Patterns of E-Cigarette Use Among Youth and Young Adults: Review of the Impact of E-Cigarettes on Cigarette Smoking

Patterns of E-Cigarette Use Among Youth and Young Adults: Review of the Impact of E-Cigarettes on... Abstract There is concern that e-cigarette use among youth and young adults (YAs) may lead to future cigarette or other combustible tobacco product use. A synthesis of the literature on this topic is needed because existing longitudinal studies are limited in number and not consistent in their conclusions. We conducted a search in PubMed through December 31, 2017 for peer-reviewed studies related to e-cigarette patterns of use. Of 588 relevant studies, 26 had a youth or YA sample, were longitudinal in design, and assessed e-cigarette use at baseline and cigarette smoking at follow-up. Most studies followed a sample over time and compared cigarette smoking at follow-up between baseline e-cigarette users and nonusers. Other studies examined the difference at follow-up in cigarette smoking status among smokers according to e-cigarette use at baseline. Results suggest that, among never smokers, e-cigarette use is associated with the future (6 months to 2.5 years) cigarette trial; however, firm conclusions cannot be drawn because of limitations including small sample size, measurement of experimental use (ie, ever use, past 30-day use) rather than established use, and inadequate controls for potentially confounding variables. Conclusions also cannot be drawn from studies examining the impact of e-cigarette use among smokers due to the limited number of studies and additional limitations. A comprehensive understanding of this literature is needed to inform policy makers and consumers for evidence-based decision-making and to guide future research on e-cigarette use among youth and young adults. Implications The present article provides a review of the impact of e-cigarette use on subsequent cigarette smoking among youth and YAs. Studies presented here suggest that e-cigarette use among nonsmokers is associated with subsequent cigarette smoking, but study designs are subject to numerous limitations. Future research should focus on addressing the characteristics that put youth and YAs at the risk of using either product and how appeal and accessibility of these products are related to product use in order to inform future policy-making. Introduction With the rise in popularity of electronic cigarettes (e-cigarettes) since 2010,1,2 interest in the relationship between e-cigarette use and subsequent cigarette smoking, particularly among youth and young adults (YAs), has increased.3–6 A recent meta-analysis examined this relationship among never smokers at baseline and found evidence for an association between e-cigarette and subsequent cigarette smoking (ever and past 30-day).7,8 However, many of the studies included in this analysis are at risk of bias, so, in accordance with best practices for quantitative reviews,9 it is potentially misleading to combine their results in a meta-analysis. Nonrandomized studies control for different confounders in their analyses, and the effect estimates and standard errors do not correct for this imbalance between studies.9,10 Thus, a qualitative synthesis of study designs and results is needed. Some of the issues reviewed here have been discussed in previous reviews;11,12 we expand on their critiques, focus on describing studies they have not already reviewed in-depth, and provide detailed discussion of methodological issues. Population-level estimates of cigarette smoking and e-cigarette use among youth and YAs indicate that e-cigarette use has increased (until recently) whereas cigarette smoking has steadily decreased. In the United States, ever and past 30-day e-cigarette use among youth increased from 2011 to 2015, but declined in 2016, whereas cigarette smoking declined each year.13–15 Among YAs, current (every day or some days) use of e-cigarettes has remained lower than current cigarette smoking; however, current e-cigarette use rose until 2014 and declined in 2014–2016,16,17 whereas cigarette smoking has steadily declined over the past decade.18 Similar trends have been noted in the United Kingdom.19,20 It is therefore possible, though not definitive, that e-cigarettes may have played a role in the decline of cigarette smoking. Most e-cigarette users are or have been cigarette smokers or have tried other tobacco products. In 2015, 65.2% of US youth past 30-day e-cigarette users had used another tobacco product in the past 30 days, and 86.1% had ever used another tobacco product.21 Similarly, among YAs in 2015, 58.8% of every day or some day e-cigarette users were current smokers and 29.8% were former smokers.22 Only 9.7% of YA never smokers reported ever trying an e-cigarette, and only 6.5% of never smokers in 12th grade reported past 30-day e-cigarette use in 2014.16,23 The proportion of youth and YA never smokers who try e-cigarettes and go on to become smokers is, therefore, likely to be considerably lower than the (already low) proportion of the total youth and YA population who try e-cigarettes.11 Longitudinal observational studies are required to determine the temporal sequence of exposures (e-cigarettes) and outcomes (cigarettes). A review of the literature published prior to February 2016 found only four longitudinal studies that included data for youth and YAs and on e-cigarette use and cigarette smoking,24 and the above-mentioned meta-analysis found nine studies.7 The current review provides an update to these reviews, critically appraises the quality of relevant studies, and evaluates the strength of existing evidence. It is important to note that some of the studies in the review were designed to look at general patterns of tobacco product use, but none were designed specifically with the aim of detecting associations between e-cigarette and cigarette use. Methods This analysis draws from a larger systematic review on the literature published on e-cigarettes.25,26 A search of the published literature on e-cigarettes indexed in PubMed was conducted through December 31, 2017, using the following search terms: “e-cigarette*” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “vape” OR “vaping.” Additional articles were reviewed based on targeted searches and expert recommendation. Eligible publications consisted of experimental studies, quasi-experimental studies, observational studies, case reports, case series, qualitative studies, mixed methods, and preclinical/animal studies providing empirical data on e-cigarettes. Publications were restricted to English-language articles published in peer-reviewed international journals. Additional inclusion criteria required that each study: (1) includes a sample of youth (up to age 18 years) or YAs (18 to 29 years), (2) is longitudinal in design, and (3) assesses e-cigarette use and cigarette smoking at baseline and cigarette smoking at follow-up. Studies with a full adult sample with results stratified by age to distinguish YAs were also included. Study data were extracted by two reviewers. The first conducted primary data extraction, and the second checked the accuracy of the extraction. The two reviewers assessed quality for each study according to criteria listed for observational studies by the National Heart, Lung, and Blood Institute (NHLBI).27 Reference to statistical significance in the remainder of this paper relates to either 95% confidence interval limits or p values (see Supplementary Tables for details), although p values should not be interpreted to convey information about effect sizes. Results Of the 1346 publications included in the full review (Figure 1), 588 were relevant to e-cigarette use and 26 met our final inclusion criteria. Ten studies included samples of youth or YAs who were never smokers at baseline,28–37 five included samples of smokers and never smokers at baseline stratifying results by these two groups (each study is reported in two separate sections of this review),38–42 five included samples of smokers and never smokers at baseline analyzed together,43–47 and six included a sample of only smokers.48–53 Full study details are available in online Supplementary Material. See Table 1 for a summary of the studies’ findings. Figure 1. View largeDownload slide Flowchart of studies included in the systematic review. Figure 1. View largeDownload slide Flowchart of studies included in the systematic review. Table 1. Summary of Findings From Included Studies (n = 26*) Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  YA = young adult *Total studies listed in table is 31 because five studies stratified analyses by smokers and never smokers View Large Table 1. Summary of Findings From Included Studies (n = 26*) Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  YA = young adult *Total studies listed in table is 31 because five studies stratified analyses by smokers and never smokers View Large Baseline Never Smokers Youth: Ever or Past 30-Day E-cigarette Use at Baseline Eleven studies measured the impact of ever or past 30-day e-cigarette use on subsequent cigarette smoking among youth who were never smokers at baseline.28–31,34,36–39,41,42 Of the US-based studies, three are from a longitudinal study of 9–11th grade students in public and private schools in Oahu, Hawaii,29,30,39 one is from a longitudinal cohort study of 9th graders in public high schools in Southern California,31 one is from the Children’s Health Study in California,28 and one is from a subsample of 12th grade students from the Monitoring the Future Study.38 Of the studies based in countries outside the United States, three are from longitudinal cohort studies of students in secondary schools in Scotland,34 Canada,42 and Mexico,36 and two are from school-based smoking interventions in England41 and the Netherlands.37 Three analyses came out of a study of 9–11th grade students in public and private schools in Oahu, Hawaii (2013: n = 2338; 2014: n = 2239).29,30,39 The first analysis from this study examined e-cigarette use at baseline and ever cigarette smoking at follow-up among never smokers by propensity to smoke (low- or high-risk groups derived from items assessing parental support, rebelliousness, and willingness to smoke).30 Findings suggest that the association of baseline e-cigarette use and ever cigarette smoking at follow-up was stronger for those with a low-risk to smoke compared to those at high-risk. Other than gender, ethnicity, and parental education, potential confounding variables were not controlled in this analysis. The second analysis highlighted cognitive and social risk factors that mediate the relationship between e-cigarette use at baseline and cigarette smoking at follow-up, such as peer smoking affiliations and smoking expectancies.29 The significant direct relationship between ever use of e-cigarettes in 2013 and ever use of cigarettes in 2014 was rendered nonsignificant when marijuana use and smoking expectancies were included as mediating variables. Frequency/intensity of e-cigarette and cigarette smoking was not measured. The third study39 measured the dose–response relationship between e-cigarette use and subsequent cigarette smoking and found that any e-cigarette use at baseline was related to a statistically significant increase in likelihood of onset of smoking at follow-up, but the likelihood of smoking onset did not differ significantly across different levels of frequency of use (monthly/weekly/daily). The analysis from the Southern California study31 (three other papers44,45,47 were published from this study that are described later) found that, among never combustible smokers at baseline (n = 2530; Fall 2013), ever e-cigarette users had significantly higher odds of reporting past 6-month cigarette (aOR = 2.96, 95% CI = 2.00 to 4.38) smoking at either follow-up (the average of 6- and 12-month follow-up assessments). A longitudinal analysis28 from the Children’s Health Study in Southern California in Spring of 2014 found that those who reported having ever used e-cigarettes at baseline (n = 213) had 5.49 times the odds of reporting ever cigarette smoking at follow-up (n = 39) (16 months) (but not in the past 30 days) and had 7.50 times the odds of past 30-day cigarette smoking (n = 18), compared to never e-cigarette users (ever cigarette: n = 12; past 30-day cigarette: n = 4). E-cigarette users who were not susceptible to cigarette smoking at baseline had greater odds of reporting ever use of cigarettes at follow-up compared with never e-cigarette users (OR = 9.69, 95% CI = 4.02 to 23.4); this relationship was not significant among those susceptible to cigarette smoking. A prospective panel of 12th grade students in the United States (Monitoring the Future) was assessed in 2014 and 2015.38Among baseline never cigarette smokers (n = 246), youth who had used e-cigarettes in the past 30 days at baseline (n = 11) had 4.78 times the risk of reporting incidence of smoking (controlling for past 30-day marijuana use) 1 year later compared with youth who had not used e-cigarettes in the past 30 days at baseline (n = 235). This study had a loss to follow-up rate of 58%, presenting potential response bias. There were three school-based longitudinal cohort studies published outside of the United States.34,36,42 In the Determining the Impact of Smoking Point-of-Sale Legislation Among Youth (DISPLAY) study34 in Scotland (2015–2016), ever e-cigarette users at baseline (n = 183) had significantly higher odds compared with never e-cigarette users (n = 1942) of reporting ever cigarette smoking one year later in adjusted analyses (aOR = 6.64, 95% CI = 3.60 to 12.26). Researchers did not measure frequency of use of either product. Another study based in Canada42 called the Cannabis, Obesity, Mental health, Physical activity, Alcohol use, Smoking, and Sedentary behavior study (COMPASS) (2013/2014-2014/2015) found that among never smokers at baseline (n = 15794), past 30-day e-cigarette users at baseline (n = 487) had significantly higher odds (vs. no past 30-day use) of reporting ever cigarette smoking 1 year later (aOR = 2.12, 95% CI = 1.68 to 2.66); however, potentially confounding variables beyond basic demographics were not controlled for in the analysis. A study of Mexican middle school students (2015–2016) found that participants who had ever used e-cigarettes at baseline were more likely than those who had not to ever smoke cigarettes at follow-up (1.5 years later) (aRR = 1.40, 95% CI = 1.22 to 1.60), but this relationship was not significant for past 30-day cigarette smoking at follow-up (aRR = 1.43, 95% CI = 0.94 to 2.16).36 This study reported potential differential attrition. A smoking initiation intervention in England found that, among never smokers at baseline (n = 1726), ever smoking a cigarette at follow-up (1 year) was predicted by baseline ever use of e-cigarettes (n = 343) (OR = 4.06, 95% CI = 2.94 to 5.60); baseline friends’ smoking was a significant moderator (p < .001) of this relationship, with the association weaker among those with few or most friends who smoke (vs. none).41 Although the authors measured infrequent (monthly) and frequent (weekly) e-cigarette use at baseline, they did not explore the impact of varying frequency of e-cigarette use on smoking, which is likely due to the small sample sizes for these subgroups. Youth: Nicotine Content of E-Cigarette Use at Baseline One study measured the impact of nicotine content in e-cigarettes on cigarette smoking. This study in the Netherlands was designed to measure the impact of school smoking policies on smoking behavior and found that, among students with a below median propensity to smoke cigarettes, those who had ever versus never used an e-cigarette with nicotine at baseline had 7.8 times the odds (95% CI = 1.90 to 32.04; p < .01) (adjusting for age, sex, and education) of reporting that they ever smoked a cigarette 6 months later,37 and ever users of e-cigarettes without nicotine had 6.1 times the odds (95% CI = 2.18 to 16.90; p = .001) of smoking. Among students with an above median propensity to smoke, the associations were weaker (nicotine: aOR = 2.89, 95% CI = 1.47 to 5.68; no nicotine: aOR = 3.30, 95% CI = 2.33 to 4.67). The authors interpret this finding to suggest that those who are not likely to smoke may do so following e-cigarette use; however, the exposure and outcome measured are ever use of each product, limiting the ability to determine the impact on progression of smoking. Young Adults: Ever or Past 30-Day E-Cigarette Use at Baseline Three studies examined the prospective relationship between ever or past 30-day e-cigarettes and cigarettes among never smoking YAs, two from college student samples32,35 and one from a sample of Hispanic YAs in Los Angeles.40 The Spit for Science project (n = 3757),32 a university-wide longitudinal study assessing environmental factors associated with substance use found that among only e-cigarette ever users at baseline (n = 153), 24.2% (n = 37) had tried smoking cigarettes, 5.2% (n = 8) were ever cigarette only users (had stopped using e-cigarettes), 46.4% (n = 71) remained e-cigarette-only ever users, and 24.2% (n = 37) were ever dual users at follow-up. Baseline ever e-cigarette users (aOR = 3.37; 95% CI = 1.91 to 5.94) and past 30-day e-cigarette users (aOR = 3.41; 95% CI = 1.57 to 7.41) had increased odds of reporting ever cigarette smoking at follow-up in adjusted analyses. Ever e-cigarette users (but not past 30-day e-cigarette users) had increased odds (aOR = 3.30; 95% CI = 1.20 to 9.05) of reporting past 30-day cigarette smoking at follow-up compared to never e-cigarette users. However, sample sizes for all of these transitions were small; thus, estimates may be imprecise and have limited generalizability. The Marketing and Promotions across Colleges in Texas project (Project M-PACT) measured student tobacco use every six months at 24 colleges in Texas.35 A significantly higher proportion of e-cigarette ever users at Wave 1 (n = 114, 20.1%) reported ever cigarette smoking by Wave 4 (reported at any wave, Waves 2–4) compared with nonusers (n = 168, 8.4%) (p < .001). Among students who used no other tobacco products at Wave 1, ever e-cigarette use predicted significantly greater odds of ever cigarette smoking by Wave 4 (aOR = 2.26; 95% CI = 1.35 to 3.76), but among users of other tobacco products the relationship was not significant (aOR = 1.13; 95% CI = 0.81 to 1.58).35 Frequency of e-cigarette or cigarette use was not measured. A longitudinal analysis of data from a study on the cultural factors of substance use included 1332 Hispanic YAs in Los Angeles (2014 and 2015).40 After adjusting for covariates, nonsmokers who used e-cigarettes at baseline had 3.32 times the odds of reporting past 30-day cigarette smoking (n = 10) at follow-up (1 year) (95% CI = 1.55 to 7.10) compared with those who did not report e-cigarette use at baseline. This study is limited by the small sample of e-cigarette users and low generalizability. Youth and Young Adults: Ever E-Cigarette Use at Baseline In a prospective study, 16 to 26-year-old never cigarette smokers who were nonsusceptible to smoking (n = 694) at the second wave (2012–2013) of the Dartmouth Media, Advertising and Health Study33 were followed up at the third wave (2013–2014) to assess the impact of Wave 2 ever e-cigarette use (n = 16) on smoking progression (defined as nonsmoking nonsusceptibles, nonsmoking susceptibles, and smoking initiators). At Wave 3, 5/16 of Wave 2 e-cigarette users had progressed to nonsmoking susceptible status compared with 63/678 of baseline non-e-cigarette users; further, 6/16 progressed to smoking initiation compared with 65/678 of baseline non-e-cigarette users. Compared with those who did not use e-cigarettes at Wave 2, those who did had higher odds of reporting being susceptible nonsmokers (aOR = 8.5, 95% CI = 1.3 to 57.2) and ever smoking cigarettes (aOR = 8.3, 95% CI = 1.2 to 58.6) at Wave 3. The small sample size of Wave 2 e-cigarette users resulted in imprecise estimates (wide confidence intervals), and potentially important confounders (eg, other tobacco or substance use) were not included in the analyses. Summary A few studies examine the relationship between the use of e-cigarettes and subsequent cigarette smoking among never smoking youth, but limited studies examine this relationship among never smoking YAs. Generally, studies across ages suggest that e-cigarette use at any frequency is associated with ever, past 30-day, or past 6-month cigarette smoking 6–20 months later. Baseline Smokers and Never Smokers Six studies analyzed the prospective relationship between e-cigarette use and cigarette smoking among youth with a combined never smoking and smoking sample, analyzed together.42–47 One study was from a sample of middle school students in Oregon,43 four were from longitudinal cohort studies of students in high schools in Southern California44,45,47 and Connecticut,46 and one was from a school-based cohort study in Canada.42 Youth: Ever, Past 30-Day or 6-Month E-Cigarette Use at Baseline In the Southern California study of 9th graders in 10 public high schools in Los Angeles, described previously,31,45,47 past 6-month e-cigarette use at baseline was associated with past 6-month cigarette smoking at follow-up (r = 0.21, p < .001).44 This study did not control for confounding variables identified in the study (eg, family/peer tobacco use) or baseline-smoking status and did not separate e-cigarette and hookah use in their latent transition analysis. A survey of 8th graders in 11 middle schools in Oregon found that, over the course of 1 year, baseline e-cigarette accelerators (ever e-cigarette users at baseline that increased to past 30-day use at follow-up; n = 56) had 10 times the odds of reporting cigarette smoking (past 30-day or ever) in the spring of 9th grade, compared with infrequent/nonusers of e-cigarettes at baseline (n = 1035). This analysis did not control for confounding variables, including baseline-smoking status.43 A longitudinal survey of high school students in Connecticut (n = 808) found that past 30-day users of e-cigarettes at Wave 1 (Fall, 2013) (n = 72) had significantly higher odds (OR = 7.08; 95% CI = 3.43 to 20.10) of reporting past 30-day cigarette smoking at Wave 2 (Spring, 2014) compared with non-e-cigarette users.46 Past month e-cigarette users at Wave 2 (n = 97) also had higher odds (OR = 3.87; 95% CI = 2.34 to 21.42) of reporting past month cigarette smoking at Wave 3 (Spring, 2015) compared with nonusers. Although e-cigarette and cigarette use frequencies were captured, this was not included in the analyses. The COMPASS study previously described examined daily smoking after 1 year among high school students in Canada who either had never smoked or never smoked seven days in a row at baseline.42 Almost 4% of this sample reported smoking for 7 days in a row at follow-up, and reporting past 30-day e-cigarette use at baseline (vs. no use) was a significant predictor (aOR = 1.79; 95% CI = 1.41 to 2.28), controlling for baseline-smoking status. Youth: Frequency of E-Cigarette Use at Baseline Researchers from the Southern California study31,44,47 assessed the association between baseline e-cigarette use frequency with the frequency (number of days smoked in the past 30 days) and heaviness (cigarettes per day on smoking days) of cigarette smoking at follow-up (1 year).45 Adjusting for baseline smoking and covariates (sociodemographic, environmental, and intrapersonal factors), each incremental increase in baseline e-cigarette use [never, prior (ever, but not past 30 days), infrequent (1–2 days in past 30 days), frequent (≥3 days in the past 30 days)] was associated with proportionally higher odds of smoking cigarettes at higher levels of frequency (nonsmoker, infrequent, frequent) (OR = 1.37; 95% CI = 1.16 to 1.61) and smoking heaviness (0, <1, 1, ≥2 cigarettes per day on smoking days) at follow-up (OR = 1.26, 95% CI = 1.07 to 1.48). Study limitations include potentially limited generalizability to other locations and age groups, short follow-up period, and no assessment of e-cigarette use at follow-up. Youth: Nicotine Concentration in E-Cigarette Use at Baseline One study examined the impact of e-cigarette nicotine concentration on cigarette smoking. Another analysis from the Southern California study31,44,45 in Spring 2015, when the students were 10th graders, examined cigarette smoking 6 months later (Fall 2015) among students who were past 30-day e-cigarette users and reported the nicotine concentration of their e-cigarettes (n = 181).47 For each one-level increase in baseline e-cigarette nicotine concentration, the odds of reporting frequent smoking (≥3 days in the past 30 days; vs. no smoking) at follow-up were 2.26 times greater (95% CI = 1.28 to 3.98) (controlling for baseline-smoking status); there was no association between nicotine concentration at baseline and infrequent smoking (1–2 days in the past 30 days). Compared with smokers at follow-up who did not use e-cigarettes with nicotine at baseline (n = 11), those who used high nicotine concentrations (n = 11; ≥18 mg/mL) smoked 7.03 times as many cigarettes per day (95% CI = 6.11 to 7.95); there was no difference in cigarettes per day for students who used no nicotine and low (1–5 mg/mL) or medium (6–17 mg/mL) concentrations.47 This study was limited by its small sample size and short follow-up period. Summary There are few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Three studies43,44,46 suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 0.5–1.5 years later, but none of these studies controlled for baseline-smoking status. Other studies suggest that greater frequency45 of e-cigarette use with higher nicotine concentrations47 is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking). Another suggests that past 30-day e-cigarette use is associated with the initiation of daily smoking 1 year later.42 Baseline Smokers Three studies examined the relationship between e-cigarette use and subsequent cigarette smoking among smoking youth.38,39,41 One was from a study of 9th-11th grade students in Oahu, Hawaii,39 one was from a subsample of 12th grade students from the Monitoring the Future Study,38 and another was from a school-based smoking intervention in England.41 Youth: Ever or Past 30-Day E-Cigarette Use at Baseline Among high school students in Hawaii39 who were smokers at baseline, baseline ever e-cigarette use did not predict a change in cigarette smoking frequency over time. Among 12th grade students from the Monitoring the Future study38 who were baseline ever cigarette smokers, youth who had used e-cigarettes in the past 30 days at baseline had 2.15 times the risk of reporting cigarette smoking at the 1-year follow-up compared with those who had not used e-cigarettes in the past 30 days. This relationship was not significant among baseline past 30-day cigarette smokers. The third analysis was from the above-described school-based smoking intervention in England.41 Among students who had tried cigarettes at baseline (n = 318), ever use of e-cigarettes at baseline significantly predicted escalation (to rarely, occasional, or frequent smoking) of cigarette smoking at follow-up in unadjusted analyses (OR = 2.16; 95% CI = 1.01 to 4.62), but this relationship was not significant in adjusted analyses (aOR = 1.89; 95% CI = 0.82 to 4.33); attitudes about smoking and intention to smoke were significant effect moderators (p < .05).41 Young Adults: Ever or Past 30-Day E-Cigarette Use at Baseline Six studies measured the longitudinal relationship between e-cigarette use and subsequent cigarette smoking among smoking YAs.40,49–53 One study was from a sample of Hispanic YAs in Los Angeles,40 two were from college student samples,49,51 one was from a sample of nondaily cigarette smokers,50 and two were from a longitudinal study of smokers in the greater Chicago area.52,53 The longitudinal study of Hispanic YAs in Los Angeles previously described40 found that cigarette smokers who used e-cigarettes in 2014 were not significantly more likely to remain cigarette smokers in 2015 (aOR = 1.31; 95% CI = 0.73 to 2.36). The Smokeless Tobacco Use in College Students49 study examined trajectories and correlates of smokeless tobacco use in a cohort of students from 11 colleges in North Carolina and Virginia over the course of their college careers. Among a subsample of past 30-day cigarette smokers with no history of e-cigarette use, ever using an e-cigarette at least once in Waves 1–4 (Fall 2010 to Spring 2012) was associated with increased odds of past 30-day cigarette smoking at Wave 6 (Spring 2013) (aOR = 2.48; 95% CI = 1.32 to 4.66). E-cigarette use at only one wave, however, did not predict subsequent cigarette smoking at Wave 6, but reporting e-cigarette use at two or more waves did (aOR = 3.76; 95% CI = 1.81 to 7.79). This study did not assess frequency of e-cigarette use. Young Adults: Frequency of E-Cigarette Use at Baseline A longitudinal survey of YAs measured daily cigarette consumption and e-cigarette use for 1 year among those who smoked cigarettes monthly for the past 6 months, but had not smoked daily (n = 391).50 Over the course of the year, lagged e-cigarette use predicted both cigarette quantity [incidence rate ratio (IRR) = 1.40; 95% CI = 1.17 to 1.68] and frequency (IRR = 1.18; 95% CI = 1.03 to 1.37), meaning that those who used e-cigarettes at one time-point (3, 6, 9, or 12 months) smoked 40% more cigarettes per day and used cigarettes on 18% more days at the next time-point compared with those who had not used e-cigarettes.50 An analysis from the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) Study52,53 (Waves 5–8; 2011–2015) (n = 586) found that e-cigarette use frequency at each wave of the study was not significantly associated with smoking frequency at the next wave, both directly (β = 0.021, p = .081) and mediated through nicotine dependence (β = 0.005, p = .693).53 This was also found for a subsample of participants who reported using e-cigarettes to quit smoking.52 Young Adults: E-Cigarette Use for Smoking Cessation at Baseline Two studies compared cigarette smoking following use of e-cigarettes for the explicit purpose of smoking cessation. Project M-PACT (previously described) studied quitting behavior among college students in Texas who had a history (100 lifetime cigarettes) of cigarette smoking (n = 627).51 Compared with nonusers of e-cigarettes at baseline, those who used e-cigarettes in the past 30 days for smoking cessation at baseline had 1.95 times the odds (95% CI = 1.16 to 3.28) of being a nonsmoker 6 months later and 1.66 times (95% CI = 1.00 to 2.74) 1 year later; this relationship was not significant for those who had used e-cigarettes at baseline but not for smoking cessation.51 Another analysis from the SECASP Study (Waves 5–8; 2011–2015; n = 586) found that among participants reporting use of e-cigarettes to quit smoking (Wave 5: n = 62; Wave 6: n = 101; Wave 7: n = 148; Wave 8: n = 166) past-wave e-cigarette use was not associated with cigarette smoking at the subsequent wave, but among those who did not use e-cigarettes to quit smoking, past-wave e-cigarette use was associated with more frequent smoking at the next wave for those at very low and high levels of nicotine dependence.52,53 Youth and Young Adults: Ever E-Cigarette Use at Baseline Only one study examined e-cigarette use and subsequent smoking-related outcomes among a sample of smokers with a combined youth and YA sample.48 This study included a sample of youth and YAs participating in the Youth Quitline service (counseling with no pharmacological treatment) in Hong Kong.48 Participants smoked ≥1 cigarette in the past 30 days and were aged 25 and younger (n = 189). After 6 months, point prevalence abstinence (7 days) was lower among ever e-cigarette users than nonusers (13.4% vs. 20.8%), but there was no significant relationship between ever e-cigarette use and any smoking cessation outcome (ie, quit attempts). Only 15.5% used e-cigarettes that contained nicotine and only six participants reported planning to quit with e-cigarettes. Summary There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth and YA smokers. One study38 suggests that, among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette (past-year) 1 year later, but there was no association among recent smokers. Other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later,39–41,53 whereas another found that more smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later.49 One study found that fewer smokers who tried an e-cigarette successfully quit within 6 months.48 Regarding use of e-cigarettes explicitly to quit smoking, one study found that use of e-cigarettes to quit in the past 30 days was associated with quitting 6–12 months later,51 but another study found no relationship.52 Discussion Etter6 outlines a number of criteria for studies addressing the relationship explored in this review based on Hill’s guidelines for causal inference,54 including controlling for confounding variables, establishing a temporal sequence of exposure (e-cigarette use) and outcome (cigarette smoking), and measuring a dose-response effect (ie, frequency/intensity of use of both products). Table 2 lists these criteria and measures of quality from NHLBI’s quality assessment tool for observational studies27 and indicates which studies met those criteria. None of these studies were designed a priori to examine the link specifically between e-cigarette use and subsequent smoking, and so were not designed to assess the range of potential confounding influences that could explain, in whole or in part, the observed association between e-cigarette use and smoking. Only one of the studies included in this review met all criteria (Table 2) necessary to address our main research question.47 However, this study had a relatively short follow-up period of 6 months and a small sample size, limiting the power to detect an effect. The association between the reported high concentration nicotine use via e-cigarettes at baseline and higher number of cigarettes per day at follow-up was based on only 11 smokers.47 Table 2. Assessment of included study methodologies* Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  *Adapted from the National Heart, Lung, and Blood Institute’s criteria for observational studies; **Beyond basic demographic variables; aAdjusted for either interpersonal (eg, peer/family smoking) or intrapersonal (eg, other tobacco use, sensation-seeking) factors; bAdjusted for both interpersonal and intrapersonal factors; cNicotine content was measured, but not device type; dMeasured nicotine content, but did not include this data in the analyses View Large Table 2. Assessment of included study methodologies* Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  *Adapted from the National Heart, Lung, and Blood Institute’s criteria for observational studies; **Beyond basic demographic variables; aAdjusted for either interpersonal (eg, peer/family smoking) or intrapersonal (eg, other tobacco use, sensation-seeking) factors; bAdjusted for both interpersonal and intrapersonal factors; cNicotine content was measured, but not device type; dMeasured nicotine content, but did not include this data in the analyses View Large Studies examining the impact of e-cigarette use on later cigarette smoking among never smoking youth and YAs suggest a positive association between e-cigarette use at any frequency and subsequent cigarette smoking trial.28–42 However, these studies have limitations that prevent us from drawing strong conclusions (Table 2). Only one study assessed the frequency or dose of e-cigarette use exposure,39 and none measured the frequency/quantity of subsequent cigarette smoking. Only half of the studies examined continued use of e-cigarettes at follow-up,29,31,32,34,38,39,42 and only one measured self-reported nicotine content.37 Many studies controlled for potential confounding variables, but only five studies29,31,32,35,36 controlled for at least one variable in three major domains: demographic, interpersonal (ie, family/peer smoking), and intrapersonal (ie, other tobacco use, sensation-seeking). The importance of addressing confounding is highlighted by the study of youth in Hawaii that found a stronger association between e-cigarette use and subsequent cigarette smoking among youth considered at risk of smoking.30 When accounting for the mediating effect of marijuana use and smoking expectancies on smoking outcomes, the relationship became nonsignificant, suggesting that the relationship between the use of e-cigarettes and subsequent cigarette smoking is more complex and not a simple direct effect.29 The remaining studies were limited by small sample size (and even smaller number of those who smoked at follow-up), short follow-up period, or low generalizability.32,33,37,38,40,47 Of the six studies that included smokers and never smokers together in the sample, only three controlled for smoking status at baseline.42,45,47 Only two of these studies measured the dose of e-cigarette exposure at baseline and frequency or quantity of cigarette smoking at follow-up.45,47 One of these studies measured self-reported nicotine content.47 Studies of smokers at baseline had mixed findings with respect to whether e-cigarette use was associated with continued or discontinued smoking at follow-up,38–40,48–52 and only two studies controlled for a range of potential confounding variables.49,51 Concerns have been raised that e-cigarettes appeal to youth who would otherwise not use other tobacco products, leading directly to smoking cigarettes.5 The current evidence does not permit firm conclusions in this regard, nor does it allow us to determine whether, as some have hypothesized, e-cigarette use might discourage cigarette smoking among some youth who would have smoked cigarettes anyway.5 Our conclusions differ from the recently published report from the National Academies of Sciences, Engineering and Medicine, which asserts that there is substantial evidence that e-cigarette use increases risk of ever using combustible tobacco cigarettes among youth and YAs.12 We do not deny that there is a detectable association between use of e-cigarettes and subsequent smoking, but the nature of this association is clearly not simple and direct, and is likely the result of a combination of indirect influences. We also cannot rule out the possibility that methodological shortcomings in most of the studies could have unknown effects on their findings. Our review differs in several important ways that may lead us to somewhat different interpretations of the evidence: (1) we did not include any supplementary literature (eg, qualitative studies or studies examining the impact on smoking of other tobacco products), (2) our literature search was conducted through 2017 so included more studies, and (3) we were more conservative in our evaluation of risk of bias (ie, controlling for potentially confounding variables) to support causal inferences. An important consideration for this body of literature is accounting for so-called common-liability characteristics, such as general behavioral factors (eg, risk-taking and adolescent attitudes toward authorities), that predispose toward a wide range of substance use and other risky behaviors.55,56 These characteristics are known risk factors for polytobacco use.57,58 These youth are often more likely to have mental illness and to be exposed to tobacco use and other risky behaviors among their peers and family, putting them at risk for smoking cigarettes or using other tobacco products.6,59,60 Without ruling out other such characteristics of e-cigarette and cigarette users alike, which the majority of studies (17 out of the 26) included in this review have not done, one cannot claim with certainty that use of one product leads directly and causally to another, although this possibility also cannot be ruled out. Another consideration when examining the relationship between e-cigarettes and cigarettes is nicotine addiction. One could hypothesize that using e-cigarettes with nicotine (ie, a “starter product”) could lead to an initial level of addiction that cigarettes may eventually be better at satisfying. However, evidence on self-reported tobacco dependence among adults in the Population Assessment of Tobacco and Health Study shows that e-cigarettes produce lower levels of dependence compared with cigarettes.61 Further, while daily e-cigarette users have higher dependence compared to nondaily users,62 very few youth use e-cigarettes daily—1.1% in 2016.63 Use of other noncombustible tobacco or nicotine delivery products that have been shown to be addictive (although lower than cigarettes) have not been associated with subsequent cigarette smoking.6,55,64 All studies included in this review but two37,47 failed to assess device type (which can affect the efficiency of nicotine delivery65) and nicotine content, which play a role in the products’ potential to induce dependence. However, self-reported nicotine content, particularly among youth, may be an unreliable measure.66 Measuring e-cigarette use simultaneously with cigarette smoking or at only one time-point during the course of a study renders it difficult to establish temporal precedence. The majority of studies had a 6- or 12-month follow-up, which is a relatively short period of time to examine meaningful, sustained changes in smoking behavior. Measuring ever, past-year, past 6-month, or past 30-day use as categorical indicators of exposure also inflates prevalence rates in that they conflate both experimental users and regular users. Measuring varying levels of frequency or intensity of use of both products over longer time horizons is required to determine if and how e-cigarette use leads to regular smoking. In addition, only two studies51,52 measured reasons for use of e-cigarettes, which for smokers could be to quit smoking or, for nonsmokers, to experiment.10 Only two studies examined the link between e-cigarette use and smoking among young people who want to quit smoking. This gap in research illustrates the need to determine the harm reduction potential of e-cigarettes for this population. It is also important to view the results of the studies included in this review in the context of the broader trends at the national level, which suggest that as e-cigarette use has increased, cigarette smoking has declined among both youth and YA populations. However, as of now, no direct determination can be made of the role e-cigarettes may have played in the cigarette decline.5 At a minimum, there is no evidence to date suggesting that the presence of e-cigarettes in the US market has resulted in increased youth cigarette use at the population level. Conclusions Studies included in this review consistently find that e-cigarette use among nonsmokers is associated with subsequent cigarette smoking. Although these studies have stoked concerns about a gateway effect, it is difficult to draw strong conclusions because of methodological limitations of the studies. Studies measuring the impact of e-cigarette use among smokers on continued or discontinued cigarette smoking, in general, did not find significant associations, and are also limited in number and by deficient study designs. Strong causal inferences are currently unsupported, but it is possible that e-cigarette use will increase the risk of smoking for some youth and decrease it for others. One important consideration is that it is likely that youth who use both products share a number of vulnerabilities that put them at risk of using either product, regardless of order. Future research should focus on addressing these characteristics when examining tobacco use patterns. Supplementary Material Supplementary Tables can be found online at https://academic.oup.com/ntr/ Funding This study was funded by Truth Initiative, but the views in this paper do not necessarily represent those of Truth Initiative. Declaration of Interests The authors have no conflicts of interest to report. Acknowledgments The authors would like to thank Lindsay Pitzer and Ollie Ganz for their contributions to reviewing the included papers and guiding the manuscript content. References 1. Arrazola RA, Singh T, Corey CGet al.  ; Centers for Disease Control and Prevention (CDC). Tobacco use among middle and high school students - United States, 2011-2014. MMWR Morb Mortal Wkly Rep . 2015; 64( 14): 381– 385. Google Scholar PubMed  2. King BA, Patel R, Nguyen KH, Dube SR. Trends in awareness and use of electronic cigarettes among US adults, 2010-2013. Nicotine Tob Res . 2015; 17( 2): 219– 227. Google Scholar CrossRef Search ADS PubMed  3. Grana RA. 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Google Scholar CrossRef Search ADS   63. Centers for Disease Control and Prevention. Codebook for NYTS 2016 . Atlanta, GA: Department of Health and Human Services. 2016. 64. Maki J. The incentives created by a harm reduction approach to smoking cessation: snus and smoking in Sweden and Finland. Int J Drug Policy . 2015; 26( 6): 569– 574. Google Scholar CrossRef Search ADS PubMed  65. Farsalinos KE, Spyrou A, Tsimopoulou K, Stefopoulos C, Romagna G, Voudris V. Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci Rep . 2014; 4: 4133. Google Scholar CrossRef Search ADS PubMed  66. Miech R, Patrick ME, O’Malley PM, Johnston LD. What are kids vaping? Results from a national survey of US adolescents. Tob Control . 2017; 26( 4): 386– 391. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nicotine and Tobacco Research Oxford University Press

Patterns of E-Cigarette Use Among Youth and Young Adults: Review of the Impact of E-Cigarettes on Cigarette Smoking

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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1462-2203
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1469-994X
D.O.I.
10.1093/ntr/nty103
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Abstract

Abstract There is concern that e-cigarette use among youth and young adults (YAs) may lead to future cigarette or other combustible tobacco product use. A synthesis of the literature on this topic is needed because existing longitudinal studies are limited in number and not consistent in their conclusions. We conducted a search in PubMed through December 31, 2017 for peer-reviewed studies related to e-cigarette patterns of use. Of 588 relevant studies, 26 had a youth or YA sample, were longitudinal in design, and assessed e-cigarette use at baseline and cigarette smoking at follow-up. Most studies followed a sample over time and compared cigarette smoking at follow-up between baseline e-cigarette users and nonusers. Other studies examined the difference at follow-up in cigarette smoking status among smokers according to e-cigarette use at baseline. Results suggest that, among never smokers, e-cigarette use is associated with the future (6 months to 2.5 years) cigarette trial; however, firm conclusions cannot be drawn because of limitations including small sample size, measurement of experimental use (ie, ever use, past 30-day use) rather than established use, and inadequate controls for potentially confounding variables. Conclusions also cannot be drawn from studies examining the impact of e-cigarette use among smokers due to the limited number of studies and additional limitations. A comprehensive understanding of this literature is needed to inform policy makers and consumers for evidence-based decision-making and to guide future research on e-cigarette use among youth and young adults. Implications The present article provides a review of the impact of e-cigarette use on subsequent cigarette smoking among youth and YAs. Studies presented here suggest that e-cigarette use among nonsmokers is associated with subsequent cigarette smoking, but study designs are subject to numerous limitations. Future research should focus on addressing the characteristics that put youth and YAs at the risk of using either product and how appeal and accessibility of these products are related to product use in order to inform future policy-making. Introduction With the rise in popularity of electronic cigarettes (e-cigarettes) since 2010,1,2 interest in the relationship between e-cigarette use and subsequent cigarette smoking, particularly among youth and young adults (YAs), has increased.3–6 A recent meta-analysis examined this relationship among never smokers at baseline and found evidence for an association between e-cigarette and subsequent cigarette smoking (ever and past 30-day).7,8 However, many of the studies included in this analysis are at risk of bias, so, in accordance with best practices for quantitative reviews,9 it is potentially misleading to combine their results in a meta-analysis. Nonrandomized studies control for different confounders in their analyses, and the effect estimates and standard errors do not correct for this imbalance between studies.9,10 Thus, a qualitative synthesis of study designs and results is needed. Some of the issues reviewed here have been discussed in previous reviews;11,12 we expand on their critiques, focus on describing studies they have not already reviewed in-depth, and provide detailed discussion of methodological issues. Population-level estimates of cigarette smoking and e-cigarette use among youth and YAs indicate that e-cigarette use has increased (until recently) whereas cigarette smoking has steadily decreased. In the United States, ever and past 30-day e-cigarette use among youth increased from 2011 to 2015, but declined in 2016, whereas cigarette smoking declined each year.13–15 Among YAs, current (every day or some days) use of e-cigarettes has remained lower than current cigarette smoking; however, current e-cigarette use rose until 2014 and declined in 2014–2016,16,17 whereas cigarette smoking has steadily declined over the past decade.18 Similar trends have been noted in the United Kingdom.19,20 It is therefore possible, though not definitive, that e-cigarettes may have played a role in the decline of cigarette smoking. Most e-cigarette users are or have been cigarette smokers or have tried other tobacco products. In 2015, 65.2% of US youth past 30-day e-cigarette users had used another tobacco product in the past 30 days, and 86.1% had ever used another tobacco product.21 Similarly, among YAs in 2015, 58.8% of every day or some day e-cigarette users were current smokers and 29.8% were former smokers.22 Only 9.7% of YA never smokers reported ever trying an e-cigarette, and only 6.5% of never smokers in 12th grade reported past 30-day e-cigarette use in 2014.16,23 The proportion of youth and YA never smokers who try e-cigarettes and go on to become smokers is, therefore, likely to be considerably lower than the (already low) proportion of the total youth and YA population who try e-cigarettes.11 Longitudinal observational studies are required to determine the temporal sequence of exposures (e-cigarettes) and outcomes (cigarettes). A review of the literature published prior to February 2016 found only four longitudinal studies that included data for youth and YAs and on e-cigarette use and cigarette smoking,24 and the above-mentioned meta-analysis found nine studies.7 The current review provides an update to these reviews, critically appraises the quality of relevant studies, and evaluates the strength of existing evidence. It is important to note that some of the studies in the review were designed to look at general patterns of tobacco product use, but none were designed specifically with the aim of detecting associations between e-cigarette and cigarette use. Methods This analysis draws from a larger systematic review on the literature published on e-cigarettes.25,26 A search of the published literature on e-cigarettes indexed in PubMed was conducted through December 31, 2017, using the following search terms: “e-cigarette*” OR “electronic cigarette” OR “electronic cigarettes” OR “electronic nicotine delivery” OR “vape” OR “vaping.” Additional articles were reviewed based on targeted searches and expert recommendation. Eligible publications consisted of experimental studies, quasi-experimental studies, observational studies, case reports, case series, qualitative studies, mixed methods, and preclinical/animal studies providing empirical data on e-cigarettes. Publications were restricted to English-language articles published in peer-reviewed international journals. Additional inclusion criteria required that each study: (1) includes a sample of youth (up to age 18 years) or YAs (18 to 29 years), (2) is longitudinal in design, and (3) assesses e-cigarette use and cigarette smoking at baseline and cigarette smoking at follow-up. Studies with a full adult sample with results stratified by age to distinguish YAs were also included. Study data were extracted by two reviewers. The first conducted primary data extraction, and the second checked the accuracy of the extraction. The two reviewers assessed quality for each study according to criteria listed for observational studies by the National Heart, Lung, and Blood Institute (NHLBI).27 Reference to statistical significance in the remainder of this paper relates to either 95% confidence interval limits or p values (see Supplementary Tables for details), although p values should not be interpreted to convey information about effect sizes. Results Of the 1346 publications included in the full review (Figure 1), 588 were relevant to e-cigarette use and 26 met our final inclusion criteria. Ten studies included samples of youth or YAs who were never smokers at baseline,28–37 five included samples of smokers and never smokers at baseline stratifying results by these two groups (each study is reported in two separate sections of this review),38–42 five included samples of smokers and never smokers at baseline analyzed together,43–47 and six included a sample of only smokers.48–53 Full study details are available in online Supplementary Material. See Table 1 for a summary of the studies’ findings. Figure 1. View largeDownload slide Flowchart of studies included in the systematic review. Figure 1. View largeDownload slide Flowchart of studies included in the systematic review. Table 1. Summary of Findings From Included Studies (n = 26*) Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  YA = young adult *Total studies listed in table is 31 because five studies stratified analyses by smokers and never smokers View Large Table 1. Summary of Findings From Included Studies (n = 26*) Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  Baseline Sample  Findings  Conclusions  Never smokers      Youth (11 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever,28–30,34,36,37,41past 30-day,28 and past 6-month cigarette smoking31 at follow-up (one study found no association36) ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever,42past 30-day,38 and daily42 cigarette smoking at follow-up ▪ Significant association between e-cigarette use at baseline and ever cigarette smoking at follow-up among e-cigarette users at any frequency (no significant difference among different frequency groups)39  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking youth. Studies suggest that e-cigarette use at any frequency is associated with ever, past 30-day, past 6-month or daily cigarette smoking 6 to 20 months later; however, one study found no association between ever e-cigarette use and past 30-day cigarette use 20 months later.  YAs (3 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever32,35 and past 30-day32 cigarette smoking at follow-up ▪ Significant association between past 30-day use of e-cigarettes at baseline and ever32 and past 30-day40 cigarette smoking at follow-up  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smoking YAs. Studies suggest more ever or past 30-day users of e-cigarettes smoked cigarettes ever or in the past 30 days 1–1.5 years later.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and ever cigarette smoking at follow-up33  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among never smokers in combined youth and YA samples. One study suggests that more never smokers who ever tried e-cigarettes ever tried cigarettes one year later.  Smokers and never smokers  Youth (6 studies)  ▪ Significant association between ever use of e-cigarettes at baseline and ever or past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status43 ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up, not controlling for baseline-smoking status46 ▪ Significant association between past 30-day use of e-cigarettes at baseline and daily cigarette smoking at follow-up, controlling for baseline-smoking status.42 ▪ Significant correlation between past 6-month use of e-cigarettes at baseline and past 6-month cigarette smoking at follow-up44 ▪ Significant association between e-cigarette use at baseline with greater frequency of cigarette smoking at follow-up, with each increment higher in frequency of e-cigarette use, controlling for baseline-smoking status45 ▪ Significant association between use of e-cigarettes with higher nicotine concentration at baseline and frequent cigarette smoking and more cigarettes per day at follow-up, controlling for baseline-smoking status; no significant association with infrequent cigarette smoking47  There are a few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Studies suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 6 months to 1.5 years later, but these studies did not control for baseline-smoking status. One study suggests a relationship between past 30-day e-cigarette use and initiation of daily smoking one year later, controlling for baseline-smoking status. Other studies suggest greater frequency of e-cigarette use with higher nicotine concentration is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking).  Smokers  Youth (3 studies)  ▪ Significant association between past 30-day use of e-cigarettes at baseline and past 12-month cigarette smoking at follow-up among ever smokers at baseline who had not smoked in the past 30 days;38 no significant association among past 30-day smokers at baseline38 ▪ No significant association between ever use of e-cigarettes at baseline and change in frequency of cigarette smoking at follow-up39,41  There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth smokers. One study suggests that among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette in the next year, but there was no association between these behaviors among recent smokers. Two other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later.  YAs (6 studies)  ▪ No significant association between past 30-day use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day smokers at baseline40,53 ▪ Significant association between past 6-month use of e-cigarettes at baseline and past 30-day cigarette smoking at follow-up among past 30-day cigarette smokers at baseline49 ▪ Significant association between past 9- to 14-day use of e-cigarettes at baseline and greater frequency of cigarette smoking and more cigarettes per day at follow-up50 ▪ Significant association between past 30-day use of e-cigarettes for smoking cessation at baseline and no cigarette smoking (quitting) at follow-up;51 no significant association for past 30-day users of e-cigarettes not for smoking cessation51 ▪ Significant association between past 30-day use of e-cigarettes not for smoking cessation at baseline and greater frequency of cigarette smoking at follow-up for smokers with very low or high nicotine dependence;52 no significant association for past 30-day users of e-cigarettes for smoking cessation52  There are a few studies and mixed evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among YA smokers. Two studies suggest no relationship between past 30-day use of e-cigarettes and past 30-day smoking one year later among smokers, while another suggests smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later. Another study suggests that recent e-cigarette use predicts greater frequency/quantity of smoking in the short-term (3 months). Regarding use of e-cigarettes for the purpose of quitting smoking, one study suggests use of e-cigarettes to quit in the past 30 days is associated with quitting 6 and 12 months later, but use for reasons other than to quit is not; conversely, another study suggests no relationship between past 30-day e-cigarette use to quit and smoking frequency one year later, while use for reasons other than to quit is associated with increased smoking frequency.  Youth and YAs (1 study)  ▪ Significant association between ever use of e-cigarettes at baseline and 7-day point prevalence abstinence of cigarette smoking at follow-up, but not with quit attempts48  There is limited evidence on the relationship between use of e-cigarettes and subsequent cigarette smoking among combined youth and YA samples of smokers. One study suggests that fewer smokers who tried an e-cigarette successfully quit within 6 months.  YA = young adult *Total studies listed in table is 31 because five studies stratified analyses by smokers and never smokers View Large Baseline Never Smokers Youth: Ever or Past 30-Day E-cigarette Use at Baseline Eleven studies measured the impact of ever or past 30-day e-cigarette use on subsequent cigarette smoking among youth who were never smokers at baseline.28–31,34,36–39,41,42 Of the US-based studies, three are from a longitudinal study of 9–11th grade students in public and private schools in Oahu, Hawaii,29,30,39 one is from a longitudinal cohort study of 9th graders in public high schools in Southern California,31 one is from the Children’s Health Study in California,28 and one is from a subsample of 12th grade students from the Monitoring the Future Study.38 Of the studies based in countries outside the United States, three are from longitudinal cohort studies of students in secondary schools in Scotland,34 Canada,42 and Mexico,36 and two are from school-based smoking interventions in England41 and the Netherlands.37 Three analyses came out of a study of 9–11th grade students in public and private schools in Oahu, Hawaii (2013: n = 2338; 2014: n = 2239).29,30,39 The first analysis from this study examined e-cigarette use at baseline and ever cigarette smoking at follow-up among never smokers by propensity to smoke (low- or high-risk groups derived from items assessing parental support, rebelliousness, and willingness to smoke).30 Findings suggest that the association of baseline e-cigarette use and ever cigarette smoking at follow-up was stronger for those with a low-risk to smoke compared to those at high-risk. Other than gender, ethnicity, and parental education, potential confounding variables were not controlled in this analysis. The second analysis highlighted cognitive and social risk factors that mediate the relationship between e-cigarette use at baseline and cigarette smoking at follow-up, such as peer smoking affiliations and smoking expectancies.29 The significant direct relationship between ever use of e-cigarettes in 2013 and ever use of cigarettes in 2014 was rendered nonsignificant when marijuana use and smoking expectancies were included as mediating variables. Frequency/intensity of e-cigarette and cigarette smoking was not measured. The third study39 measured the dose–response relationship between e-cigarette use and subsequent cigarette smoking and found that any e-cigarette use at baseline was related to a statistically significant increase in likelihood of onset of smoking at follow-up, but the likelihood of smoking onset did not differ significantly across different levels of frequency of use (monthly/weekly/daily). The analysis from the Southern California study31 (three other papers44,45,47 were published from this study that are described later) found that, among never combustible smokers at baseline (n = 2530; Fall 2013), ever e-cigarette users had significantly higher odds of reporting past 6-month cigarette (aOR = 2.96, 95% CI = 2.00 to 4.38) smoking at either follow-up (the average of 6- and 12-month follow-up assessments). A longitudinal analysis28 from the Children’s Health Study in Southern California in Spring of 2014 found that those who reported having ever used e-cigarettes at baseline (n = 213) had 5.49 times the odds of reporting ever cigarette smoking at follow-up (n = 39) (16 months) (but not in the past 30 days) and had 7.50 times the odds of past 30-day cigarette smoking (n = 18), compared to never e-cigarette users (ever cigarette: n = 12; past 30-day cigarette: n = 4). E-cigarette users who were not susceptible to cigarette smoking at baseline had greater odds of reporting ever use of cigarettes at follow-up compared with never e-cigarette users (OR = 9.69, 95% CI = 4.02 to 23.4); this relationship was not significant among those susceptible to cigarette smoking. A prospective panel of 12th grade students in the United States (Monitoring the Future) was assessed in 2014 and 2015.38Among baseline never cigarette smokers (n = 246), youth who had used e-cigarettes in the past 30 days at baseline (n = 11) had 4.78 times the risk of reporting incidence of smoking (controlling for past 30-day marijuana use) 1 year later compared with youth who had not used e-cigarettes in the past 30 days at baseline (n = 235). This study had a loss to follow-up rate of 58%, presenting potential response bias. There were three school-based longitudinal cohort studies published outside of the United States.34,36,42 In the Determining the Impact of Smoking Point-of-Sale Legislation Among Youth (DISPLAY) study34 in Scotland (2015–2016), ever e-cigarette users at baseline (n = 183) had significantly higher odds compared with never e-cigarette users (n = 1942) of reporting ever cigarette smoking one year later in adjusted analyses (aOR = 6.64, 95% CI = 3.60 to 12.26). Researchers did not measure frequency of use of either product. Another study based in Canada42 called the Cannabis, Obesity, Mental health, Physical activity, Alcohol use, Smoking, and Sedentary behavior study (COMPASS) (2013/2014-2014/2015) found that among never smokers at baseline (n = 15794), past 30-day e-cigarette users at baseline (n = 487) had significantly higher odds (vs. no past 30-day use) of reporting ever cigarette smoking 1 year later (aOR = 2.12, 95% CI = 1.68 to 2.66); however, potentially confounding variables beyond basic demographics were not controlled for in the analysis. A study of Mexican middle school students (2015–2016) found that participants who had ever used e-cigarettes at baseline were more likely than those who had not to ever smoke cigarettes at follow-up (1.5 years later) (aRR = 1.40, 95% CI = 1.22 to 1.60), but this relationship was not significant for past 30-day cigarette smoking at follow-up (aRR = 1.43, 95% CI = 0.94 to 2.16).36 This study reported potential differential attrition. A smoking initiation intervention in England found that, among never smokers at baseline (n = 1726), ever smoking a cigarette at follow-up (1 year) was predicted by baseline ever use of e-cigarettes (n = 343) (OR = 4.06, 95% CI = 2.94 to 5.60); baseline friends’ smoking was a significant moderator (p < .001) of this relationship, with the association weaker among those with few or most friends who smoke (vs. none).41 Although the authors measured infrequent (monthly) and frequent (weekly) e-cigarette use at baseline, they did not explore the impact of varying frequency of e-cigarette use on smoking, which is likely due to the small sample sizes for these subgroups. Youth: Nicotine Content of E-Cigarette Use at Baseline One study measured the impact of nicotine content in e-cigarettes on cigarette smoking. This study in the Netherlands was designed to measure the impact of school smoking policies on smoking behavior and found that, among students with a below median propensity to smoke cigarettes, those who had ever versus never used an e-cigarette with nicotine at baseline had 7.8 times the odds (95% CI = 1.90 to 32.04; p < .01) (adjusting for age, sex, and education) of reporting that they ever smoked a cigarette 6 months later,37 and ever users of e-cigarettes without nicotine had 6.1 times the odds (95% CI = 2.18 to 16.90; p = .001) of smoking. Among students with an above median propensity to smoke, the associations were weaker (nicotine: aOR = 2.89, 95% CI = 1.47 to 5.68; no nicotine: aOR = 3.30, 95% CI = 2.33 to 4.67). The authors interpret this finding to suggest that those who are not likely to smoke may do so following e-cigarette use; however, the exposure and outcome measured are ever use of each product, limiting the ability to determine the impact on progression of smoking. Young Adults: Ever or Past 30-Day E-Cigarette Use at Baseline Three studies examined the prospective relationship between ever or past 30-day e-cigarettes and cigarettes among never smoking YAs, two from college student samples32,35 and one from a sample of Hispanic YAs in Los Angeles.40 The Spit for Science project (n = 3757),32 a university-wide longitudinal study assessing environmental factors associated with substance use found that among only e-cigarette ever users at baseline (n = 153), 24.2% (n = 37) had tried smoking cigarettes, 5.2% (n = 8) were ever cigarette only users (had stopped using e-cigarettes), 46.4% (n = 71) remained e-cigarette-only ever users, and 24.2% (n = 37) were ever dual users at follow-up. Baseline ever e-cigarette users (aOR = 3.37; 95% CI = 1.91 to 5.94) and past 30-day e-cigarette users (aOR = 3.41; 95% CI = 1.57 to 7.41) had increased odds of reporting ever cigarette smoking at follow-up in adjusted analyses. Ever e-cigarette users (but not past 30-day e-cigarette users) had increased odds (aOR = 3.30; 95% CI = 1.20 to 9.05) of reporting past 30-day cigarette smoking at follow-up compared to never e-cigarette users. However, sample sizes for all of these transitions were small; thus, estimates may be imprecise and have limited generalizability. The Marketing and Promotions across Colleges in Texas project (Project M-PACT) measured student tobacco use every six months at 24 colleges in Texas.35 A significantly higher proportion of e-cigarette ever users at Wave 1 (n = 114, 20.1%) reported ever cigarette smoking by Wave 4 (reported at any wave, Waves 2–4) compared with nonusers (n = 168, 8.4%) (p < .001). Among students who used no other tobacco products at Wave 1, ever e-cigarette use predicted significantly greater odds of ever cigarette smoking by Wave 4 (aOR = 2.26; 95% CI = 1.35 to 3.76), but among users of other tobacco products the relationship was not significant (aOR = 1.13; 95% CI = 0.81 to 1.58).35 Frequency of e-cigarette or cigarette use was not measured. A longitudinal analysis of data from a study on the cultural factors of substance use included 1332 Hispanic YAs in Los Angeles (2014 and 2015).40 After adjusting for covariates, nonsmokers who used e-cigarettes at baseline had 3.32 times the odds of reporting past 30-day cigarette smoking (n = 10) at follow-up (1 year) (95% CI = 1.55 to 7.10) compared with those who did not report e-cigarette use at baseline. This study is limited by the small sample of e-cigarette users and low generalizability. Youth and Young Adults: Ever E-Cigarette Use at Baseline In a prospective study, 16 to 26-year-old never cigarette smokers who were nonsusceptible to smoking (n = 694) at the second wave (2012–2013) of the Dartmouth Media, Advertising and Health Study33 were followed up at the third wave (2013–2014) to assess the impact of Wave 2 ever e-cigarette use (n = 16) on smoking progression (defined as nonsmoking nonsusceptibles, nonsmoking susceptibles, and smoking initiators). At Wave 3, 5/16 of Wave 2 e-cigarette users had progressed to nonsmoking susceptible status compared with 63/678 of baseline non-e-cigarette users; further, 6/16 progressed to smoking initiation compared with 65/678 of baseline non-e-cigarette users. Compared with those who did not use e-cigarettes at Wave 2, those who did had higher odds of reporting being susceptible nonsmokers (aOR = 8.5, 95% CI = 1.3 to 57.2) and ever smoking cigarettes (aOR = 8.3, 95% CI = 1.2 to 58.6) at Wave 3. The small sample size of Wave 2 e-cigarette users resulted in imprecise estimates (wide confidence intervals), and potentially important confounders (eg, other tobacco or substance use) were not included in the analyses. Summary A few studies examine the relationship between the use of e-cigarettes and subsequent cigarette smoking among never smoking youth, but limited studies examine this relationship among never smoking YAs. Generally, studies across ages suggest that e-cigarette use at any frequency is associated with ever, past 30-day, or past 6-month cigarette smoking 6–20 months later. Baseline Smokers and Never Smokers Six studies analyzed the prospective relationship between e-cigarette use and cigarette smoking among youth with a combined never smoking and smoking sample, analyzed together.42–47 One study was from a sample of middle school students in Oregon,43 four were from longitudinal cohort studies of students in high schools in Southern California44,45,47 and Connecticut,46 and one was from a school-based cohort study in Canada.42 Youth: Ever, Past 30-Day or 6-Month E-Cigarette Use at Baseline In the Southern California study of 9th graders in 10 public high schools in Los Angeles, described previously,31,45,47 past 6-month e-cigarette use at baseline was associated with past 6-month cigarette smoking at follow-up (r = 0.21, p < .001).44 This study did not control for confounding variables identified in the study (eg, family/peer tobacco use) or baseline-smoking status and did not separate e-cigarette and hookah use in their latent transition analysis. A survey of 8th graders in 11 middle schools in Oregon found that, over the course of 1 year, baseline e-cigarette accelerators (ever e-cigarette users at baseline that increased to past 30-day use at follow-up; n = 56) had 10 times the odds of reporting cigarette smoking (past 30-day or ever) in the spring of 9th grade, compared with infrequent/nonusers of e-cigarettes at baseline (n = 1035). This analysis did not control for confounding variables, including baseline-smoking status.43 A longitudinal survey of high school students in Connecticut (n = 808) found that past 30-day users of e-cigarettes at Wave 1 (Fall, 2013) (n = 72) had significantly higher odds (OR = 7.08; 95% CI = 3.43 to 20.10) of reporting past 30-day cigarette smoking at Wave 2 (Spring, 2014) compared with non-e-cigarette users.46 Past month e-cigarette users at Wave 2 (n = 97) also had higher odds (OR = 3.87; 95% CI = 2.34 to 21.42) of reporting past month cigarette smoking at Wave 3 (Spring, 2015) compared with nonusers. Although e-cigarette and cigarette use frequencies were captured, this was not included in the analyses. The COMPASS study previously described examined daily smoking after 1 year among high school students in Canada who either had never smoked or never smoked seven days in a row at baseline.42 Almost 4% of this sample reported smoking for 7 days in a row at follow-up, and reporting past 30-day e-cigarette use at baseline (vs. no use) was a significant predictor (aOR = 1.79; 95% CI = 1.41 to 2.28), controlling for baseline-smoking status. Youth: Frequency of E-Cigarette Use at Baseline Researchers from the Southern California study31,44,47 assessed the association between baseline e-cigarette use frequency with the frequency (number of days smoked in the past 30 days) and heaviness (cigarettes per day on smoking days) of cigarette smoking at follow-up (1 year).45 Adjusting for baseline smoking and covariates (sociodemographic, environmental, and intrapersonal factors), each incremental increase in baseline e-cigarette use [never, prior (ever, but not past 30 days), infrequent (1–2 days in past 30 days), frequent (≥3 days in the past 30 days)] was associated with proportionally higher odds of smoking cigarettes at higher levels of frequency (nonsmoker, infrequent, frequent) (OR = 1.37; 95% CI = 1.16 to 1.61) and smoking heaviness (0, <1, 1, ≥2 cigarettes per day on smoking days) at follow-up (OR = 1.26, 95% CI = 1.07 to 1.48). Study limitations include potentially limited generalizability to other locations and age groups, short follow-up period, and no assessment of e-cigarette use at follow-up. Youth: Nicotine Concentration in E-Cigarette Use at Baseline One study examined the impact of e-cigarette nicotine concentration on cigarette smoking. Another analysis from the Southern California study31,44,45 in Spring 2015, when the students were 10th graders, examined cigarette smoking 6 months later (Fall 2015) among students who were past 30-day e-cigarette users and reported the nicotine concentration of their e-cigarettes (n = 181).47 For each one-level increase in baseline e-cigarette nicotine concentration, the odds of reporting frequent smoking (≥3 days in the past 30 days; vs. no smoking) at follow-up were 2.26 times greater (95% CI = 1.28 to 3.98) (controlling for baseline-smoking status); there was no association between nicotine concentration at baseline and infrequent smoking (1–2 days in the past 30 days). Compared with smokers at follow-up who did not use e-cigarettes with nicotine at baseline (n = 11), those who used high nicotine concentrations (n = 11; ≥18 mg/mL) smoked 7.03 times as many cigarettes per day (95% CI = 6.11 to 7.95); there was no difference in cigarettes per day for students who used no nicotine and low (1–5 mg/mL) or medium (6–17 mg/mL) concentrations.47 This study was limited by its small sample size and short follow-up period. Summary There are few studies that examine the relationship between use of e-cigarettes and subsequent cigarette smoking among youth in a combined smoking and never smoking sample. Three studies43,44,46 suggest a relationship between ever or past 30-day use of e-cigarettes and ever/past 30-day/past 6-month cigarette smoking 0.5–1.5 years later, but none of these studies controlled for baseline-smoking status. Other studies suggest that greater frequency45 of e-cigarette use with higher nicotine concentrations47 is related to greater frequency of cigarette smoking 6 months later (but not infrequent smoking). Another suggests that past 30-day e-cigarette use is associated with the initiation of daily smoking 1 year later.42 Baseline Smokers Three studies examined the relationship between e-cigarette use and subsequent cigarette smoking among smoking youth.38,39,41 One was from a study of 9th-11th grade students in Oahu, Hawaii,39 one was from a subsample of 12th grade students from the Monitoring the Future Study,38 and another was from a school-based smoking intervention in England.41 Youth: Ever or Past 30-Day E-Cigarette Use at Baseline Among high school students in Hawaii39 who were smokers at baseline, baseline ever e-cigarette use did not predict a change in cigarette smoking frequency over time. Among 12th grade students from the Monitoring the Future study38 who were baseline ever cigarette smokers, youth who had used e-cigarettes in the past 30 days at baseline had 2.15 times the risk of reporting cigarette smoking at the 1-year follow-up compared with those who had not used e-cigarettes in the past 30 days. This relationship was not significant among baseline past 30-day cigarette smokers. The third analysis was from the above-described school-based smoking intervention in England.41 Among students who had tried cigarettes at baseline (n = 318), ever use of e-cigarettes at baseline significantly predicted escalation (to rarely, occasional, or frequent smoking) of cigarette smoking at follow-up in unadjusted analyses (OR = 2.16; 95% CI = 1.01 to 4.62), but this relationship was not significant in adjusted analyses (aOR = 1.89; 95% CI = 0.82 to 4.33); attitudes about smoking and intention to smoke were significant effect moderators (p < .05).41 Young Adults: Ever or Past 30-Day E-Cigarette Use at Baseline Six studies measured the longitudinal relationship between e-cigarette use and subsequent cigarette smoking among smoking YAs.40,49–53 One study was from a sample of Hispanic YAs in Los Angeles,40 two were from college student samples,49,51 one was from a sample of nondaily cigarette smokers,50 and two were from a longitudinal study of smokers in the greater Chicago area.52,53 The longitudinal study of Hispanic YAs in Los Angeles previously described40 found that cigarette smokers who used e-cigarettes in 2014 were not significantly more likely to remain cigarette smokers in 2015 (aOR = 1.31; 95% CI = 0.73 to 2.36). The Smokeless Tobacco Use in College Students49 study examined trajectories and correlates of smokeless tobacco use in a cohort of students from 11 colleges in North Carolina and Virginia over the course of their college careers. Among a subsample of past 30-day cigarette smokers with no history of e-cigarette use, ever using an e-cigarette at least once in Waves 1–4 (Fall 2010 to Spring 2012) was associated with increased odds of past 30-day cigarette smoking at Wave 6 (Spring 2013) (aOR = 2.48; 95% CI = 1.32 to 4.66). E-cigarette use at only one wave, however, did not predict subsequent cigarette smoking at Wave 6, but reporting e-cigarette use at two or more waves did (aOR = 3.76; 95% CI = 1.81 to 7.79). This study did not assess frequency of e-cigarette use. Young Adults: Frequency of E-Cigarette Use at Baseline A longitudinal survey of YAs measured daily cigarette consumption and e-cigarette use for 1 year among those who smoked cigarettes monthly for the past 6 months, but had not smoked daily (n = 391).50 Over the course of the year, lagged e-cigarette use predicted both cigarette quantity [incidence rate ratio (IRR) = 1.40; 95% CI = 1.17 to 1.68] and frequency (IRR = 1.18; 95% CI = 1.03 to 1.37), meaning that those who used e-cigarettes at one time-point (3, 6, 9, or 12 months) smoked 40% more cigarettes per day and used cigarettes on 18% more days at the next time-point compared with those who had not used e-cigarettes.50 An analysis from the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) Study52,53 (Waves 5–8; 2011–2015) (n = 586) found that e-cigarette use frequency at each wave of the study was not significantly associated with smoking frequency at the next wave, both directly (β = 0.021, p = .081) and mediated through nicotine dependence (β = 0.005, p = .693).53 This was also found for a subsample of participants who reported using e-cigarettes to quit smoking.52 Young Adults: E-Cigarette Use for Smoking Cessation at Baseline Two studies compared cigarette smoking following use of e-cigarettes for the explicit purpose of smoking cessation. Project M-PACT (previously described) studied quitting behavior among college students in Texas who had a history (100 lifetime cigarettes) of cigarette smoking (n = 627).51 Compared with nonusers of e-cigarettes at baseline, those who used e-cigarettes in the past 30 days for smoking cessation at baseline had 1.95 times the odds (95% CI = 1.16 to 3.28) of being a nonsmoker 6 months later and 1.66 times (95% CI = 1.00 to 2.74) 1 year later; this relationship was not significant for those who had used e-cigarettes at baseline but not for smoking cessation.51 Another analysis from the SECASP Study (Waves 5–8; 2011–2015; n = 586) found that among participants reporting use of e-cigarettes to quit smoking (Wave 5: n = 62; Wave 6: n = 101; Wave 7: n = 148; Wave 8: n = 166) past-wave e-cigarette use was not associated with cigarette smoking at the subsequent wave, but among those who did not use e-cigarettes to quit smoking, past-wave e-cigarette use was associated with more frequent smoking at the next wave for those at very low and high levels of nicotine dependence.52,53 Youth and Young Adults: Ever E-Cigarette Use at Baseline Only one study examined e-cigarette use and subsequent smoking-related outcomes among a sample of smokers with a combined youth and YA sample.48 This study included a sample of youth and YAs participating in the Youth Quitline service (counseling with no pharmacological treatment) in Hong Kong.48 Participants smoked ≥1 cigarette in the past 30 days and were aged 25 and younger (n = 189). After 6 months, point prevalence abstinence (7 days) was lower among ever e-cigarette users than nonusers (13.4% vs. 20.8%), but there was no significant relationship between ever e-cigarette use and any smoking cessation outcome (ie, quit attempts). Only 15.5% used e-cigarettes that contained nicotine and only six participants reported planning to quit with e-cigarettes. Summary There are mixed findings related to the relationship between use of e-cigarettes and subsequent cigarette smoking among youth and YA smokers. One study38 suggests that, among nonrecent smokers, more past 30-day e-cigarette users smoked a cigarette (past-year) 1 year later, but there was no association among recent smokers. Other studies suggest no relationship between trying an e-cigarette and a change in frequency of smoking one year later,39–41,53 whereas another found that more smokers who used an e-cigarette in the past 6 months remained cigarette smokers 1–3 years later.49 One study found that fewer smokers who tried an e-cigarette successfully quit within 6 months.48 Regarding use of e-cigarettes explicitly to quit smoking, one study found that use of e-cigarettes to quit in the past 30 days was associated with quitting 6–12 months later,51 but another study found no relationship.52 Discussion Etter6 outlines a number of criteria for studies addressing the relationship explored in this review based on Hill’s guidelines for causal inference,54 including controlling for confounding variables, establishing a temporal sequence of exposure (e-cigarette use) and outcome (cigarette smoking), and measuring a dose-response effect (ie, frequency/intensity of use of both products). Table 2 lists these criteria and measures of quality from NHLBI’s quality assessment tool for observational studies27 and indicates which studies met those criteria. None of these studies were designed a priori to examine the link specifically between e-cigarette use and subsequent smoking, and so were not designed to assess the range of potential confounding influences that could explain, in whole or in part, the observed association between e-cigarette use and smoking. Only one of the studies included in this review met all criteria (Table 2) necessary to address our main research question.47 However, this study had a relatively short follow-up period of 6 months and a small sample size, limiting the power to detect an effect. The association between the reported high concentration nicotine use via e-cigarettes at baseline and higher number of cigarettes per day at follow-up was based on only 11 smokers.47 Table 2. Assessment of included study methodologies* Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  *Adapted from the National Heart, Lung, and Blood Institute’s criteria for observational studies; **Beyond basic demographic variables; aAdjusted for either interpersonal (eg, peer/family smoking) or intrapersonal (eg, other tobacco use, sensation-seeking) factors; bAdjusted for both interpersonal and intrapersonal factors; cNicotine content was measured, but not device type; dMeasured nicotine content, but did not include this data in the analyses View Large Table 2. Assessment of included study methodologies* Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  Article  Assessed dose of e-cig use?  Assessed dose of cigarette use?  Exposure measured more than once over time?  Controlled for potential confounding variables?**  Assessed e-cig product type or nicotine content?  Barrington-Trimis (2016)28  No  No  No  Yesa  No  Best (2017)34  No  No  Yes  Yesa  No  Bold (2017)46  No  No  Yes  Yesa  No  Conner (2017)41  No  Yes  No  Yesa  No  Doran (2017)50  Yes  Yes  Yes  Yesa  No  Goldenson (2017)47  Yes  Yes  Yes  Yesb  Yesc  Hammond (2017)42  No  Yes  Yes  No  No  Huh (2016)44  No  No  Yes  No  No  Leventhal (2016)45  Yes  Yes  No  Yesb  No  Leventhal (2015)31  No  No  Yes  Yesb  No  Loukas (2018)35  No  No  No  Yesb  No  Lozano (2017)36  No  No  No  Yesb  No  Mantey (2017)51  No  No  No  Yesb  No  Miech (2017)38  No  No  Yes  Yesa  No  Primack (2015)33  No  No  No  Yesa  No  Selya (2017)52  Yes  Yes  Yes  Yesa  No  Selya (2018)53  Yes  Yes  Yes  Yesa  No  Spindle (2017)32  No  No  Yes  Yesb  No  Sutfin (2015)49  No  Yes  Yes  Yesb  No  Treur (2017)37  No  No  No  Yesa  Yesc  Unger (2016)40  No  No  Unclear  Yesa  No  Wang (2017)48  No  Yes  No  Yesa  Yesc,d  Westling (2017)43  No  No  Yes  No  No  Wills (2016a)29  No  No  Yes  Yesb  No  Wills (2016b)30  No  No  Unclear  Yesa  No  Wills (2017)39  Yes  No  Yes  Yesa  No  *Adapted from the National Heart, Lung, and Blood Institute’s criteria for observational studies; **Beyond basic demographic variables; aAdjusted for either interpersonal (eg, peer/family smoking) or intrapersonal (eg, other tobacco use, sensation-seeking) factors; bAdjusted for both interpersonal and intrapersonal factors; cNicotine content was measured, but not device type; dMeasured nicotine content, but did not include this data in the analyses View Large Studies examining the impact of e-cigarette use on later cigarette smoking among never smoking youth and YAs suggest a positive association between e-cigarette use at any frequency and subsequent cigarette smoking trial.28–42 However, these studies have limitations that prevent us from drawing strong conclusions (Table 2). Only one study assessed the frequency or dose of e-cigarette use exposure,39 and none measured the frequency/quantity of subsequent cigarette smoking. Only half of the studies examined continued use of e-cigarettes at follow-up,29,31,32,34,38,39,42 and only one measured self-reported nicotine content.37 Many studies controlled for potential confounding variables, but only five studies29,31,32,35,36 controlled for at least one variable in three major domains: demographic, interpersonal (ie, family/peer smoking), and intrapersonal (ie, other tobacco use, sensation-seeking). The importance of addressing confounding is highlighted by the study of youth in Hawaii that found a stronger association between e-cigarette use and subsequent cigarette smoking among youth considered at risk of smoking.30 When accounting for the mediating effect of marijuana use and smoking expectancies on smoking outcomes, the relationship became nonsignificant, suggesting that the relationship between the use of e-cigarettes and subsequent cigarette smoking is more complex and not a simple direct effect.29 The remaining studies were limited by small sample size (and even smaller number of those who smoked at follow-up), short follow-up period, or low generalizability.32,33,37,38,40,47 Of the six studies that included smokers and never smokers together in the sample, only three controlled for smoking status at baseline.42,45,47 Only two of these studies measured the dose of e-cigarette exposure at baseline and frequency or quantity of cigarette smoking at follow-up.45,47 One of these studies measured self-reported nicotine content.47 Studies of smokers at baseline had mixed findings with respect to whether e-cigarette use was associated with continued or discontinued smoking at follow-up,38–40,48–52 and only two studies controlled for a range of potential confounding variables.49,51 Concerns have been raised that e-cigarettes appeal to youth who would otherwise not use other tobacco products, leading directly to smoking cigarettes.5 The current evidence does not permit firm conclusions in this regard, nor does it allow us to determine whether, as some have hypothesized, e-cigarette use might discourage cigarette smoking among some youth who would have smoked cigarettes anyway.5 Our conclusions differ from the recently published report from the National Academies of Sciences, Engineering and Medicine, which asserts that there is substantial evidence that e-cigarette use increases risk of ever using combustible tobacco cigarettes among youth and YAs.12 We do not deny that there is a detectable association between use of e-cigarettes and subsequent smoking, but the nature of this association is clearly not simple and direct, and is likely the result of a combination of indirect influences. We also cannot rule out the possibility that methodological shortcomings in most of the studies could have unknown effects on their findings. Our review differs in several important ways that may lead us to somewhat different interpretations of the evidence: (1) we did not include any supplementary literature (eg, qualitative studies or studies examining the impact on smoking of other tobacco products), (2) our literature search was conducted through 2017 so included more studies, and (3) we were more conservative in our evaluation of risk of bias (ie, controlling for potentially confounding variables) to support causal inferences. An important consideration for this body of literature is accounting for so-called common-liability characteristics, such as general behavioral factors (eg, risk-taking and adolescent attitudes toward authorities), that predispose toward a wide range of substance use and other risky behaviors.55,56 These characteristics are known risk factors for polytobacco use.57,58 These youth are often more likely to have mental illness and to be exposed to tobacco use and other risky behaviors among their peers and family, putting them at risk for smoking cigarettes or using other tobacco products.6,59,60 Without ruling out other such characteristics of e-cigarette and cigarette users alike, which the majority of studies (17 out of the 26) included in this review have not done, one cannot claim with certainty that use of one product leads directly and causally to another, although this possibility also cannot be ruled out. Another consideration when examining the relationship between e-cigarettes and cigarettes is nicotine addiction. One could hypothesize that using e-cigarettes with nicotine (ie, a “starter product”) could lead to an initial level of addiction that cigarettes may eventually be better at satisfying. However, evidence on self-reported tobacco dependence among adults in the Population Assessment of Tobacco and Health Study shows that e-cigarettes produce lower levels of dependence compared with cigarettes.61 Further, while daily e-cigarette users have higher dependence compared to nondaily users,62 very few youth use e-cigarettes daily—1.1% in 2016.63 Use of other noncombustible tobacco or nicotine delivery products that have been shown to be addictive (although lower than cigarettes) have not been associated with subsequent cigarette smoking.6,55,64 All studies included in this review but two37,47 failed to assess device type (which can affect the efficiency of nicotine delivery65) and nicotine content, which play a role in the products’ potential to induce dependence. However, self-reported nicotine content, particularly among youth, may be an unreliable measure.66 Measuring e-cigarette use simultaneously with cigarette smoking or at only one time-point during the course of a study renders it difficult to establish temporal precedence. The majority of studies had a 6- or 12-month follow-up, which is a relatively short period of time to examine meaningful, sustained changes in smoking behavior. Measuring ever, past-year, past 6-month, or past 30-day use as categorical indicators of exposure also inflates prevalence rates in that they conflate both experimental users and regular users. Measuring varying levels of frequency or intensity of use of both products over longer time horizons is required to determine if and how e-cigarette use leads to regular smoking. In addition, only two studies51,52 measured reasons for use of e-cigarettes, which for smokers could be to quit smoking or, for nonsmokers, to experiment.10 Only two studies examined the link between e-cigarette use and smoking among young people who want to quit smoking. This gap in research illustrates the need to determine the harm reduction potential of e-cigarettes for this population. It is also important to view the results of the studies included in this review in the context of the broader trends at the national level, which suggest that as e-cigarette use has increased, cigarette smoking has declined among both youth and YA populations. However, as of now, no direct determination can be made of the role e-cigarettes may have played in the cigarette decline.5 At a minimum, there is no evidence to date suggesting that the presence of e-cigarettes in the US market has resulted in increased youth cigarette use at the population level. Conclusions Studies included in this review consistently find that e-cigarette use among nonsmokers is associated with subsequent cigarette smoking. Although these studies have stoked concerns about a gateway effect, it is difficult to draw strong conclusions because of methodological limitations of the studies. Studies measuring the impact of e-cigarette use among smokers on continued or discontinued cigarette smoking, in general, did not find significant associations, and are also limited in number and by deficient study designs. Strong causal inferences are currently unsupported, but it is possible that e-cigarette use will increase the risk of smoking for some youth and decrease it for others. One important consideration is that it is likely that youth who use both products share a number of vulnerabilities that put them at risk of using either product, regardless of order. Future research should focus on addressing these characteristics when examining tobacco use patterns. Supplementary Material Supplementary Tables can be found online at https://academic.oup.com/ntr/ Funding This study was funded by Truth Initiative, but the views in this paper do not necessarily represent those of Truth Initiative. Declaration of Interests The authors have no conflicts of interest to report. Acknowledgments The authors would like to thank Lindsay Pitzer and Ollie Ganz for their contributions to reviewing the included papers and guiding the manuscript content. References 1. Arrazola RA, Singh T, Corey CGet al.  ; Centers for Disease Control and Prevention (CDC). Tobacco use among middle and high school students - United States, 2011-2014. MMWR Morb Mortal Wkly Rep . 2015; 64( 14): 381– 385. Google Scholar PubMed  2. King BA, Patel R, Nguyen KH, Dube SR. Trends in awareness and use of electronic cigarettes among US adults, 2010-2013. Nicotine Tob Res . 2015; 17( 2): 219– 227. Google Scholar CrossRef Search ADS PubMed  3. Grana RA. 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For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Nicotine and Tobacco ResearchOxford University Press

Published: May 17, 2018

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