By Kristina Fiore

Taking a multivitamin every day for many years didn't cut the risk of death in an analysis of three prospective cohort studies that involved more than 20 years of follow-up.

Daily multivitamin use was actually associated with a slightly increased risk of death in the first half of follow-up compared with taking no multivitamin (HR 1.04, 95% CI 1.02-1.07), according to Erikka Loftfield, PhD, MPH, of the National Cancer Institute, and colleagues.

There was also no mortality benefit in the second half of follow-up (HR 1.04, 95% CI 0.99-1.08), nor for any individual cause of death including heart disease, cancer, and cerebrovascular disease, the researchers reported.

"Since many people in the U.S. and worldwide continue to use multivitamins every day, our goal was to design a study that would systematically address limitations of prior studies to help tackle this uncertainty," Loftfield said in an email. "I think we've added an important study to the evidence base showing that multivitamin use does not improve longevity."

Pieter Cohen, MD, of Cambridge Health Alliance in Massachusetts, who has conducted research on dietary supplements and is not involved with the current paper, said the findings are consistent with data from earlier randomized controlled trials.

"It's hard for me to be worried about [the mortality signal] given that we have randomized controlled trials ... saying multivitamins don't kill you," including the Physicians Health Study II, said Cohen. "I'm not going to tell patients to stop their multivitamin."

"This just suggests that even if you take a multivitamin for 20 years, it's not going to help you live longer," he added.

Use of multivitamins fell 6% from 1999 to 2011, which may have been due in part to the publication of several studies that showed they didn't reduce the risk of cardiovascular disease, cancer, or death, the researchers said. Nonetheless, one in three adults still uses multivitamins, they added.

In 2022, the U.S. Preventive Services Task Force ruled there was insufficient evidence supporting the harms or benefits of multivitamin use on mortality, in part because past studies -- particularly observational ones -- are limited by confounders such as the healthy or sick user effect. On one hand, those who take multivitamins may have healthier eating habits, exercise more, and smoke less. On the other, patients diagnosed with disease may increase their multivitamin use because of perceived health benefits.

To control for those potential sources of bias, the researchers analyzed data on 390,124 participants from three prospective cohort studies in the U.S.: the NIH-AARP Diet and Health Study (n=327,732), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (n=42,732), and the Agricultural Health Study (n=19,660).

Participants had baseline assessments from 1993 to 2001, with follow-up occurring from 1998 to 2004, as well as extended follow-up of up to 27 years, with a median 23.5 years of follow-up overall. The first follow-up period included the initial 12 years of follow-up, and the second period included the last 15 years of follow-up.

Patients were healthy at baseline, with no history of cancer or other chronic diseases. The median age was 61.4, and 55.4% were male. They self-reported multivitamin use, and there was extensive characterization of potential confounders, the researchers said.

A total of 164,762 deaths occurred during follow-up.

Loftfield and colleagues saw no effects of daily multivitamin use on risk of death by diet quality; nor was there any effect by race and ethnicity. However, daily multivitamin use and all-cause death risk was higher for the youngest age group (those under 55) during the first follow-up period (HR 1.15, 95% CI 1.05-1.26).

In the time-varying analysis that involved 234,593 participants from all three cohorts -- those who had a baseline and a second multivitamin use assessment -- daily multivitamin use was associated with a 4% higher risk of all-cause mortality in the first follow-up period (HR 1.04, 95% CI 1.02-1.07) but not in the second period (HR 0.98, 95% CI 0.93-1.04).

"The results of the time-varying analysis, incorporating a second multivitamin use assessment, were consistent with the pooled baseline estimates and support our conclusion of no mortality benefit," the researchers wrote.

In an accompanying invited commentary, Neal Barnard, MD, of George Washington University in Washington, D.C., and colleagues said the findings confirm the "mostly negative results of prior studies" and that they "make a case for obtaining vitamins from food sources, rather than supplements, to the extent possible."

For instance, the Nurses' Health Study and the Health Professionals Follow-up Study found that increased intake of fruits and vegetables was associated with reduced mortality, with the highest benefits seen for those who ate at least five servings per day, they wrote.

"Refocusing nutrition interventions on food, rather than supplements, may provide the mortality benefits that multivitamins cannot deliver," Barnard and colleagues wrote. "A healthful dietary pattern delivers micronutrients while also providing healthful macronutrients and fiber and limiting consumption of saturated fat and cholesterol."

The study was limited by the potential for residual confounding due to poorly measured or unmeasured confounders; by the possibility of selection bias, as participants with missing data may be different from those with complete data; and by the fact that all three studies included mostly white individuals.