People who eat a diet rich in antioxidants appear to have a modestly lower risk of developing cervical cancer, a recent study showed.

Based on an index assessing dietary intake of six antioxidants, each one-unit increase in the index was linked to an 11.4% lower prevalence of cervical cancer.

When the authors assessed the risk across various subgroups based on demographics or certain health status indicators, the association remained. But closer examination of the study’s methods showed substantial weaknesses, such as insufficient control for confounding, a small population, and a cross-sectional design.

Antioxidants’ Role in Countering Inflammation

The rationale behind investigating a link between antioxidants and cervical cancer has to do with antioxidants’ role in countering inflammation, which can slow the process of clearing a human papillomavirus (HPV) infection.

“Recent review evidence suggests that protective dietary factors may influence HPV infection and cervical cancer development by modulating immune responses, oxidative stress, and inflammation,” Maozhu Lang, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China, and colleagues wrote in the International Journal of Gynecology & Obstetrics.

That the underlying mechanism is immune modulation “is a solid hypothesis,” Mitchell Clark, MD, MPH, told Medscape Medical News. But they’re taking their hypothesis a step ahead of what the data can necessarily show.

After referencing previous research, the authors suggest “maybe there’s something about the diet that prevents the conversion [from HPV infection] to cervical cancer. That’s a very big stretch,” continued Clark, who is an assistant professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine in New Haven, Connecticut.

How Dietary Intake Was Measured?

The researchers analyzed data from two nonconsecutive 24-hour dietary recalls, one during an in-person interview and one by phone 3-10 days later. They then calculated a Composite Dietary Antioxidant Index (CDAI) for each of six nutrients: zinc, selenium, carotenoids, and vitamins A, C, and E. The CDAI is a unit-less statistic that subtracts the mean population intake of each nutrient from each participant’s mean intake based on the two daily intake recalls and then divides that difference by the standard deviation.

Since the CDAI is a population-based ratio, it does not correlate to an actual amount of antioxidant intake.

Study Limitations

The findings come from a retrospective, cross-sectional, observational study with participants in eight cycles of the National Health and Nutrition Examination Survey (NHANES; 2003-2018). NHANES is a nationally representative survey conducted by the CDC that adequately represents the US population. While the survey had an initial 80,312 participants, this study’s final population was 1044 people after exclusions for missing data.

The study matched 174 people with self-reported cervical cancer to 870 control participants by demographic characteristics, education, household income, BMI, and marital, smoking, alcohol consumption, hypertension, and diabetes status. After adjustment for those covariates, they identified less prevalence of cervical cancer for each one-unit increase in the CDAI (odds ratio, 0.886; P = .003).

“It’s a very small population, and we don’t have a lot of information about the characteristics of the people included,” said Clark, commenting on the study.

An observational study also cannot offer any insight into causality, but cross-sectional studies are particularly limiting since data from a one-time survey provides only a single snapshot in time of participants’ diet, behavior, and cancer status. Nearly all cervical cancer cases are caused by HPV, and it can take 15-20 years before an HPV infection subsequently develops into cervical dysplasia or cancer.

“With this cancer in particular and that long timeline, there are so many things that happen along the way that may influence someone’s ability to clear the infection earlier — meaning they are less likely to get cervical cancer — or environmental and health factors that are contributing to persistent infection and increased risk of high-grade dysplasia and progression to cervical cancer,” Clark said.

A snapshot in time with two 24-hour dietary recalls rarely accurately represents longitudinal dietary habits. Even smoking status collected at one point in time may not reflect a person’s lifetime smoking status, he continued.

Others limitations to using 24-hour dietary recalls is that they are subject to recall bias and social desirability bias, potentially exaggerating, minimizing, or omitting certain foods.

The researchers considered multiple covariates associated with risk for cancer but plenty of information is missing that makes it hard to assess a real association between antioxidant intake and the risk for cervical cancer, Clark said. These include HPV vaccination status, history of cervical cancer screenings or their adherence to screening recommendations, history of cervical dysplasia, history of HPV infection or any HPV-related malignancies, and whether a participant had an autoimmune condition or was taking any immunosuppressing medications.

“Chronic steroid use, patients who are immunocompromised due to HIV, patients who may be using methotrexate or have rheumatoid arthritis — all of those are things we know inhibit the immune system,” which affects HPV status and the ability of the body to clear HPV, Clark continued.

“The whole crux of the problem here is that HPV is so prevalent in the community,” he explained. “Most reproductive age adults will be exposed to HPV at some point in their life, and the vast majority of them will clear the virus with natural immunity that they develop to the virus or through vaccination long before the HPV has an opportunity to integrate into the cells of the lower genital tract or the head and neck and begin oncogenic transformation into a malignancy.”

Further, while age was a covariate included by the authors, their Table 1 does not provide the actual ages of the participants.

“We would need to know the proportion of younger people and whether they were evenly distributed between young, middle, and older patients,” Clark said. “We know that younger patients are far more likely to clear their HPV infections spontaneously compared to older people, and in older people who have persistent HPV, the longer it is persistent, the more likely they are to progress into a cervical cancer.”

Antioxidant Intake’s Potential Link to Overall Health

The study cannot assess health-seeking behaviors or other health behaviors that might be associated with both antioxidant intake and risk for cervical cancer. It’s possible, Clark said, that dietary status in general reflects overall better access to health.

“Are we just perhaps capturing a group of people who are better connected to health literacy and access to preventive care,” Clark said, “because we know the majority of cervical cancers are in patients who do not adhere to screening guidelines.”

Although the authors included education and income level, they are not strong enough proxies alone to account for differences in overall lifestyles or access to HPV vaccination or cervical cancer screening.

In considering access to ob/gyn and family medicine in rural areas, for example, there may be significant overlaps between health deserts and food deserts, Clark said. The study did not include geographic location or participants’ urbanicity as covariates.

Broadly speaking, more robust studies that consider long-term dietary patterns and lifestyle factors would be necessary, likely paired with in vitro or animal model mechanistic studies, to better characterize what role antioxidants might play in cervical cancer risk. Improving access to HPV vaccination and cervical cancer screenings would also have a bigger impact on risk reduction, Clark said, and may be easier to implement than behavioral dietary changes.

The research was funded by the National Key Clinical Specialty Construction Project. The authors reported no conflicts of interest. Clark reported consulting for AbbVie.

Tara Haelle is a science/health journalist based in Dallas.