- Click here for explanation of classification scheme.

To assess whether fish or marine omega-3 fatty acid intake is inversely associated with major causes of death in a cohort of women with generally low coronary heart disease mortality.

The Iowa Women’s Health Study cohort comprises of 41,836 women, aged 55 to 69 years, recruited via a baseline questionnaire mailed in 1986.

None described.

Design

Cohort study.

Study Protocol

• Baseline risk factors and medical history described in detail in an earlier publication
• Baseline dietary intake assessed by using a 127-item food frequency questionnaire
  • Four fish and seafood questions asked about frequency of intake of
    • Dark-meat fish such as mackerel, salmon, sardines, bluefish, or swordfish [84g to 140g (three to five ounces)]
    • Canned tuna [84g to 112g (three to four ounces)]
    • Other fish [84g to 140g (three to five ounces)]
    • Shrimp, lobster or scallops as a main dish [98g (3.5 ounces)]
  • Frequency categories ranged from "never or less than once per month" to "six or more per day"
• In 1987, 1989, 1992 and 1997 cancer incidence and most deaths identified
  • By annual linkage of cohort identifiers to
    • Iowa state-wide cancer incidence and death records
    • Questionnaires mailed to the cohort
    • National Death Index
  • By ICD-9 and ICD-10 codes: Cardiovascular [International Classification of Diseases, Ninth Revision (ICD-9) codes 390 to 459; International Classification of Diseases, Tenth Revision (ICD-10 codes I00 to I99), coronary heart disease (ICD-9 codes 410 to 414, 429.2; ICD-10 codes I20 to I25, I51.6), stroke (ICD-9 codes 430 to 438; ICD-10 codes I60 to I69, G45), and cancer (ICD-9 codes 140 to 239; ICD-10 codes C00 to D48]. 

Statistical Analysis

• Quintiles to analyze our single 1986 assessment of total fish and seafood intake and of marine omega-3 intake
• Analysis of covariance to examine the relation of fish quintiles to other risk factors
• Poisson regression or proportional hazards models to compute relative risks and 95% confidence intervals (95% CI) of death, adjusted for age and energy and covariates previously reported to be associated with total and cardiovascular mortality in this cohort.

 

Timing of Measurements

• Baseline questionnaire about risk factors, medical history and food intake (1986)
• Cancer incidence and most deaths identified by annual linkage of cohort identifiers to:
  • Iowa state-wide cancer incidence and death records and by questionnaires mailed to the cohort in 1987, 1989, 1992 and 1997
  • Follow-up surveys of the National Death Index
• Cause of death as assigned by state health departments, as follows:
  • Cardiovascular
    • International Classification of Diseases, Ninth Revision (ICD-9) codes 390 to 459
    • International Classification of Diseases, Tenth Revision (ICD-10) codes I00 to I99, coronary heart disease (ICD-9 codes 410 to 414, 429.2; ICD-10 codes I20 to I25, I51.6), stroke (ICD-9 codes 430 to 438; ICD-10 codes I60 to I69, G45), 
  • Cancer (ICD-9 codes 140 to 239; ICD-10 codes C00 to D48)

Dependent Variables

• Mortality measured by person-years
• Cardiovascular disease mortality measured by number of events
• Coronary heart disease mortality measured by number of events
• Stroke mortality measured by number of events
• Cancer mortality measured by number of events
• Other mortality measured by number of events
• Breast cancer incidence measured by number of events

Independent Variables

Total fish and seafood intake during 1986.

 

• Initial N: 41,836 women
• Age: 55 to 69

Anthropometrics

Distribution of Baseline Risk Factors in Relation to Baseline Fish Intake Among Participants Initially Free of Cancer and Cardiovascular Disease, Iowa Women’s Health Study, 1986

Frequency of Fish Intake Per Week (Servings, Approximate Quintiles) P for Trend <0.5 0.5 to <1.0 1.0 to 1.5 >1.5 to <2.5 ≥2.5 Prevalence (%)             Age more than 62 years 50 49 48 46 45 <0.0001 Education, high school or higher 69 64 60 56 54 <0.0001 Low level of physical activity 57 54 47 43 38 <0.0001 Alcohol nonconsumer 68 62 53 45 47 <0.0001 Current smoker 16 15 15 16 14 0.004 First livebirth at age 30 years or more 6 6 6 6 5 0.17 Current estrogen user 10 11 11 13 13 <0.0001 Vitamin user 30 30 33 35 37 <0.0001 Body mass index more than 30kg/m2 23 22 22 22 25 <0.0001 Waist/hip ratio more than 0.85 42 42 40 40 39 0.06 Diabetes 5 5 5 5 6 0.63 Hypertension 33 33 34 36 37 <0.0001 Mean             Energy intake (kcal per day) 1,607 1,673 1,797 1,888 1,973 <0.0001 Whole-grain intake (servings per week) 9.6 10.2 11.1 11.9 13.5 <0.0001 Fruit and vegetables intake (servings per week) 34.9 37.3 42.6 47.4 55.2 <0.0001 Red meat intake (servings per week) 5.7 5.9 6.0 6.0 5.8 <0.0001 Keys score* 17.9 18.2 18.5 18.7 19.1 <0.0001 Cholesterol (mg per day) 231 247 271 290 318 <0.0001 Saturated fat intake (g per day) 22.9 23.3 24.3 24.9 24.6 <0.0001 Alpha-linolenic intake (g per day) 0.96 1.01 1.09 1.14 1.21 <0.0001

Relative Risks of Total and Cause-specific Deaths and Incident Breast Cancer in Relation to Baseline Fish Intake Among Participants Initially Free of Cancer and Cardiovascular Disease, Iowa Women’s Health Study, 1986 to 2000

Frequency of Fish Intake Per Week (Servings, Approximate Quintiles) P for Trend <0.5 0.5 to <1.0 1.0 to 1.5 >1.5 to <2.5 ≥2.5 Mortality person-years 50,038 77,410 174,852 48,325 92,341   Total mortality (number of events) 606 833 1848 476 890   RR1* 1.0 0.90 0.88 0.83 0.82 0.003 95% CI† Reference 0.8, 1.00 0.81, 0.97 0.73, 0.94 0.74, 0.91   RR2‡ 1.0 0.99 0.97 0.93 0.93 0.15 95% CI Reference 0.88, 1.11 0.88, 1.07 0.83, 1.05 0.83, 1.05   Cardiovascular disease mortality (number of events) 220 304 590 144 331   RR1* 1.0 0.91 0.79 0.71 0.87 0.005 95% CI Reference 0.77, 1.09 0.68, 0.93 0.57, 0.88 0.73, 1.03   RR2‡ 1.0 1.03 0.86 0.79 0.95 0.11 95% CI Reference 0.85, 1.23 0.73, 1.02 0.63, 0.99 0.78, 1.15   Coronary heart disease mortality (number of events) 121 181 337 80 203   RR1* 1.0 0.99 0.82 0.71 0.95 0.02 95% CI Reference 0.78, 1.24 0.66, 1.01 0.53, 0.94 0.76, 1.20   RR2‡ 1.0 1.11 0.86 0.75 1.04 0.31 95% CI Reference 0.87, 1.42 0.69, 1.08 0.55, 1.03 0.80, 1.34   Stroke mortality (number of events) 38 69 115 26 65   RR1* 1.0 1.21 0.91 0.75 1.01 0.23 95% CI Reference 0.82, 1.81 0.63, 1.33 0.45, 1.24 0.68, 1.53   RR2‡ 1.0 1.30 0.95 0.90 1.06 0.65 95% CI Reference 0.86, 1.96 0.64, 1.41 0.53, 1.53 0.67, 1.67   Cancer mortality (number of events) 227 305 779 201 328   RR1* 1.0 0.88 0.99 0.93 0.80 0.01 95% CI Reference 0.74, 1.04 0.86, 1.15 0.77, 1.13 0.67, 0.95   RR2‡ 1.0 0.97 1.10 1.03 0.91 0.61 95% CI Reference 0.81, 1.16 0.93, 1.29 0.84, 1.27 0.75, 1.11   Other mortality (number of events) 159 224 479 131 231   RR1* 1.0 0.92 0.86 0.85 0.78 0.18 95% CI Reference 0.75, 1.13 0.72, 1.03 0.67, 1.07 0.64, 0.96   RR2‡ 1.0 0.95 0.93 0.96 0.93 0.61 95% CI Reference 0.77, 1.18 0.76, 1.12 0.75, 1.23 0.74, 1.17   Breast cancer incidence (number of events) 210 320 762 219 374   Person-years 47,369 72,809 164,196 45,162 86,143   RR1* 1.0 1.04 1.01 1.04 1.01 0.99 95% CI Reference 0.87, 1.24 0.87, 1.19 0.86, 1.26 0.85, 1.20   RR2‡ 1.0 0.96 0.91 0.97 0.92 0.49 95% CI Reference 0.80, 1.16 0.77, 1.08 0.79, 1.19 0.76, 1.12

* Relative risk (RR) adjusted for age (continuous) and energy intake (quintiles).

^† CI (confidence interval).

^‡ Relative risk adjusted for age, energy intake, educational level (less than high school, high school or more than high school), physical activity level (low, medium or high), alcohol consumption (0, less than 4.0g or 4.0g per day or more), smoking status (current, former or never), pack-years of cigarette smoking (continuous), age at first livebirth (nullipara, less than 30 years, or 30 years or more), estrogen use (current, former or never), vitamin use (yes, no or unknown), body mass index (quintiles), waist/hip ratio (quintiles), diabetes (yes or no), hypertension (yes, no or unknown), intake of whole grains, fruit and vegetables, red meat, cholesterol and saturated fat (all in quintiles).

Relative Risks of Total Mortality and Breast Cancer Incidence in Relation to Baseline Quintiles of Estimated Omega-3 Fatty Acids from Fish Among Participants Initially Free of Cancer or Cardiovascular Disease, Iowa Women’s Health Study, 1986 to 2000

Quintile of Omega-3 Fatty Acid Intake (g per Day) P for Trend ≤0.05 0.06–0.10 0.11–0.16 0.17–0.26 ≥0.27 Mean intake 0.02 0.08 0.13 0.21 0.47   Total mortality             Person-years 86,882 82,248 96,107 89,342 88,387   Number of events 960 835 1,014 959 885   RR1* 1.0 0.94 0.97 0.96 0.91 0.40 95% CI† Reference 0.85, 1.03 0.89, 1.06 0.88, 1.05 0.83, 1.00   RR2‡ 1.0 0.98 1.01 1.04 0.96 0.79 95% CI Reference 0.89, 1.08 0.91, 1.10 0.94, 1.14 0.86, 1.06   Breast cancer incidence             Person-years 81,929 77,150 90,043 83,798 82,759   No. of events 384 340 437 364 360   RR1* 1.0 1.04 1.01 1.02 1.01 0.99 95% CI Reference 0.90, 1.20 0.88, 1.16 0.89, 1.18 0.87, 1.17   RR2‡ 1.0 0.99 0.94 0.92 0.91 0.19 95% CI Reference 0.84, 1.15 0.81, 1.09 0.79, 1.08 0.77, 1.08

* Relative risk (RR) adjusted for age (continuous) and energy intake (quintiles).

^† CI, confidence interval.

^‡ Relative risk adjusted for age, energy intake, educational level (less than high school, high school or more than high school), physical activity level (low, medium or high), alcohol consumption (zero, less than 4.0g or 4.0g per day or more), smoking status (current, former or never), pack-years of cigarette smoking (continuous), age at first livebirth (nullipara, less than 30 years or 30 years or more), estrogen use (current, former or never), vitamin use (yes, no or unknown), body mass index (quintiles), waist/hip ratio (quintiles), diabetes (yes or no), hypertension (yes, no or unknown), intake of whole grains, fruit and vegetables, red meat, cholesterol and saturated fat (all in quintiles).

Other Findings

A secondary analysis (not shown in the tables): The association of total mortality with fish intake for women who at baseline were free of cancer but reported a history of myocardial infarction, angina or other heart disease:

• 1,069 deaths, 42,095 person-years
• A modest, inverse association between fish intake and total mortality in these women
• The age- and energy-adjusted relative risks of total mortality across quintiles of fish intake were
  • 1.00, 1.09 (95% CI: 0.88, 1.36),
  • 0.95 (95% CI: 0.78, 1.15)
  • 0.83 (95% CI: 0.64, 1.07)
  • 0.88 (95% CI: 0.71, 1.10)
• P for trend: 0.14
• This association was eliminated with multivariate adjustment (P for trend = 0.88)
• Estimated marine omega-3 fatty acid intake and specific groups of fish or seafood also were unrelated to total mortality (P for trend, 0.85) in women with a history of heart disease.

Plant-derived alpha-linolenic acid was modestly inversely associated with total mortality (relative risks across tertiles = 1.0, 0.95, 0.85; P for trend = 0.01, adjusted for all covariates).

In conclusion, in this sample of post-menopausal women, greater fish intake was weakly, but not independently, associated with a reduced rate of death. There was also no independent association of fish intake with coronary heart disease or stroke mortality. These findings do not argue against recommending fish as part of a healthy diet, as other evidence suggests benefit. Nevertheless, we could not verify that fish and marine omega-3 fatty acid intake had independent health benefits in these post-menopausal women.

Government:

National Cancer Institute grant CA39742

There are several major flaws in this study.

• The authors did not query the use of fish-oil supplements by the participants. They cite minimal use by participants of the WHS as justification. However, at least 30% of the subjects in each quintile of this study reported vitamin use. Omission of this data may have lead to underestimation of fish-derived fatty acid intake and consequent null findings.
• The EPA and DHA content of livestock and chickens (and chicken eggs) was not addressed by the authors. Iowans may have greater accessibility to free-range livestock and chickens than residents of other states. This could be another source of measurement error.
• The authors did not account for medications that may have influenced subsequent death from cardiac disease
• The questionnaire used to define fish-derived omega-3 fatty acids was not validated prior to use
• A single self-reported assessment of intake is likely inadequate to capture meaningful consumption data. Dietary habits could have been misrepresented or changed in subsequent years during the study.