of relationship is quite a leap, when nothing is mentioned about environment, genetic predisposition, obesity,smoking, etc. Also, self-reporting of supplements is often unreliable. Thanks for any light you can shed on this issue. Sincerely,
Marcia Roark

Conflict of Interest: None declared
Dietary Supplements and Mortality Rate in Older Women
Posted on October 14, 2011
Pamela B. Baines, MD
Pamela B. Baines, MD, PA
Conflict of Interest: None Declared
One suspects, from reading the conclusions of this study, that the authors have a bias against nutritional supplements, particularly vitamins. Observational studies typically cannot demonstrate causality, so attributing a risk to vitamin supplements is a stretch, plus the degree of risk presented does not appear to be significant. If you look at the situation with iron supplements, most women (other than those hooked on Geritol), do not normally take supplemental iron without a perceived need, such as a diagnosis of anemia. An underlying medical condition such as anemia might be expected to increase relative mortality risk over the 16- year period examined, and would be a significant confounding factor. I am concerned that the media and many physicians will now scare patients who should be taking supplemental vitamins or minerals into stopping them.
Conflict of Interest: None declared
What does the highly publicized recent study tell us about supplement use?
Posted on November 21, 2011
Douglas MacKay, ND
Council for Responsible Nutrition
Conflict of Interest: None Declared
The methodology used to identify “users” and “non-users” (Table 2) and used throughout the data analysis is flawed. Given that the cohort of supplement users demonstrated improved biomarkers of good health and healthy lifestyle habits, an overall comparison of “users” to “non-users” of dietary supplements is an important omission in the manuscript. If such a comparison demonstrated decreased or no change in risk of total mortality, this finding would significantly weaken the relevance of individual findings for multivitamins, vitamin B6, copper, and iron. A finding of reduced or decreased risk for all “users” combined would challenge the authors’ conclusions about risks associated with vitamin and mineral use. The manuscript excluded a full discussion of recent studies on the same topic, such as the “Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study” by Park et al (8). This study included 182,099 participants, both men and women, from multiple ethnic backgrounds. Park et al found no associations between multivitamin use and mortality from all causes, cardiovascular diseases, or cancer in “users” vs. “non-users.” The findings did not vary across subgroups by ethnicity, age, body mass index, pre-existing illness, single vitamin/mineral supplement use, hormone replacement therapy use, or smoking status. There also was no evidence indicating that multivitamin use was associated with risk of cancer, overall or at major sites such as lung, colon/rectum, prostate, and breast. In conclusion, there was no clear decrease or increase in mortality from all causes, cardiovascular disease, or cancer, nor in morbidity from overall or major cancers among multivitamin supplement users (8).
The inherent limitations of observational studies, confounded by the classification of “users” and “non-users” adopted by Mursu et al, makes the findings of the current study questionable at best. The manuscript lacks discussions of similar recent studies and includes statements of the authors’ opinions, such as, “We recommend that [dietary supplements] be used with strong medically based cause, such as symptomatic nutrient deficiency….” In my opinion, waiting until a diagnosis of scurvy before taking action is irresponsible. Therefore, the findings reported by Mursu et al. should be interpreted with caution and do not justify changes to integrative clinicians’ recommendations regarding multivitamins or other nutrients.

Conflict of Interest: Douglas MacKay is the Vice President, Scientific & Regulatory Affairs at the Council for Responsible Nutrition
Dietary supplements -- more consideration
Posted on December 20, 2011
Jeffrey B. Blumberg, PhD
Tufts University
Conflict of Interest: None Declared
As also mentioned in the Readers Reply by Douglas MacKay, the report relating to mortality among users and nonusers of nutrient supplements in the Iowa Women's Health Study (1) is puzzling because the authors’ definition of "nonusers" of dietary supplements actually includes many “users” of these products. At baseline, there were 24,329 women who used supplements and 14,443 women who used no supplements (Table 1). The number of multivitamin users is listed as 12,769 and the other 25,474 women are classified as nonusers (Table 2); thus, nonusers group include 11,031 women who are users of supplements other than multivitamins. As another example of this curious definition of users and nonusers, 4,082 women reported using vitamin D supplements with 33,105 others being listed as nonusers; thus, 18,662 women in the nonusers group were actually taking supplements, including supplements like multivitamins and calcium that are typically formulated with vitamin D. Table 1 indicates that 67% (16,278) of the baseline supplement users were alive and responding to a subsequent survey in 2004, compared to only 20% (2,846) of the nonusers, though the authors make no mention of this apparent difference in survival. More importantly, it is surprising that Mursu and his colleagues appear not to have addressed the fundamental question that they raise in their study, i.e., is there a difference in overall difference in mortality between older women who actually take dietary supplements and those who take none? Indeed, if there is a significant increase in mortality among older women taking multivitamins and other dietary supplements who, compared to nonusers, also have a lower prevalence of energy and saturated fat intake, diabetes, hypertension, overweight, and smoking and also a greater amount of fruit, vegetable, and whole grain consumption, higher education, and physical activity, it would be interesting to know the cause of their deaths.
1. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: The Iowa Women's Health Study. Arch Intern Med 2011;171(18):1625-1633.

Conflict of Interest: None declared
Dear Authors,
Posted on December 3, 2011
Kathleen Welch, MD
pvt practice
Conflict of Interest: None Declared
Why (and how) do Finnish authors in Finland report on the Iowa Women's Health study? And recent studies seem to indicate that calcium supplements increase the risk of heart disease. Any comments?
Sincerely,
Kathleen Welch MD

Conflict of Interest: None declared
Dietary Supplements and Mortality Rate in Older Women: A “Supplement” to the Story.
Posted on November 23, 2011
Ayaz Virji, MD
Take Care Health
Conflict of Interest: None Declared
The publication by Mursu et al. demonstrates that multivitamin use in a carte blanche style does not reduce all-cause mortality in women, but to the contrary, may slightly increase it. The Mursu study, though well executed, exhibits a number of methodological limitations. The study utilizes the Harvard Service Food Frequency Questionnaire (HSFFQ), originally designed to assess the diets of low-income women in order to gather information on dietary supplement utilization. The dietary supplement portion of the questionnaire has not been independently validated. In addition, there exist a certain subset of patients who inappropriately substitute dietary supplements in place of medications to manage chronic disease. This concerning, yet uncaptured, trend could potentially confound the results. The study does not report on the specific doses, excluding calcium and iron, or the source of the supplements. Both qualities play an important role. For example, Recent studies show that supplemental doses > 400 IU of vitamin E may increase one’s risk of developing congestive heart failure and prostate cancer – though in aggregate the data are inconclusive (2,3). However, the Nurses’ Health Study found that women consuming 100 IU daily had a 44% reduction in developing major coronary disease (4).
Various isomers of the same vitamin have different effects. Considering vitamin E again, á tocopherol and ã tocopherol have different anti-inflammatory properties and bioavailability. It is likely that a healthy ratio of the two is more important to preventing coronary artery disease than is taking one isomer in excess, which may deplete the other (5). In addition, unlike pharmaceutical agents, the source of vitamin supplements plays an important role as well. Synthetic vitamin E (dl) is thought to be much less potent than its natural vitamin E (d) counterpart and may have a varying clinical effect.
It would be imprudent to make broad, imprecise statements about the “ineffectivity” of dietary supplements as a whole, though it may be tempting to do so. A targeted, rational strategy for supplement use developed in partnership with a medical provider is likely to lead to a different outcome than that reported in the current study. The authors themselves concede “It is not advisable to make a causal statement of excess risk based on these observational data (1).”
1. Mursu J, Robien K, Harmack LJ, et al. Dietary supplements and mortality rate in older women. Arch Intern Med. 2011;171:1625-33.
2. Klein EA, Thompson IM, Tangen CM, et al. JAMA 2011;306:1549-56.
3. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA 2005;293:1328-47.
4. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328:1444-49.
5. Jiang Q, Christen S, Shigenaga MK, et al. ã-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74:714-22.

Conflict of Interest: None declared
Submit a Comment

Multimedia

Dietary Supplements and Mortality Rate in Older Women: The Iowa Women's Health Study
Arch Intern Med.2011;171(18):1625-1633.eTables

eTables -Download PDF (79 KB). This file requires Adobe Reader®.

eTable 1. Characteristics of supplemental iron and calcium users at baseline

eTable 2. Number and type of 15 supplements self-reported at each of three study rounds among women of Iowa Women’s Health Study
Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles