Dietary Fat Intake and Risk of Uterine Leiomyomata

A Prospective Ultrasound Study

Theodore M. Brasky; Traci N. Bethea; Amelia K. Wesselink; Ganesa R. Wegienka; Donna D. Baird; Lauren A. Wise

Disclosures

Am J Epidemiol. 2020;189(12):1538-1546. 

In This Article

Discussion

In this prospective cohort study of reproductive-aged Black women who underwent serial ultrasound during a 5-year period, dietary intakes of total fat and most individual fatty acids were not appreciably associated with UL incidence. However, higher dietary intakes of total marine ω-3 PUFAs, particularly docosahexaenoic acid, were associated with increases in UL incidence. To our knowledge, this study represents the first prospective ultrasound study of dietary fat and UL incidence.

In SELF, findings regarding intake of the marine ω-3 PUFA docosahexaenoic acid (quartile 4 vs. 1: HR = 1.49) were consistent with a prior report from the BWHS (2,695 cases), in which higher intakes of marine ω-3 PUFA (along with their fish sources) were associated with 13%–21% increased risks of UL.[13] Although hazard ratios were imprecise, our findings for the marine ω-3 PUFAs eicosapentaenoic acid (HR = 1.25) and docosapentaenoic acid (HR = 1.22) are similar in magnitude to those of the BWHS. Two other studies have reported on fish intake and UL risk in White women.[21,22] Similar to our findings on fish intake, a cohort study examining Great Lakes sport-caught fish intake reported 20% increase in risk of self-reported UL associated with fish consumption.[22] In contrast, an Italian clinic-based case-control study reported 30% reductions in the odds of UL among women in the second (odds ratio = 0.7, 95% CI: 0.5, 0.8) and third tertiles (odds ratio = 0.7, 95% CI: 0.6, 0.9) of fish consumption relative to the first;[21] however, this study might have been prone to recall bias.

Our observation of 43% higher UL risk for greater intakes of palmitoleic acid (which derives from vegetable oils and animal fats) is not clearly supported by data from the BWHS (quintile 5 vs. 1: HR = 1.09, 95% CI: 0.97, 1.23).[13] Additionally, in the BWHS, total MUFA (HR = 1.15, 95% CI: 1.02, 1.30), as well as individual MUFAs oleic acid (HR = 1.13, 95% CI: 1.00, 1.27) and erucic acid (HR = 1.17, 95% CI: 1.04, 1.32), were positively associated with UL risk.[13] Although imprecise, our results for intake of total MUFA (HR = 1.17) and oleic acid (HR = 1.23) were also similar in direction and magnitude to those found in the BWHS (Web Table 2).

We did not observe associations for the remaining fat groups or individual fatty acids. In the BWHS, there were relatively small inverse associations for intakes of SFAs caprylic acid (HR = 0.89, 95% CI: 0.78, 0.99) and caproic acid (HR = 0.86, 95% CI: 0.76, 0.97).[13] In the present study, hazard ratios for caprylic acid (HR = 0.92) were consistent, but those for caproic acid (HR = 1.04) were contrary to those reported previously[13] (Web Table 2).

The present study has several limitations. Foremost, with 1,171 women under study and 277 incident cases, the study had low power to identify small associations between dietary fats and UL risk. The use of dietary self-report is also subject to error.[23] Given the study's prospective design, we expect this error to be nondifferential, but it could have attenuated our results. Further, the FFQ did not collect data on the specific types of fish consumed, which would be expected to add nondifferential error in the estimation of marine ω-3 PUFAs. Unfortunately, we did not measure fatty acids in circulation (e.g., plasma phospholipids), which could provide a more reliable estimate of association with UL risk. We additionally could not account for supplemental intakes of ω-3 PUFAs. As is the case with any observational study, residual confounding could have influenced our findings. For instance, participants were not queried at baseline on childhood abuse[24–26] or past uterine infections, which may confound the fat-UL association. In addition, analyses were not adjusted for prevalent diabetes due to small numbers, nor did they account for multiple comparisons. Finally, it is important to note that our results among a study population comprised exclusively of Black women cannot fully address whether dietary fats explain the racial disparity in UL incidence.

These limitations notwithstanding, the present study has several strengths. It focuses on a population of women at high risk of UL. To our knowledge, ours is only the second prospective study and the first ultrasound-based study to examine associations of dietary fat intake with UL risk. The utilization of serial ultrasound to classify UL and minimize detection bias is a major strength, given the high proportion of UL that are undiagnosed.[4] We know of no prior study of diet and UL risk has been able to discern incident from prevalent disease using ultrasound, a detection method with high sensitivity and specificity relative to histologic evidence.[27] Finally, we were able to adjust for a wide range of potential confounders, including known and suspected risk factors for UL.

There is no clear explanation for the increased UL risk observed among women with high intakes of marine ω-3 PUFA. Indeed, a wealth of evidence suggests that marine ω-3 PUFA would be expected to have an inhibitory effect on uterine neoplasms given that they are thought to reduce inflammation through the inhibition of nuclear factor κ-B,[28,29] which acts as a transcription factor for targets associated with inflammation, including interleukin-6 and cyclooxygenase-2. Because eicosapentaenoic acid and docosahexaenoic acid are incorporated into cell phospholipids partly at the expense of arachidonic acid (ω-6 PUFA), they attenuate the ability of cyclooxygenase enzymes to synthesize proinflammatory eicosanoids.[29,30] Among observational studies, marine ω-3 PUFAs have been associated with reductions in circulating C-reactive protein, interlukin-6, and tumor necrosis factor-α.[31] In human trials, fish oil supplementation reduced several blood biomarkers of inflammation, including C-reactive protein[32,33] and tumor necrosis factor-α,[32,34] when contrasted against a placebo.

An alternative hypothesis is that persistent pollutants such as polychlorinated biphenyls or mercury—both of which bioaccumulate in fish—might explain the positive associations that we observed; however, evidence remains limited. In a cross-sectional analysis of the National Health and Nutrition Examination Survey,[35] unadjusted geometric mean levels of whole blood mercury were significantly higher in women with UL versus without UL, and positive associations were found with self-reported UL diagnosis. Data from a recent prospective analysis of blood and urinary mercury concentrations and UL prevalence, as determined by laparoscopic surgery (likely missing intramural and submucosal UL, the most common types of UL), did not support these findings.[36] In the same study, authors reported that high visceral fat concentrations of several polychlorinated biphenyls were associated with 52%–88% increased prevalence of UL.[37]

The present prospective study of Black women who underwent serial ultrasound provides additional evidence that intakes of marine ω-3 PUFAs, particularly docosahexaenoic acid, are associated with increased UL risk. If the association is real, it remains unclear whether the fatty acids themselves or persistent environmental pollutants are an underlying causal agent. Additional prospective studies with careful measurement of dietary marine ω-3 fatty acids or biomarkers of their intake, as well as ultrasound-detected UL, are needed. Biomarker measurements of exposure to persistent organic and inorganic pollutants would further help clarify the extent to which the association is explained by environmental pollutants, the fatty acids themselves, or other factors.

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