Conclusions Frequent consumption of fried foods, especially fried chicken and fried fish/shellfish, was associated with a higher risk of all cause and cardiovascular mortality in women in the US.

Results 31 558 deaths occurred during 1 914 691 person years of follow-up. For total fried food consumption, when comparing at least one serving per day with no consumption, the multivariable adjusted hazard ratio was 1.08 (95% confidence interval 1.01 to 1.16) for all cause mortality and 1.08 (0.96 to 1.22) for cardiovascular mortality. When comparing at least one serving per week of fried chicken with no consumption, the hazard ratio was 1.13 (1.07 to 1.19) for all cause mortality and 1.12 (1.02 to 1.23) for cardiovascular mortality. For fried fish/shellfish, the corresponding hazard ratios were 1.07 (1.03 to 1.12) for all cause mortality and 1.13 (1.04 to 1.22) for cardiovascular mortality. Total or individual fried food consumption was not generally associated with cancer mortality.

Objective To examine the prospective association of total and individual fried food consumption with all cause and cause specific mortality in women in the United States.

Several cohort studies in US populations showed that higher consumption of fried foods was associated with an increased risk of type 2 diabetes 3 and cardiovascular diseases, 3 4 which are among the leading causes of death. However, a study in a Mediterranean population found no association between fried food consumption and coronary heart disease. 1 Little is known about the relation between fried food consumption and mortality. 1 5 It is important to understand the associations between fried foods and health outcomes because 25-36% of North American adults consume foods, usually fried, from fast food restaurants every day. 3 6 7 Thus, we used data from a large, prospective cohort to examine the association of total and specific fried food consumption with all cause, cardiovascular, and cancer mortality in US women.

Fried foods are widely consumed in the United States and worldwide. Frying is a complex cooking process that modifies the composition of foods and the frying medium through oxidation, polymerization, and hydrogenation. 1 During frying, foods can lose water and absorb fat, and the frying oils deteriorate, especially when reused. 1 Moreover, frying makes food crunchy and more appetizing, which can lead to excess intake. 2

No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. This study used deidentified information collected in a national health study. There are no plans to disseminate the results of the research to study participants or the relevant patient community.

All statistical tests were based on a priori hypotheses and therefore there was no adjustment for multiple testing. All statistical analyses were conducted using SAS (version 9.4; SAS Institute). All tests were two sided with statistical significance set at P<0.05.

We evaluated whether the associations would vary according to the following variables: age (<65 v ≥65), race or ethnicity (white v non-white), smoking status (never smoked v ever smoked), physical activity (<10 v ≥10 metabolic equivalent task hours per week), unopposed estrogen use (never used v ever used), estrogen plus progesterone use (never used v ever used), oil used for frying at home (no fat added, olive or canola oil, others (other oils, butter, margarine, etc) or mixed use of oils), and obesity status (body mass index <30 v ≥30). For sensitivity analysis, we repeated the analyses by excluding women in the trials, adding types of oil used for home frying into the model, and adding trans fatty acid intake into the model.

Comparisons of covariates among different groups were performed using analysis of variance for continuous variables and χ 2 test for categorical variables. We used Cox proportional hazards models to estimate age adjusted and multivariable adjusted hazard ratios and 95% confidence intervals for mortality associated with total fried food consumption and its components. Person years were calculated from the baseline food frequency questionnaire until death, the last national death index search date, or the end of the previously described Women’s Health Initiative extension study 2 on 28 February 2017. Model 1 adjusted for the following variables: age at baseline, race or ethnicity, education, annual income, observational study or clinical trial, unopposed estrogen use, estrogen plus progesterone use, smoking status, physical activity, coffee intake, total energy intake, alternative healthy eating index 2010 score, baseline diabetes, cardiovascular disease, and cancer. For each of the three fried food items, mutual adjustment for other fried food items was also added. Model 2 additionally adjusted for body mass index, which was a potential mediator of the study association reported in the literature. 1

The following information was collected at baseline through self reporting: demographic characteristics (age, race/ethnicity, education, annual income), lifestyle (smoking status, physical activity, alcohol intake, coffee intake, total energy intake, overall diet quality), medical history (cardiovascular disease, cancer, diabetes), and drug use and past hormone use (unopposed estrogen use, estrogen plus progesterone use). Overall diet quality was indicated by alternative healthy eating index 2010 score. 15 This score was based on the intake levels of 11 components: vegetables, fruits, whole grains, sugar-sweetened beverages and fruit juice, nuts and legumes, red and processed meat, trans fat, long chain (n-3) fats (eicosapentaenoic and docosahexaenoic acid), polyunsaturated fatty acids, sodium, and alcohol. Recreational moderate to vigorous intensity physical activity, including walking, was assessed by questionnaire, and metabolic equivalent task hours per week of physical activity for each participant was calculated, as described in detail elsewhere. 8 16 Weight and height at baseline were measured during clinic visits using standard methods. We calculated body mass index as weight (in kilograms) divided by height (in meters squared). 2

Deaths were ascertained by reviewing death certificates, medical records, autopsy reports, and by linkage to the national death index. 14 Death certificates and hospital records were obtained and adjudicated by adjudicators who were unaware of study components or randomization assignment. Deaths in the clinical trial component of the Women’s Health Initiative were centrally adjudicated, as were major causes of cardiovascular death and the five main cancer outcomes. Other deaths were adjudicated locally. 14 Records from the most relevant hospital admission preceding death and from the time of death, autopsy records, and the death certificate were used by adjudicators to determine the causes of death. For many deaths occurring out of hospital, documentation was limited to the death certificate and records of the most recent admission to hospital before death. In these instances, the immediate and underlying cause of death was determined from the death certificate. 14 Ascertainment of outcomes was complete as of 28 February 2017. Mortality endpoints for this study included all cause (primary outcome), cardiovascular, and cancer mortality.

Total fried food consumption was the total consumption of the following three items: fried chicken, fried fish/shellfish, and other fried foods. Fried chicken was described as “fried chicken” on the questionnaire. Fried fish/shellfish was described as “fried fish, fish sandwich, and fried shellfish (shrimp and oysters)” on the questionnaire. Other questionnaire items on fried foods included “French fries, fried potatoes, fried rice, fried cassava and fritters,” “snacks such as potato chips, corn chips, tortilla chips, pork skins, Ritz and cheese crackers,” “fried plantains,” “taco and tostada,” “flauta and crispy rolled taco,” and “Indian fried bread” on the questionnaire. We assumed that all these categories consisted primarily of deep fried foods. 13 There were exceptions, such as “Ritz and cheese crackers” as part of the snacks category. However, the contribution of these single items within their general category is likely to be small. 13 The primary exposure of this study was total fried food consumption, and the secondary exposures were individual types of fried foods.

We used a standardized written protocol, centralized training of staff, and quality assurance visits by the clinical coordinating center to ensure uniform administration of data collection. Diet was measured at baseline in the Women’s Health Initiative using a self administered food frequency questionnaire developed and validated with characteristics described for the study, 10 adapted from the health habits and lifestyle questionnaire. 11 The three sections of the Women’s Health Initiative’s food frequency questionnaire included 122 composite and single food line items asking about frequency of consumption and portion size, and 19 adjustment questions related to type of fat intake. There were also four summary questions asking about the usual intake of fruits and vegetables and added fats for comparison with information gathered from the line items. The questionnaire was designed to record food intake relevant to multiethnic and geographically diverse population groups. The questionnaire has been shown to produce reliable estimates (correlation coefficient r all nutrients =0.76) that are comparable to those for eight days of dietary intake compiled from four 24 hour dietary recalls and four days of food records (r=0.37, 0.62, 0.41, 0.36 for energy, percentage of energy from fat, carbohydrate, and protein, respectively). 10 The nutrient database used to analyze the questionnaire is derived from the nutrition data systems for research, 12 which provides nutrient information for more than 140 nutrients and compounds, including energy, saturated fat, and sodium.

In this study, we included participants in the observational study component and clinical trial components, with the exception of the dietary modification trial. This is because participants in the dietary modification trial were randomized to evaluate the effects of a low fat diet, 9 which could affect their habitual consumption of fried foods. Of the eligible participants, 108 308 women (90 009 (96%) in the observational study; 18 299 (95%) in the clinical trial) had valid food frequency questionnaire data, which were defined as reported energy intake between 600 and 5000 kcal/day (1 kcal=4.18 kJ=0.00418 MJ). We excluded 104 women who had missing data on information about postmenopausal hormone therapy use. We also excluded 1238 women who died within three years after the baseline visit, to rule out the possibility that the participants changed their diet because of their preterminal or terminal illness. Therefore, 106 966 women (88 881 in the observational study; 18 085 in the clinical trial) were included in the present analysis.

The Women’s Health Initiative has been previously described in detail. 8 Briefly, between 1993 and 1998, postmenopausal women aged 50-79 at study entry were recruited through 40 clinical centers. Most clinics used a tracking system to calculate the response rate to their mailings and other recruitment efforts, but the types of system and information tracked varied widely across centers. No study wide system was implemented because the clinics wanted to maintain as much local flexibility as possible. Therefore, the response rate (that is, the number of women making contact for initial screening) varied across clinics and sources of mailing lists from less than 2% to about 20% for initial mailings; however, total mailing numbers and response rates to mailings are not available across clinics. A total of 373 092 women completed the initial screening form. Of these women, 68 132 (18%) underwent the subsequent screening visits to be randomized into the clinical trial, and 93 676 (25%) were enrolled in the observational study. The clinical trial consisted of four components: a dietary modification trial, two hormonal treatment trials, and a calcium and vitamin D clinical trial. The clinical trial and observational study were closed in 2004-05 and the participants were invited to continue being followed in the Women’s Health Initiative extension study, which has follow-up data to February 2017. Written informed consent was obtained from each participant. Institutional review board approval was obtained from all participating institutions.

Results

During 1 914 691 person years of follow-up (individual level mean follow-up duration 17.9 years), 31 558 deaths occurred, consisting of 9320 deaths from cardiovascular disease, 8358 deaths from cancer, and 13 880 deaths from other causes. Table 1 shows that women with more frequent total fried food consumption were more likely to be younger, non-white, with less education, and on lower income. They were more likely to be participants from the Women’s Health Initiative clinical trials, be current smokers, have lower physical activity levels, drink more coffee, have a higher total energy intake, and have a lower diet quality. They were also more likely to have diabetes but less likely to have cardiovascular disease at baseline, and more likely to have a higher body mass index. Women with higher total fried food consumption were more likely to consume calories from dietary total fat rather than carbohydrate or total protein. They tended to consume fewer vegetables, fruits, and whole grains, and more sugar-sweetened beverages, nuts and legumes, red and processed meat, trans fat, polyunsaturated fatty acid, and sodium. There was a moderate correlation between two of the three fried food items: fried chicken and fried fish/shellfish; r=0.40, P<0.001.

Table 1 Demographic characteristics according to frequency of baseline total fried food consumption. Data are percentages or mean (standard deviation) unless indicated otherwise View this table:

More frequent total fried food consumption was associated with a higher risk of all cause mortality (table 2): multivariable adjusted hazard ratio 1.01 (95% confidence interval 0.98 to 1.05) for less than one serving per week, 1.03 (0.99 to 1.07) for one to two servings per week, 1.03 (0.99 to 1.08) for three to six servings per week, and 1.08 (1.01 to 1.16) for at least one serving per day (P=0.02 for trend) compared with no consumption. For the specific fried food items, fried chicken consumption was associated with a higher risk of all cause mortality: 1.06 (1.03 to 1.09) for less than two servings per month, 1.12 (1.07 to 1.17) for two to three servings per month, and 1.13 (1.07 to 1.19) for at least one serving per week (P<0.001 for trend) compared with no consumption (table 3). Fried fish/shellfish consumption of at least one serving per week was associated with a higher risk of all cause mortality (1.07; 1.03 to 1.12). Other fried food consumption was not associated with all cause mortality. These associations persisted after additional adjustment for body mass index.

Table 2 Association of total fried food consumption with all cause and cause specific mortality among 106 966 postmenopausal women. Data are hazard ratios (95% confidence intervals) unless indicated otherwise View this table:

Table 3 Association of individual fried food consumption with all cause mortality among 106 966 postmenopausal women. Data are hazard ratios (95% confidence intervals) unless indicated otherwise View this table:

Total fried food consumption of at least one serving per day was associated with a modestly higher but not significant risk of cardiovascular mortality: hazard ratio 1.08 (95% confidence interval 0.96 to 1.22; table 2). Fried chicken consumption was associated with a higher risk of cardiovascular mortality: 1.08 (1.02 to 1.14) for less than two servings per month, 1.17 (1.08 to 1.25) for two to three servings per month, and 1.12 (1.02 to 1.23) for at least one serving per week (P<0.001 for trend) compared with no consumption (table 4). Fried fish/shellfish consumption of at least one serving per week was associated with a higher risk for cardiovascular mortality: 1.13 (1.04 to 1.22; table 4). Other fried foods were generally not associated with cardiovascular mortality. These associations persisted after additional adjustment for body mass index.

Table 4 Association of individual fried food consumption with cardiovascular mortality among 106 966 postmenopausal women. Data are hazard ratios (95% confidence intervals) unless indicated otherwise View this table:

Neither total nor specific fried food consumption was associated with cancer mortality (table 2 and table 5). However, for fried fish/shellfish consumption of less than two servings per month, the hazard ratio was 0.92 (95% confidence interval 0.87 to 0.97), and for other fried food consumption of less than two servings per month, the hazard ratio was 1.09 (1.02 to 1.17) compared with no consumption (table 5). These associations persisted after adjusting for body mass index.

Table 5 Association of individual fried food consumption with cancer mortality among 106 966 postmenopausal women. Data are hazard ratios (95% confidence intervals) unless indicated otherwise View this table:

The results of sensitivity analyses were similar when women in the clinical trial were excluded, oils used for frying were added into the model, or trans fatty acid intake was added into the model (eTables 2-3). The association of total or specific fried food consumption with all cause mortality did not vary by race or ethnicity, physical activity, or oil used for frying (P values ≥0.06). The association of total or specific fried food consumption with all cause mortality generally tended to be more obvious among women younger than 65, those who ever smoked, those who never used unopposed estrogen or estrogen plus progesterone, and those without obesity (eTable 4). The association of total or specific fried food consumption with cardiovascular mortality did not vary by race or ethnicity, smoking status, physical activity, unopposed estrogen use, estrogen plus progesterone use, oil used for frying, or obesity status (P values ≥0.07). The association of fried chicken or fried fish/shellfish consumption with cardiovascular mortality was more obvious among women younger than 65 (eTable 5). Generally, the association of total or specific fried food consumption with cancer mortality did not vary by age, race/ethnicity, smoking status, physical activity, unopposed estrogen use, or oil used for frying (P values ≥0.08); in addition, the association did not vary by obesity status or estrogen plus progesterone use after stratification (eTable 6).