Association Between Beta-Carotene Supplementation and Mortality: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Aging is a phenomenon universally involving all organisms, genetically determined, and epigenetically influenced by the environment. Numerous observational studies have shown the positive impact of non-pharmacological approaches started in younger age on chronic conditions affecting the elderly health and survival. This meta-analysis aimed to investigate the effect of beta-carotene on the total and cause-specific mortality as reported by randomized controlled trials (RCTs). Methods We searched Medline, Scopus, Web of Science, and CENTRAL Cochrane from inception to September 2021. Studies were eligible if enrolled adults with any health condition, compared beta-carotene supplements at any dose with placebo or no intervention, provided information on deaths from any cause, and were RCTs, in English. The risk of bias was assessed by the Cochrane risk of bias tool and the GRADE. Risk ratios and their 95% confidence intervals were used and a P-value less than 0.05 was considered statistically significant. Results Among 3,942 articles searched, 44 articles on 31 RCTs, which included 216,734 total subjects, 108,622 in beta-carotene supplement groups, and 108,112 in the placebo or no-intervention groups, were involved in the final analyses. In a random-effects meta-analysis of all 31 trials, beta-carotene supplements were found to have no preventive effect on mortality (risk ratio 1.02, 95% confidence interval 0.98–1.05, I2 = 42%). Further, the analysis showed no preventive effect on cancer, cardiovascular, cerebrovascular, and other mortality causes. Instead, beta-carotene supplementation significantly increased the risk of lung cancer mortality (RR 1.14, 95% CI 1.02, 1.27, I2 = 3%) but decreased the risk of human immunodeficiency virus-related mortality (RR 0.55, 95% CI 0.33, 0.92, I2 = 0). Conclusion More studies should be performed to better define the role of beta-carotene on survival, to confirm or deny our results. Therefore, the possible beneficial or harmful effects of the beta-carotene supplementation on mortality must not be overstated. Systematic Review Registration [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=259354], identifier [CRD42021259354].


Rationale
3 Describe the rationale for the review in the context of existing knowledge.
page 3 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses.

Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.
page 4

Information sources
6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.
page 4 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.
page 4 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
page 4

Data collection process
9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
page 4

Study risk of bias assessment
11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
page 4

Effect measures
12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item 5)).
page 4 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
page 4,5 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
page 4,5 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
page 4,5 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
page 4,5 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
page 4

Certainty assessment
15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Topic No. Item
Location where item is reported

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Fig. 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Study characteristics
17 Cite each included study and present its characteristics.

Risk of bias in studies
18 Present assessments of risk of bias for each included study.

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

Results of syntheses
20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
Suppl Fig  1,2 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.
pages 5,6 20c Present results of all investigations of possible causes of heterogeneity among study results. Tables 1-4 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.

Fig. 2,3 and
Tables 1-4 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.

Certainty of evidence
22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. page 8

Registration and protocol
24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.
page 4 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.
page 4 24c Describe and explain any amendments to information provided at registration or in the protocol.
page 4 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.
page 8

Competing interests
26 Declare any competing interests of review authors. page 8

Availability of data, code and other materials
27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.

Eligibility criteria
3 Specify the inclusion and exclusion criteria for the review. Yes

Information sources
4 Specify the information sources (e.g. databases, registers) used to identify studies and the date when each was last searched.

Topic
No. Item Reported?
Risk of bias 5 Specify the methods used to assess risk of bias in the included studies.

6
Specify the methods used to present and synthesize results. Yes

Included studies
7 Give the total number of included studies and participants and summarise relevant characteristics of studies.

8
Present results for main outcomes, preferably indicating the number of included studies and participants for each. If meta-analysis was done, report the summary estimate and confidence/credible interval. If comparing groups, indicate the direction of the effect (i.e. which group is favoured).

Limitations of evidence
9 Provide a brief summary of the limitations of the evidence included in the review (e.g. study risk of bias, inconsistency and imprecision).

Yes
Interpretation 10 Provide a general interpretation of the results and important implications.