Multivitamin Use and Mortality Risk in 3 Prospective US Cohorts

Abstract

Importance: One in 3 US adults uses multivitamins (MV), with a primary motivation being disease prevention. In 2022, the US Preventive Services Task Force reviewed data on MV supplementation and mortality from randomized clinical trials and found insufficient evidence for determining benefits or harms owing, in part, to limited follow-up time and external validity.

Objective: To estimate the association of MV use with mortality risk, accounting for confounding by healthy lifestyle and reverse causation whereby individuals in poor health initiate MV use.

Design, setting, and participants: This cohort study used data from 3 prospective cohort studies in the US, each with baseline MV use (assessed from 1993 to 2001), and follow-up MV use (assessed from 1998 to 2004), extended duration of follow-up up to 27 years, and extensive characterization of potential confounders. Participants were adults, without a history of cancer or other chronic diseases, who participated in National Institutes of Health-AARP Diet and Health Study (327 732 participants); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (42 732 participants); or Agricultural Health Study (19 660 participants). Data were analyzed from June 2022 to April 2024.

Exposure: Self-reported MV use.

Main outcomes and measures: The main outcome was mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.

Results: Among 390 124 participants (median [IQR] age, 61.5 [56.7-66.0] years; 216 202 [55.4%] male), 164 762 deaths occurred during follow-up; 159 692 participants (40.9%) were never smokers, and 157 319 participants (40.3%) were college educated. Among daily MV users, 49.3% and 42.0% were female and college educated, compared with 39.3% and 37.9% among nonusers, respectively. In contrast, 11.0% of daily users, compared with 13.0% of nonusers, were current smokers. MV use was not associated with lower all-cause mortality risk in the first (multivariable-adjusted HR, 1.04; 95% CI, 1.02-1.07) or second (multivariable-adjusted HR, 1.04; 95% CI, 0.99-1.08) halves of follow-up. HRs were similar for major causes of death and time-varying analyses.

Conclusions and relevance: In this cohort study of US adults, MV use was not associated with a mortality benefit. Still, many US adults report using MV to maintain or improve health.

Figure 1.. Stratified Baseline Estimates for the Association of Daily Multivitamin Use and All-Cause Mortality (N = 390 124)

The proportional hazards assumption was violated (P < .001). Therefore, follow-up time was stratified by the midpoint, and hazard ratios (HRs) were calculated using an interaction term between follow-up period and the exposure variable. Follow-up period 1 was the first 12 years of follow-up, and follow-up period 2 was the last 15 years of follow-up. P value represents the significance of the likelihood ratio test of each effect modifier. Models were stratified by study and adjusted for sex (male or female), age at enrollment (years), race and ethnicity, education (≤11 years; 12 years, completed high school or General Educational Development; post–high school training; some college; college and postgraduate; or other), body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) category, marital status (married or living as married, divorced or separated, widowed, or never married), smoking status (never smoker, former smoker, current smoker ≤20 cigarettes/d, current smoker 21-40 cigarettes/d, or current smoker >40 cigarettes/d), alcohol consumption (0 drinks per day, <1 drink/d, 1 to <2 drinks/d, 2 to <3 drinks/d, ≥3 drinks/d), physical activity level (never, low, moderate, high), coffee intake (0 cups/d, <1 cup/d, 1 cup/d, 2-3 cups/d, 4-5 cups/d, or ≥6 cups/d), family history of cancer (yes or no), Healthy Eating Index 2015 (HEI-2015) quartile (quartile 1, 21.55 to <60.90; quartile 2, 60.90 to <68.00; quartile 3, 68:00 to <74.20; quartile 4, 74.20 to <96.10), and use of individual supplements (yes or no). NA indicates not applicable.

Figure 2.. Meta-Analysis of the Time-Varying Estimates for the Association of Multivitamin Use and All-Cause Mortality

The proportional hazards assumption was violated (P < .001). Therefore, follow-up time was stratified by the midpoint, and hazard ratios (HRs) were calculated using an interaction term between follow-up period and the exposure variable. Maximum follow-up time was 24 years for the AARP cohort (172 496 participants; 78 523 deaths), 27 years for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer cohort (42 732 participants; 15 898 deaths), and 26 years for the Agricultural Health Study (AHS) cohort (19 365 participants; 3149 deaths); follow-up period 1 was the first 12 years of follow-up and follow-up period 2 was the last 15 years of follow-up. Models were adjusted sex (male or female), age at enrollment (years), race and ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Hispanic, non-Hispanic Black, or non-Hispanic White), education (≤11 years; 12 years, completed high school or General Educational Development; post–high school training; some college; college and postgraduate; or other), body mass index (calculated as weight in kilograms divided by height in meters squared) category (<18.5, 18.5 to <25, 25 to <30, ≥30), marital status (married or living as married, divorced or separated, widowed, or never married), smoking status (never smoker, former smoker, current smoker ≤20 cigarettes/d, current smoker 21-40 cigarettes/d, or current smoker >40 cigarettes/d), alcohol consumption (0 drinks per day, <1 drink/d, 1 to <2 drinks/d, 2 to <3 drinks/d, ≥3 drinks/d), physical activity level (never, low, moderate, high), coffee intake (0 cups/d, <1 cup/d, 1 cup/d, 2-3 cups/d, 4-5 cups/d, or ≥6 cups/d), family history of cancer (yes or no), Healthy Eating Index 2015 quartile (NIH-AARP: quartile 1, 21.5 to <61.5; quartile 2, 61.5 to <68.6; quartile 3, 68.6 to <74.7; quartile 4, 74.7 to 98; PLCO: quartile 1, 28.5 to <60.8; quartile 2, 60.8 to <67.3; quartile 3, 67.3 to <73.1; quartile 4, 73.1 to 95; AHS: quartile 1, 21.9 to <55.3; quartile 2, 55.3 to <61.8; quartile 3, 61.8 to <68.2; quartile 4, 68.2 to 95), and use of individual supplements (yes or no).