Cardiovascular disease (CVD) and cancer led to 26.9 million deaths worldwide in 2016 (1). The effects of dietary cholesterol and egg intake, as a part of the usual diet, on disease risk and longevity have been debated for decades. Eggs contain essential amino acids, B vitamins, unsaturated fatty acids, choline, lutein, and zeaxanthin (2), some of which (e.g., choline) have CVD-protective effects. However, eggs are also a rich source of dietary cholesterol (186 mg of cholesterol per egg) (3). It contributed to 25% of the total dietary cholesterol consumption, which is known to adversely affect blood lipids and increase the risk of mortality from CVDs.

Studies have also reported a positive link between dietary cholesterol intake and the risk of some cancers (4, 5), although this is less well established. The overall health effects are likely to reflect the interactions of cholesterol with other nutrients in eggs and explain the conflicting results reported for the association between egg consumption and health outcomes. Although findings from randomized clinical trials have suggested a modest contribution of dietary cholesterol or eggs to blood lipids (6). Their generalization to the whole population is questionable due to their wellknown limitations (7). Therefore, findings from prospective cohort studies can provide complementary evidence. Prospective cohort studies on the association between dietary cholesterol and egg intake and mortality have generated conflicting findings. Some studies revealed a possible positive association between egg consumption and mortality risk (8, 9), while others found an inverse (10, 11) or no association (12, 13). Such mixed results have also been reported for dietary cholesterol intake (1, 14, 15).

Two recent meta-analyses showed no significant association between egg consumption and the risk of all-cause and coronary heart disease (CHD) mortality (13, 16). However, these reviews missed several eligible cohort studies (17–20). Moreover, a large number of relevant articles have been published since the release of those meta-analyses (1, 14, 15, 21–26). Those published meta-analyses did not assess the risk of total CVD and cancer mortality and also the dose–response association between egg consumption and mortality.

The inconsistency in the available evidence has resulted in changes to dietary guidelines for cholesterol consumption. For example, until 2015, the American Heart Association Guidelines recommended limiting dietary cholesterol to less than 300 mg/day (27), while the current guidelines have no limitation for cholesterol consumption (28). Overall, a comprehensive systematic review and meta-analysis are needed to summarize available findings on the associations between egg and dietary cholesterol intake from all food sources (e.g., eggs, red meat, poultry, fish, and dairy products) and the risk of mortality. Therefore, we conducted a comprehensive systematic review and dose–response meta-analysis of prospective cohort studies to assess the associations of egg and dietary cholesterol intake with the risk of mortality from all-causes, CVD, and cancer in adults.

This systematic review and meta-analysis were conducted in accordance with the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines (29).

In total, we identified 6,503 articles in our initial search. After excluding duplicate articles and studies that did not meet the inclusion criteria, there were 67 potentially relevant publications (Figure 1). After full-text reviews, we excluded two articles owing to enrolling cancer patients (34, 35). Six publications were excluded because they did not report eligible risk estimates (36–41). Three articles reported risk estimates for egg consumption substituted for an iso-energetic amount of other foods and thus were excluded (42–44). One study was excluded because it contained risk estimates for the intake of eggs combined with other protein sources (45). We also excluded one abstract without the required data for a meta-analysis (46). In addition, we found studies with significant participant overlap, including articles from the National Health and Nutrition Examination Survey (NHANES) (16, 22), the Health Professionals Follow-Up Study (HPFS) (47, 48), and the China Health and Nutrition Survey (CHNS) (14, 49). Since these studies reported risk estimates for similar exposure and outcome variables, we included only the one with higher quality or with the highest number of cases and excluded the duplicate publications (16, 47, 49). The articles by Sun et al. (21) and Chen et al. (24) used data from the Women's Health Initiative study, with more complete data presented by Sun et al. However, the study by Chen et al. was included because it presented the RR in relation to both dietary cholesterol and egg consumption. Dehghan et al. (1) used three different datasets; two with CVD patients and one with the general population. Therefore, we included the risk estimates reported for the general population and excluded those related to patients with vascular diseases. In total, 55 studies (51 publications) remained for the final meta-analysis (1, 8–15, 17–26, 48, 50–80), of which 25 studies examined the association of egg consumption with all-cause mortality (1, 8, 9, 12–15, 17–23, 25, 26, 53, 57, 65, 68, 74–76, 79, 80), 21 with CVD mortality (1, 8–13, 15, 18, 19, 21, 22, 25, 26, 56, 64, 65, 71, 73, 75, 76), and 19 with cancer mortality (9, 12, 15, 19, 21, 25, 26, 48, 52, 59, 61–63, 65, 66, 69, 75–78). In terms of dietary cholesterol intake, 11 publications reported risk estimates for all-cause mortality (1, 8, 14, 15, 18, 22, 24, 54, 55, 58, 60), 10 for CVD mortality (1, 8, 15, 18, 22, 24, 50, 67, 70, 72), and 3 for cancer mortality (15, 24, 51).

This large-scale systematic review and dose–response analyses included information from up to 2,772,486 participants in 55 studies. Our comprehensive analyses provide some evidence for an adverse association between high dietary intake of eggs and cholesterol with respect to all-cause and cancer mortality. However, for all outcomes, daily intakes below 0.5 eggs or 250 mg cholesterol were not associated with mortality risk, supporting the role of modest egg and cholesterol intakes as part of a healthy diet. Despite known associations between high serum cholesterol and CVD risk, we saw no evidence for any association with CVD risk, and further work is required to examine the role of cholesterol-lowering medication or functional foods, in moderating the possible effects of high dietary cholesterol intakes.

Eggs are one of the major dietary sources of cholesterol. It has been shown that dietary cholesterol can increase the plasma levels of total cholesterol and also increase the ratio of total cholesterol to HDL cholesterol (81). Since elevated plasma concentrations of cholesterol have an adverse effect on health outcomes and longevity, dietary cholesterol might have a similar effect. However, findings from epidemiological studies on the link between dietary cholesterol and longevity are conflicting. In this study, we found that egg and dietary cholesterol intake were positively associated with the risk of all-cause mortality. Two previously published meta-analyses on the relationship between egg consumption and all-cause mortality showed no evidence for an association (13, 16). This inconsistency might be explained by including a larger number of studies with a much larger number of deaths and participants in the current meta-analysis compared with previous ones. In addition, unlike the previous meta-analyses, we conducted the dose–response analyses that take into consideration the different ranges of egg and cholesterol intakes among different studies.

In the overall analyses conducted in the current meta-analysis, there was evidence of moderate-to-high between-study heterogeneity. Although the meta-regression revealed that study location and dietary assessment tools were the main sources of heterogeneity, other sources of heterogeneity might be involved. Different adjustments for key confounders (i.e., energy intake and BMI) and different follow-up durations are other sources based on the subgroup analyses. In this study, we tried to control the effects of heterogeneity on our findings by using a random-effects model for combining the risk estimates.

In fact, we found that the associations of egg and dietary cholesterol intake with all-cause mortality were non-linear. Intakes of ≤1.5 eggs/day and ≤450 mg/day dietary cholesterol did not influence the risk of all-cause mortality, while the higher amounts were associated with an increased risk of all-cause mortality. In addition to cholesterol, eggs are a rich source of nutrients, including multivitamins, minerals, and high-quality protein. However, according to our study, it seems other nutrients in the egg could not fully diminish the deleterious effects of the egg cholesterol.

Randomized controlled trials have shown that eggs and dietary cholesterol have a modest contribution to plasma concentrations of LDL cholesterol (82). Dietary cholesterol may prompt the oxidation of LDL, endothelial dysfunction, and arterial inflammation, which can raise the risk of CVD. We found no significant association between egg and dietary cholesterol intake and CVD mortality in the overall analysis. It is possible that the lack of association with CVD mortality may at least in part be explained by reverse causation bias. For example, participants might have changed their egg consumption after developing chronic diseases or other conditions related to CVD risk. There are also many cholesterol-lowering margarines containing plant sterols that may be more commonly consumed by people who are at an increased CVD risk. For the primary prevention of cardiovascular disease, major guidelines (83) recommend statins for individuals who are destined to develop atherosclerotic CVD. Increasing evidence suggests that statins with lipid- and non-lipid-related functions have cardio-protective effects (84). A few studies controlled for cholesterol-lowering medications in their analysis. Thus, the use of lipid-lowering drugs, such as statins, as a confounder could attenuate a positive association between dietary intake of eggs and cholesterol and CVD mortality.

We found that egg consumption was associated with an increased risk of cancer mortality, with a similar finding for dietary cholesterol. This is in line with previous meta-analyses on cancer risk. For example, a meta-analysis by Ruohuang et al. reported that egg consumption was associated with an increased risk of breast cancer among the European, Asian, and postmenopausal populations (85). There were two other reports indicating a positive link between egg consumption and cancer risk (86, 87). In terms of dietary cholesterol, in a meta-analysis of cohort studies, Wang et al. showed that the intake of red meat and processed meat, known as rich sources of cholesterol, was positively associated with the risk of cancer mortality (88). Preclinical studies have suggested that deregulation of cholesterol homeostasis is an important contributing factor to cancer development and mortality (89). Based on these studies, increased cellular cholesterol levels, which may result from high dietary cholesterol intake or disrupted cholesterol homeostasis, can lead to increased cancer cell proliferation (90, 91).

Despite evidence for a positive association between egg and dietary cholesterol intake and cancer risk or mortality, there was notable heterogeneity and the significant association was not observed in several studies (19, 24, 51, 59, 61). These inconsistencies may be explained by different characteristics of included studies, such as different follow-up periods and different adjustments in statistical analysis. For instance, in the subgroup analyses, we found a significant positive association between egg consumption and cancer mortality in studies with a follow-up duration of ≥15 years but not in those that had a short follow-up period (<15 years). Further high-quality studies are needed to confirm our findings.

We conducted a comprehensive meta-analysis of prospective studies, which included more than 2.7 million participants and 228,425 deaths. With this comprehensive data, we were able to conduct linear and non-linear dose–response analyses, which allowed us to determine dose–response effects and the shape of the possible associations. However, some limitations should be considered when interpreting the current results. First, since our included studies were observational in nature, causality cannot be established. Second, the role of residual confounders resulting from unmeasured behavioral and biological factors or errors in the measurement of covariates cannot be entirely excluded owing to the observational design of included studies. Third, although most studies had controlled for potential confounders, adjustment strategies were not consistent across the studies, and some did not consider dietary variables typically associated with egg intake (e.g., intakes of processed and unprocessed meats), which would have affected their findings. Fifth, we did not have data on cooking methods for eggs or feeding methods for chicken that could alter the nutritional composition of the eggs. Sixth, findings might not be generalizable to low- or middle-income economics, in which diets are carbohydrate-rich, and consumption of protein sources is low. Finally, the majority of studies used a questionnaire to estimate the intake of eggs.

These data suggest possible increases in all-cause and cancer mortality with high daily intake of eggs and cholesterol. However, intakes of ≤1.5 eggs/day and ≤450 mg/day of dietary cholesterol did not influence the risk of all-cause/CVD mortality. Due to small risk estimates and moderate between-study heterogeneity in some associations, our findings on all-cause mortality should be considered with caution. Further studies are needed to confirm our findings regarding CVD mortality.

Findings from previous studies on egg consumption and the risk of mortality have been inconclusive. A high intake of eggs and dietary cholesterol is associated with an increased risk of mortality from all causes and cancer. Egg consumption was not associated with cardiovascular disease risk. Each additional egg per day was associated with a 5% higher risk of all-cause and a 13% higher risk of cancer mortality. Each 100 mg/day increment in dietary cholesterol intake was associated with a 6% higher risk of all-cause mortality and a 6% higher risk of cancer mortality.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

MDM and KL contributed to the literature search and data extraction. SN and OS contributed to data analysis. OS and SN drafted the manuscript, which was critically revised for important intellectual content by all authors. EH and JB contributed to the methodology, statistical analysis, and manuscript drafting. OS supervised the study. SN is a guarantor and had full access to all the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the final manuscript.

The meta-analysis was funded by the Gerash University of Medical Sciences, Gerash, Iran. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.