latest research on e cigarettes

• Open access
• Published: 18 May 2021

An updated overview of e-cigarette impact on human health

• Patrice Marques   ORCID: orcid.org/0000-0003-0465-1727 1 , 2 ,
• Laura Piqueras   ORCID: orcid.org/0000-0001-8010-5168 1 , 2 , 3 &
• Maria-Jesus Sanz   ORCID: orcid.org/0000-0002-8885-294X 1 , 2 , 3  

Respiratory Research volume  22 , Article number:  151 ( 2021 ) Cite this article

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The electronic cigarette ( e-cigarette ), for many considered as a safe alternative to conventional cigarettes, has revolutionised the tobacco industry in the last decades. In e-cigarettes , tobacco combustion is replaced by e-liquid heating, leading some manufacturers to propose that e-cigarettes have less harmful respiratory effects than tobacco consumption. Other innovative features such as the adjustment of nicotine content and the choice of pleasant flavours have won over many users. Nevertheless, the safety of e-cigarette consumption and its potential as a smoking cessation method remain controversial due to limited evidence. Moreover, it has been reported that the heating process itself can lead to the formation of new decomposition compounds of questionable toxicity. Numerous in vivo and in vitro studies have been performed to better understand the impact of these new inhalable compounds on human health. Results of toxicological analyses suggest that e-cigarettes can be safer than conventional cigarettes, although harmful effects from short-term e-cigarette use have been described. Worryingly, the potential long-term effects of e-cigarette consumption have been scarcely investigated. In this review, we take stock of the main findings in this field and their consequences for human health including coronavirus disease 2019 (COVID-19).

Electronic nicotine dispensing systems (ENDS), commonly known as electronic cigarettes or e-cigarettes , have been popularly considered a less harmful alternative to conventional cigarette smoking since they first appeared on the market more than a decade ago. E-cigarettes are electronic devices, essentially consisting of a cartridge, filled with an e-liquid, a heating element/atomiser necessary to heat the e-liquid to create a vapour that can be inhaled through a mouthpiece, and a rechargeable battery (Fig.  1 ) [ 1 , 2 ]. Both the electronic devices and the different e-liquids are easily available in shops or online stores.

Effect of the heating process on aerosol composition. Main harmful effects documented. Several compounds detected in e-cigarette aerosols are not present in e-liquid s and the device material also seems to contribute to the presence of metal and silicate particles in the aerosols. The heating conditions especially on humectants, flavourings and the low-quality material used have been identified as the generator of the new compounds in aerosols. Some compounds generated from humectants (propylene glycol and glycerol) and flavourings, have been associated with clear airways impact, inflammation, impairment of cardiovascular function and toxicity. In addition, some of them are carcinogens or potential carcinogens

The e-liquid typically contains humectants and flavourings, with or without nicotine; once vapourised by the atomiser, the aerosol (vapour) provides a sensation similar to tobacco smoking, but purportedly without harmful effects [ 3 ]. However, it has been reported that the heating process can lead to the generation of new decomposition compounds that may be hazardous [ 4 , 5 ]. The levels of nicotine, which is the key addictive component of tobacco, can also vary between the commercially available e-liquids, and even nicotine-free options are available. For this particular reason, e-cigarettes are often viewed as a smoking cessation tool, given that those with nicotine can prevent smoking craving, yet this idea has not been fully demonstrated [ 2 , 6 , 7 ].

Because e-cigarettes are combustion-free, and because most of the damaging and well-known effects of tobacco are derived from this reaction, there is a common and widely spread assumption that e-cigarette consumption or “vaping” is safer than conventional cigarette smoking. However, are they risk-free? Is there sufficient toxicological data on all the components employed in e-liquids ? Do we really know the composition of the inhaled vapour during the heating process and its impact on health? Can e-cigarettes be used to curb tobacco use? Do their consumption impact on coronavirus disease 2019 (COVID-19)? In the present review, we have attempted to clarify these questions based on the existing scientific literature, and we have compiled new insights related with the toxicity derived from the use of these devices.

Effect of e-cigarette vapour versus conventional cigarette exposure: in vivo and in vitro effects

Numerous studies have been performed to evaluate the safety/toxicity of e-cigarette use both in vivo and in in vitro cell culture.

One of the first studies in humans involved the analysis of 9 volunteers that consumed e-cigarettes , with or without nicotine, in a ventilated room for 2 h [ 8 ]. Pollutants in indoor air, exhaled nitric oxide (NO) and urinary metabolite profiles were analysed. The results of this acute experiment revealed that e-cigarettes are not emission-free, and ultrafine particles formed from propylene glycol (PG) could be detected in the lungs. The study also suggested that the presence of nicotine in e-cigarettes increased the levels of NO exhaled from consumers and provoked marked airway inflammation; however, no differences were found in the levels of exhaled carbon monoxide (CO), an oxidative stress marker, before and after e-cigarette consumption [ 8 ]. A more recent human study detected significantly higher levels of metabolites of hazardous compounds including benzene, ethylene oxide, acrylonitrile, acrolein and acrylamide in the urine of adolescent dual users ( e-cigarettes and conventional tobacco consumers) than in adolescent e-cigarette -only users (Table 1 ) [ 9 ]. Moreover, the urine levels of metabolites of acrylonitrile, acrolein, propylene oxide, acrylamide and crotonaldehyde, all of which are detrimental for human health, were significantly higher in e-cigarette -only users than in non-smoker controls, reaching up to twice the registered values of those from non-smoker subjects (Table 1 ) [ 9 ]. In line with these observations, dysregulation of lung homeostasis has been documented in non-smokers subjected to acute inhalation of e-cigarette aerosols [ 10 ].

Little is known about the effect of vaping on the immune system. Interestingly, both traditional and e-cigarette consumption by non-smokers was found to provoke short-term effects on platelet function, increasing platelet activation (levels of soluble CD40 ligand and the adhesion molecule P-selectin) and platelet aggregation, although to a lesser extent with e-cigarettes [ 11 ]. As found with platelets, the exposure of neutrophils to e-cigarette aerosol resulted in increased CD11b and CD66b expression being both markers of neutrophil activation [ 12 ]. Additionally, increased oxidative stress, vascular endothelial damage, impaired endothelial function, and changes in vascular tone have all been reported in different human studies on vaping [ 13 , 14 , 15 , 16 , 17 ]. In this context, it is widely accepted that platelet and leukocyte activation as well as endothelial dysfunction are associated with atherogenesis and cardiovascular morbidity [ 18 , 19 ]. In line with these observations the potential association of daily e-cigarettes consumption and the increased risk of myocardial infarction remains controversial but benefits may occur when switching from tobacco to chronic e-cigarette use in blood pressure regulation, endothelial function and vascular stiffness (reviewed in [ 20 ]). Nevertheless, whether or not e-cigarette vaping has cardiovascular consequences requires further investigation.

More recently, in August 2019, the US Centers for Disease Control and Prevention (CDC) declared an outbreak of the e-cigarette or vaping product use-associated lung injury (EVALI) which caused several deaths in young population (reviewed in [ 20 ]). Indeed, computed tomography (CT scan) revealed local inflammation that impaired gas exchange caused by aerosolised oils from e-cigarettes [ 21 ]. However, most of the reported cases of lung injury were associated with use of e-cigarettes for tetrahydrocannabinol (THC) consumption as well as vitamin E additives [ 20 ] and not necessarily attributable to other e-cigarette components.

On the other hand, in a comparative study of mice subjected to either lab air, e-cigarette aerosol or cigarette smoke (CS) for 3 days (6 h-exposure per day), those exposed to e-cigarette aerosols showed significant increases in interleukin (IL)-6 but normal lung parenchyma with no evidence of apoptotic activity or elevations in IL-1β or tumour necrosis factor-α (TNFα) [ 22 ]. By contrast, animals exposed to CS showed lung inflammatory cell infiltration and elevations in inflammatory marker expression such as IL-6, IL-1β and TNFα [ 22 ]. Beyond airway disease, exposure to aerosols from e-liquids with or without nicotine has also been also associated with neurotoxicity in an early-life murine model [ 23 ].

Results from in vitro studies are in general agreement with the limited number of in vivo studies. For example, in an analysis using primary human umbilical vein endothelial cells (HUVEC) exposed to 11 commercially-available vapours, 5 were found to be acutely cytotoxic, and only 3 of those contained nicotine [ 24 ]. In addition, 5 of the 11 vapours tested (including 4 that were cytotoxic) reduced HUVEC proliferation and one of them increased the production of intracellular reactive oxygen species (ROS) [ 24 ]. Three of the most cytotoxic vapours—with effects similar to those of conventional high-nicotine CS extracts—also caused comparable morphological changes [ 24 ]. Endothelial cell migration is an important mechanism of vascular repair than can be disrupted in smokers due to endothelial dysfunction [ 25 , 26 ]. In a comparative study of CS and e-cigarette aerosols, Taylor et al . found that exposure of HUVEC to e-cigarette aqueous extracts for 20 h did not affect migration in a scratch wound assay [ 27 ], whereas equivalent cells exposed to CS extract showed a significant inhibition in migration that was concentration dependent [ 27 ].

In cultured human airway epithelial cells, both e-cigarette aerosol and CS extract induced IL-8/CXCL8 (neutrophil chemoattractant) release [ 28 ]. In contrast, while CS extract reduced epithelial barrier integrity (determined by the translocation of dextran from the apical to the basolateral side of the cell layer), e-cigarette aerosol did not, suggesting that only CS extract negatively affected host defence [ 28 ]. Moreover, Higham et al . also found that e-cigarette aerosol caused IL-8/CXCL8 and matrix metallopeptidase 9 (MMP-9) release together with enhanced activity of elastase from neutrophils [ 12 ] which might facilitate neutrophil migration to the site of inflammation [ 12 ].

In a comparative study, repeated exposure of human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates led to alterations in morphology, suppression of proliferation and induction of apoptosis, with changes in all three parameters greater in cells exposed to CS condensate [ 29 ]. Likewise, both e-cigarette aerosol and CS extract increased cell death in adenocarcinomic human alveolar basal epithelial cells (A549 cells), and again the effect was more damaging with CS extract than with e-cigarette aerosol (detrimental effects found at 2 mg/mL of CS extract vs. 64 mg/mL of e-cigarette extract) [ 22 ], which is in agreement with another study examining battery output voltage and cytotoxicity [ 30 ].

All this evidence would suggest that e-cigarettes are potentially less harmful than conventional cigarettes (Fig.  2 ) [ 11 , 14 , 22 , 24 , 27 , 28 , 29 ]. Importantly, however, most of these studies have investigated only short-term effects [ 10 , 14 , 15 , 22 , 27 , 28 , 29 , 31 , 32 ], and the long-term effects of e-cigarette consumption on human health are still unclear and require further study.

Comparison of the degree of harmful effects documented from e-cigarette and conventional cigarette consumption. Human studies, in vivo mice exposure and in vitro studies. All of these effects from e-cigarettes were documented to be lower than those exerted by conventional cigarettes, which may suggest that e-cigarette consumption could be a safer option than conventional tobacco smoking but not a clear safe choice

Consequences of nicotine content

Beyond flavour, one of the major issues in the e-liquid market is the range of nicotine content available. Depending on the manufacturer, the concentration of this alkaloid can be presented as low , medium or high , or expressed as mg/mL or as a percentage (% v/v). The concentrations range from 0 (0%, nicotine-free option) to 20 mg/mL (2.0%)—the maximum nicotine threshold according to directive 2014/40/EU of the European Parliament and the European Union Council [ 33 , 34 ]. Despite this normative, however, some commercial e-liquids have nicotine concentrations close to 54 mg/mL [ 35 ], much higher than the limits established by the European Union.

The mislabelling of nicotine content in e-liquids has been previously addressed [ 8 , 34 ]. For instance, gas chromatography with a flame ionisation detector (GC-FID) revealed inconsistencies in the nicotine content with respect to the manufacturer´s declaration (average of 22 ± 0.8 mg/mL vs. 18 mg/mL) [ 8 ], which equates to a content ~ 22% higher than that indicated in the product label. Of note, several studies have detected nicotine in those e-liquids labelled as nicotine-free [ 5 , 35 , 36 ]. One study detected the presence of nicotine (0.11–6.90 mg/mL) in 5 of 23 nicotine-free labelled e-liquids by nuclear magnetic resonance spectroscopy [ 35 ], and another study found nicotine (average 8.9 mg/mL) in 13.6% (17/125) of the nicotine-free e-liquids as analysed by high performance liquid chromatography (HPLC) [ 36 ]. Among the 17 samples tested in this latter study 14 were identified to be counterfeit or suspected counterfeit. A third study detected nicotine in 7 of 10 nicotine-free refills, although the concentrations were lower than those identified in the previous analyses (0.1–15 µg/mL) [ 5 ]. Not only is there evidence of mislabelling of nicotine content among refills labelled as nicotine-free, but there also seems to be a history of poor labelling accuracy in nicotine-containing e-liquids [ 37 , 38 ].

A comparison of the serum levels of nicotine from e-cigarette or conventional cigarette consumption has been recently reported [ 39 ]. Participants took one vape from an e-cigarette , with at least 12 mg/mL of nicotine, or inhaled a conventional cigarette, every 20 s for 10 min. Blood samples were collected 1, 2, 4, 6, 8, 10, 12 and 15 min after the first puff, and nicotine serum levels were measured by liquid chromatography-mass spectrometry (LC–MS). The results revealed higher serum levels of nicotine in the conventional CS group than in the e-cigarette group (25.9 ± 16.7 ng/mL vs. 11.5 ± 9.8 ng/mL). However, e-cigarettes containing 20 mg/mL of nicotine are more equivalent to normal cigarettes, based on the delivery of approximately 1 mg of nicotine every 5 min [ 40 ].

In this line, a study compared the acute impact of CS vs. e-cigarette vaping with equivalent nicotine content in healthy smokers and non-smokers. Both increased markers of oxidative stress and decreased NO bioavailability, flow-mediated dilation, and vitamin E levels showing no significant differences between tobacco and e-cigarette exposure (reviewed in [ 20 ]). Inasmuch, short-term e-cigarette use in healthy smokers resulted in marked impairment of endothelial function and an increase in arterial stiffness (reviewed in [ 20 ]). Similar effects on endothelial dysfunction and arterial stiffness were found in animals when they were exposed to e-cigarette vapor either for several days or chronically (reviewed in [ 20 ]). In contrast, other studies found acute microvascular endothelial dysfunction, increased oxidative stress and arterial stiffness in smokers after exposure to e-cigarettes with nicotine, but not after e-cigarettes without nicotine (reviewed in [ 20 ]). In women smokers, a study found a significant difference in stiffness after smoking just one tobacco cigarette, but not after use of e-cigarettes (reviewed in [ 20 ]).

It is well known that nicotine is extremely addictive and has a multitude of harmful effects. Nicotine has significant biologic activity and adversely affects several physiological systems including the cardiovascular, respiratory, immunological and reproductive systems, and can also compromise lung and kidney function [ 41 ]. Recently, a sub-chronic whole-body exposure of e-liquid (2 h/day, 5 days/week, 30 days) containing PG alone or PG with nicotine (25 mg/mL) to wild type (WT) animals or knockout (KO) mice in α7 nicotinic acetylcholine receptor (nAChRα7-KO) revealed a partly nAChRα7-dependent lung inflammation [ 42 ]. While sub-chronic exposure to PG/nicotine promote nAChRα7-dependent increased levels of different cytokines and chemokines in the bronchoalveolar lavage fluid (BALF) such as IL-1α, IL-2, IL-9, interferon γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1/CCL2) and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), the enhanced levels of IL-1β, IL-5 and TNFα were nAChRα7 independent. In general, most of the cytokines detected in BALF were significantly increased in WT mice exposed to PG with nicotine compared to PG alone or air control [ 42 ]. Some of these effects were found to be through nicotine activation of NF-κB signalling albeit in females but not in males. In addition, PG with nicotine caused increased macrophage and CD4 + /CD8 + T-lymphocytes cell counts in BALF compared to air control, but these effects were ameliorated when animals were sub-chronically exposed to PG alone [ 42 ].

Of note, another study indicated that although RANTES/CCL5 and CCR1 mRNA were upregulated in flavour/nicotine-containing e-cigarette users, vaping flavour and nicotine-less e-cigarettes did not significantly dysregulate cytokine and inflammasome activation [ 43 ].

In addition to its toxicological effects on foetus development, nicotine can disrupt brain development in adolescents and young adults [ 44 , 45 , 46 ]. Several studies have also suggested that nicotine is potentially carcinogenic (reviewed in [ 41 ]), but more work is needed to prove its carcinogenicity independently of the combustion products of tobacco [ 47 ]. In this latter regard, no differences were encountered in the frequency of tumour appearance in rats subjected to long-term (2 years) inhalation of nicotine when compared with control rats [ 48 ]. Despite the lack of carcinogenicity evidence, it has been reported that nicotine promotes tumour cell survival by decreasing apoptosis and increasing proliferation [ 49 ], indicating that it may work as a “tumour enhancer”. In a very recent study, chronic administration of nicotine to mice (1 mg/kg every 3 days for a 60-day period) enhanced brain metastasis by skewing the polarity of M2 microglia, which increases metastatic tumour growth [ 50 ]. Assuming that a conventional cigarette contains 0.172–1.702 mg of nicotine [ 51 ], the daily nicotine dose administered to these animals corresponds to 40–400 cigarettes for a 70 kg-adult, which is a dose of an extremely heavy smoker. We would argue that further studies with chronic administration of low doses of nicotine are required to clearly evaluate its impact on carcinogenicity.

In the aforementioned study exposing human gingival fibroblasts to CS condensate or to nicotine-rich or nicotine-free e-vapour condensates [ 29 ], the detrimental effects were greater in cells exposed to nicotine-rich condensate than to nicotine-free condensate, suggesting that the possible injurious effects of nicotine should be considered when purchasing e-refills . It is also noteworthy that among the 3 most cytotoxic vapours for HUVEC evaluated in the Putzhammer et al . study, 2 were nicotine-free, which suggests that nicotine is not the only hazardous component in e-cigarettes [ 24 ] .

The lethal dose of nicotine for an adult is estimated at 30–60 mg [ 52 ]. Given that nicotine easily diffuses from the dermis to the bloodstream, acute nicotine exposure by e-liquid spilling (5 mL of a 20 mg/mL nicotine-containing refill is equivalent to 100 mg of nicotine) can easily be toxic or even deadly [ 8 ]. Thus, devices with rechargeable refills are another issue of concern with e-cigarettes , especially when e-liquids are not sold in child-safe containers, increasing the risk of spilling, swallowing or breathing.

These data overall indicate that the harmful effects of nicotine should not be underestimated. Despite the established regulations, some inaccuracies in nicotine content labelling remain in different brands of e-liquids . Consequently, stricter regulation and a higher quality control in the e-liquid industry are required.

Effect of humectants and their heating-related products

In this particular aspect, again the composition of the e-liquid varies significantly among different commercial brands [ 4 , 35 ]. The most common and major components of e-liquids are PG or 1,2-propanediol, and glycerol or glycerine (propane-1,2,3-triol). Both types of compounds are used as humectants to prevent the e-liquid from drying out [ 2 , 53 ] and are classified by the Food and Drug Administration (FDA) as “Generally Recognised as Safe” [ 54 ]. In fact, they are widely used as alimentary and pharmaceutical products [ 2 ]. In an analysis of 54 commercially available e-liquids , PG and glycerol were detected in almost all samples at concentrations ranging from 0.4% to 98% (average 57%) and from 0.3% to 95% (average 37%), respectively [ 35 ].

With regards to toxicity, little is known about the effects of humectants when they are heated and chronically inhaled. Studies have indicated that PG can induce respiratory irritation and increase the probability of asthma development [ 55 , 56 ], and both PG and glycerol from e-cigarettes might reach concentrations sufficiently high to potentially cause irritation of the airways [ 57 ]. Indeed, the latter study established that one e-cigarette puff results in a PG exposure of 430–603 mg/m 3 , which is higher than the levels reported to cause airway irritation (average 309 mg/m 3 ) based on a human study [ 55 ]. The same study established that one e-cigarette puff results in a glycerol exposure of 348–495 mg/m 3 [ 57 ], which is close to the levels reported to cause airway irritation in rats (662 mg/m 3 ) [ 58 ].

Airway epithelial injury induced by acute vaping of PG and glycerol aerosols (50:50 vol/vol), with or without nicotine, has been reported in two randomised clinical trials in young tobacco smokers [ 32 ]. In vitro, aerosols from glycerol only-containing refills showed cytotoxicity in A549 and human embryonic stem cells, even at a low battery output voltage [ 59 ]. PG was also found to affect early neurodevelopment in a zebrafish model [ 60 ]. Another important issue is that, under heating conditions PG can produce acetaldehyde or formaldehyde (119.2 or 143.7 ng/puff at 20 W, respectively, on average), while glycerol can also generate acrolein (53.0, 1000.0 or 5.9 ng/puff at 20 W, respectively, on average), all carbonyls with a well-documented toxicity [ 61 ]. Although, assuming 15 puffs per e-cigarette unit, carbonyls produced by PG or glycerol heating would be below the maximum levels found in a conventional cigarette combustion (Table 2 ) [ 51 , 62 ]. Nevertheless, further studies are required to properly test the deleterious effects of all these compounds at physiological doses resembling those to which individuals are chronically exposed.

Although PG and glycerol are the major components of e-liquids other components have been detected. When the aerosols of 4 commercially available e-liquids chosen from a top 10 list of “ Best E-Cigarettes of 2014” , were analysed by gas chromatography-mass spectrometry (GC–MS) after heating, numerous compounds were detected, with nearly half of them not previously identified [ 4 ], thus suggesting that the heating process per se generates new compounds of unknown consequence. Of note, the analysis identified formaldehyde, acetaldehyde and acrolein [ 4 ], 3 carbonyl compounds with known high toxicity [ 63 , 64 , 65 , 66 , 67 ]. While no information was given regarding formaldehyde and acetaldehyde concentrations, the authors calculated that one puff could result in an acrolein exposure of 0.003–0.015 μg/mL [ 4 ]. Assuming 40 mL per puff and 15 puffs per e-cigarette unit (according to several manufacturers) [ 4 ], each e-cigarette unit would generate approximately 1.8–9 μg of acrolein, which is less than the levels of acrolein emitted by a conventional tobacco cigarette (18.3–98.2 μg) [ 51 ]. However, given that e-cigarette units of vaping are not well established, users may puff intermittently throughout the whole day. Thus, assuming 400 to 500 puffs per cartridge, users could be exposed to up to 300 μg of acrolein.

In a similar study, acrolein was found in 11 of 12 aerosols tested, with a similar content range (approximately 0.07–4.19 μg per e-cigarette unit) [ 68 ]. In the same study, both formaldehyde and acetaldehyde were detected in all of the aerosols tested, with contents of 0.2–5.61 μg and 0.11–1.36 μg, respectively, per e-cigarette unit [ 68 ]. It is important to point out that the levels of these toxic products in e-cigarette aerosols are significantly lower than those found in CS: 9 times lower for formaldehyde, 450 times lower for acetaldehyde and 15 times lower for acrolein (Table 2 ) [ 62 , 68 ].

Other compounds that have been detected in aerosols include acetamide, a potential human carcinogen [ 5 ], and some aldehydes [ 69 ], although their levels were minimal. Interestingly, the existence of harmful concentrations of diethylene glycol, a known cytotoxic agent, in e-liquid aerosols is contentious with some studies detecting its presence [ 4 , 68 , 70 , 71 , 72 ], and others finding low subtoxic concentrations [ 73 , 74 ]. Similar observations were reported for the content ethylene glycol. In this regard, either it was detected at concentrations that did not exceed the authorised limit [ 73 ], or it was absent from the aerosols produced [ 4 , 71 , 72 ]. Only one study revealed its presence at high concentration in a very low number of samples [ 5 ]. Nevertheless, its presence above 1 mg/g is not allowed by the FDA [ 73 ]. Figure  1 lists the main compounds detected in aerosols derived from humectant heating and their potential damaging effects. It would seem that future studies should analyse the possible toxic effects of humectants and related products at concentrations similar to those that e-cigarette vapers are exposed to reach conclusive results.

Impact of flavouring compounds

The range of e-liquid flavours available to consumers is extensive and is used to attract both current smokers and new e-cigarette users, which is a growing public health concern [ 6 ]. In fact, over 5 million middle- and high-school students were current users of e-cigarettes in 2019 [ 75 ], and appealing flavours have been identified as the primary reason for e-cigarette consumption in 81% of young users [ 76 ]. Since 2016, the FDA regulates the flavours used in the e-cigarette market and has recently published an enforcement policy on unauthorised flavours, including fruit and mint flavours, which are more appealing to young users [ 77 ]. However, the long-term effects of all flavour chemicals used by this industry (which are more than 15,000) remain unknown and they are not usually included in the product label [ 78 ]. Furthermore, there is no safety guarantee since they may harbour potential toxic or irritating properties [ 5 ].

With regards to the multitude of available flavours, some have demonstrated cytotoxicity [ 59 , 79 ]. Bahl et al. evaluated the toxicity of 36 different e-liquids and 29 different flavours on human embryonic stem cells, mouse neural stem cells and human pulmonary fibroblasts using a metabolic activity assay. In general, those e-liquids that were bubblegum-, butterscotch- and caramel-flavoured did not show any overt cytotoxicity even at the highest dose tested. By contrast, those e-liquids with Freedom Smoke Menthol Arctic and Global Smoke Caramel flavours had marked cytotoxic effects on pulmonary fibroblasts and those with Cinnamon Ceylon flavour were the most cytotoxic in all cell lines [ 79 ]. A further study from the same group [ 80 ] revealed that high cytotoxicity is a recurrent feature of cinnamon-flavoured e-liquids. In this line, results from GC–MS and HPLC analyses indicated that cinnamaldehyde (CAD) and 2-methoxycinnamaldehyde, but not dipropylene glycol or vanillin, were mainly responsible for the high cytotoxicity of cinnamon-flavoured e-liquids [ 80 ]. Other flavouring-related compounds that are associated with respiratory complications [ 81 , 82 , 83 ], such as diacetyl, 2,3-pentanedione or acetoin, were found in 47 out of 51 aerosols of flavoured e-liquids tested [ 84 ] . Allen et al . calculated an average of 239 μg of diacetyl per cartridge [ 84 ]. Assuming again 400 puffs per cartridge and 40 mL per puff, is it is possible to estimate an average of 0.015 ppm of diacetyl per puff, which could compromise normal lung function in the long-term [ 85 ].

The cytotoxic and pro-inflammatory effects of different e-cigarette flavouring chemicals were also tested on two human monocytic cell lines—mono mac 6 (MM6) and U937 [ 86 ]. Among the flavouring chemicals tested, CAD was found to be the most toxic and O-vanillin and pentanedione also showed significant cytotoxicity; by contrast, acetoin, diacetyl, maltol, and coumarin did not show any toxicity at the concentrations assayed (10–1000 µM). Of interest, a higher toxicity was evident when combinations of different flavours or mixed equal proportions of e-liquids from 10 differently flavoured e-liquids were tested, suggesting that vaping a single flavour is less toxic than inhaling mixed flavours [ 86 ]. Also, all the tested flavours produced significant levels of ROS in a cell-free ROS production assay. Finally, diacetyl, pentanedione, O-vanillin, maltol, coumarin, and CAD induced significant IL-8 secretion from MM6 and U937 monocytes [ 86 ]. It should be borne in mind, however, that the concentrations assayed were in the supra-physiological range and it is likely that, once inhaled, these concentrations are not reached in the airway space. Indeed, one of the limitations of the study was that human cells are not exposed to e-liquids per se, but rather to the aerosols where the concentrations are lower [ 86 ]. In this line, the maximum concentration tested (1000 µM) would correspond to approximately 80 to 150 ppm, which is far higher than the levels found in aerosols of some of these compounds [ 84 ]. Moreover, on a day-to-day basis, lungs of e-cigarette users are not constantly exposed to these chemicals for 24 h at these concentrations. Similar limitations were found when five of seven flavourings were found to cause cytotoxicity in human bronchial epithelial cells [ 87 ].

Recently, a commonly commercialized crème brûlée -flavoured aerosol was found to contain high concentrations of benzoic acid (86.9 μg/puff), a well-established respiratory irritant [ 88 ]. When human lung epithelial cells (BEAS-2B and H292) were exposed to this aerosol for 1 h, a marked cytotoxicity was observed in BEAS-2B but not in H292 cells, 24 h later. However, increased ROS production was registered in H292 cells [ 88 ].

Therefore, to fully understand the effects of these compounds, it is relevant the cell cultures selected for performing these assays, as well as the use of in vivo models that mimic the real-life situation of chronic e-cigarette vapers to clarify their impact on human health.

The e-cigarette device

While the bulk of studies related to the impact of e-cigarette use on human health has focused on the e-liquid components and the resulting aerosols produced after heating, a few studies have addressed the material of the electronic device and its potential consequences—specifically, the potential presence of metals such as copper, nickel or silver particles in e-liquids and aerosols originating from the filaments and wires and the atomiser [ 89 , 90 , 91 ].

Other important components in the aerosols include silicate particles from the fiberglass wicks or silicone [ 89 , 90 , 91 ]. Many of these products are known to cause abnormalities in respiratory function and respiratory diseases [ 89 , 90 , 91 ], but more in-depth studies are required. Interestingly, the battery output voltage also seems to have an impact on the cytotoxicity of the aerosol vapours, with e-liquids from a higher battery output voltage showing more toxicity to A549 cells [ 30 ].

A recent study compared the acute effects of e-cigarette vapor (with PG/vegetable glycerine plus tobacco flavouring but without nicotine) generated from stainless‐steel atomizer (SS) heating element or from a nickel‐chromium alloy (NC) [ 92 ]. Some rats received a single e-cigarette exposure for 2 h from a NC heating element (60 or 70 W); other rats received a similar exposure of e-cigarette vapor using a SS heating element for the same period of time (60 or 70 W) and, a final group of animals were exposed for 2 h to air. Neither the air‐exposed rats nor those exposed to e-cigarette vapor using SS heating elements developed respiratory distress. In contrast, 80% of the rats exposed to e-cigarette vapor using NC heating units developed clinical acute respiratory distress when a 70‐W power setting was employed. Thus, suggesting that operating units at higher than recommended settings can cause adverse effects. Nevertheless, there is no doubt that the deleterious effects of battery output voltage are not comparable to those exerted by CS extracts [ 30 ] (Figs.  1 and 2 ).

E-cigarettes as a smoking cessation tool

CS contains a large number of substances—about 7000 different constituents in total, with sizes ranging from atoms to particulate matter, and with many hundreds likely responsible for the harmful effects of this habit [ 93 ]. Given that tobacco is being substituted in great part by e-cigarettes with different chemical compositions, manufacturers claim that e -cigarette will not cause lung diseases such as lung cancer, chronic obstructive pulmonary disease, or cardiovascular disorders often associated with conventional cigarette consumption [ 3 , 94 ]. However, the World Health Organisation suggests that e-cigarettes cannot be considered as a viable method to quit smoking, due to a lack of evidence [ 7 , 95 ]. Indeed, the results of studies addressing the use of e-cigarettes as a smoking cessation tool remain controversial [ 96 , 97 , 98 , 99 , 100 ]. Moreover, both FDA and CDC are actively investigating the incidence of severe respiratory symptoms associated with the use of vaping products [ 77 ]. Because many e-liquids contain nicotine, which is well known for its powerful addictive properties [ 41 ], e-cigarette users can easily switch to conventional cigarette smoking, avoiding smoking cessation. Nevertheless, the possibility of vaping nicotine-free e-cigarettes has led to the branding of these devices as smoking cessation tools [ 2 , 6 , 7 ].

In a recently published randomised trial of 886 subjects who were willing to quit smoking [ 100 ], the abstinence rate was found to be twice as high in the e-cigarette group than in the nicotine-replacement group (18.0% vs. 9.9%) after 1 year. Of note, the abstinence rate found in the nicotine-replacement group was lower than what is usually expected with this therapy. Nevertheless, the incidence of throat and mouth irritation was higher in the e-cigarette group than in the nicotine-replacement group (65.3% vs. 51.2%, respectively). Also, the participant adherence to the treatment after 1-year abstinence was significantly higher in the e-cigarette group (80%) than in nicotine-replacement products group (9%) [ 100 ].

On the other hand, it is estimated that COPD could become the third leading cause of death in 2030 [ 101 ]. Given that COPD is generally associated with smoking habits (approximately 15 to 20% of smokers develop COPD) [ 101 ], smoking cessation is imperative among COPD smokers. Published data revealed a clear reduction of conventional cigarette consumption in COPD smokers that switched to e-cigarettes [ 101 ]. Indeed, a significant reduction in exacerbations was observed and, consequently, the ability to perform physical activities was improved when data was compared with those non-vapers COPD smokers. Nevertheless, a longer follow-up of these COPD patients is required to find out whether they have quitted conventional smoking or even vaping, since the final goal under these circumstances is to quit both habits.

Based on the current literature, it seems that several factors have led to the success of e-cigarette use as a smoking cessation tool. First, some e-cigarette flavours positively affect smoking cessation outcomes among smokers [ 102 ]. Second, e-cigarettes have been described to improve smoking cessation rate only among highly-dependent smokers and not among conventional smokers, suggesting that the individual degree of nicotine dependence plays an important role in this process [ 97 ]. Third, the general belief of their relative harmfulness to consumers' health compared with conventional combustible tobacco [ 103 ]. And finally, the exposure to point-of-sale marketing of e-cigarette has also been identified to affect the smoking cessation success [ 96 ].

Implication of e-cigarette consumption in COVID-19 time

Different reports have pointed out that smokers and vapers are more vulnerable to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infections or more prone to adverse outcomes if they suffer COVID-19 [ 104 ]. However, while a systematic review indicated that cigarette smoking is probably associated with enhanced damage from COVID-19, a meta-analysis did not, yet the latter had several limitations due to the small sample sizes [ 105 ].

Interestingly, most of these reports linking COVID-19 harmful effects with smoking or vaping, are based on their capability of increasing the expression of angiotensin-converting enzyme 2 (ACE2) in the lung. It is well known that ACE2 is the gate for SARS-CoV-2 entrance to the airways [ 106 ] and it is mainly expressed in type 2 alveolar epithelial cells and alveolar macrophages [ 107 ]. To date, most of the studies in this field indicate that current smokers have higher expression of ACE2 in the airways (reviewed by [ 108 ]) than healthy non-smokers [ 109 , 110 ]. However, while a recent report indicated that e-cigarette vaping also caused nicotine-dependent ACE2 up-regulation [ 42 ], others have revealed that neither acute inhalation of e-cigarette vapour nor e-cigarette users had increased lung ACE2 expression regardless nicotine presence in the e-liquid [ 43 , 110 ].

In regard to these contentions, current knowledge suggests that increased ACE2 expression is not necessarily linked to enhanced susceptibility to SARS-CoV-2 infection and adverse outcome. Indeed, elderly population express lower levels of ACE2 than young people and SARS-CoV-2/ACE2 interaction further decreases ACE2 expression. In fact, most of the deaths provoked by COVID-19 took place in people over 60 years old of age [ 111 ]. Therefore, it is plausible that the increased susceptibility to disease progression and the subsequent fatal outcome in this population is related to poor angiotensin 1-7 (Ang-1-7) generation, the main peptide generated by ACE2, and probably to their inaccessibility to its anti-inflammatory effects. Furthermore, it seems that all the efforts towards increasing ACE2 expression may result in a better resolution of the pneumonic process associated to this pandemic disease.

Nevertheless, additional complications associated to COVID-19 are increased thrombotic events and cytokine storm. In the lungs, e-cigarette consumption has been correlated to toxicity, oxidative stress, and inflammatory response [ 32 , 112 ]. More recently, a study revealed that while the use of nicotine/flavour-containing e-cigarettes led to significant cytokine dysregulation and potential inflammasome activation, none of these effects were detected in non-flavoured and non-nicotine-containing e-cigarettes [ 43 ]. Therefore, taken together these observations, e-cigarette use may still be a potent risk factor for severe COVID-19 development depending on the flavour and nicotine content.

In summary, it seems that either smoking or nicotine vaping may adversely impact on COVID-19 outcome. However, additional follow up studies are required in COVID-19 pandemic to clarify the effect of e-cigarette use on lung and cardiovascular complications derived from SARS-CoV-2 infection.

Conclusions

The harmful effects of CS and their deleterious consequences are both well recognised and widely investigated. However, and based on the studies carried out so far, it seems that e-cigarette consumption is less toxic than tobacco smoking. This does not necessarily mean, however, that e-cigarettes are free from hazardous effects. Indeed, studies investigating their long-term effects on human health are urgently required. In this regard, the main additional studies needed in this field are summarized in Table 3 .

The composition of e-liquids requires stricter regulation, as they can be easily bought online and many incidences of mislabelling have been detected, which can seriously affect consumers’ health. Beyond their unknown long-term effects on human health, the extended list of appealing flavours available seems to attract new “never-smokers”, which is especially worrying among young users. Additionally, there is still a lack of evidence of e-cigarette consumption as a smoking cessation method. Indeed, e-cigarettes containing nicotine may relieve the craving for smoking, but not the conventional cigarette smoking habit.

Interestingly, there is a strong difference of opinion on e-cigarettes between countries. Whereas countries such as Brazil, Uruguay and India have banned the sale of e-cigarettes , others such as the United Kingdom support this device to quit smoking. The increasing number of adolescent users and reported deaths in the United States prompted the government to ban the sale of flavoured e-cigarettes in 2020. The difference in opinion worldwide may be due to different restrictions imposed. For example, while no more than 20 ng/mL of nicotine is allowed in the EU, e-liquids with 59 mg/dL are currently available in the United States. Nevertheless, despite the national restrictions, users can easily access foreign or even counterfeit products online.

In regard to COVID-19 pandemic, the actual literature suggests that nicotine vaping may display adverse outcomes. Therefore, follow up studies are necessary to clarify the impact of e-cigarette consumption on human health in SARS-CoV-2 infection.

In conclusion, e-cigarettes could be a good alternative to conventional tobacco cigarettes, with less side effects; however, a stricter sale control, a proper regulation of the industry including flavour restriction, as well as further toxicological studies, including their chronic effects, are warranted.

Availability of data and materials

Not applicable.

Abbreviations

Angiotensin-converting enzyme 2

Angiotensin 1-7

Bronchoalveolar lavage fluid

Cinnamaldehyde

US Centers for Disease Control and Prevention

Carbon monoxide

Chronic obstructive pulmonary disease

Coronavirus disease 2019

Cigarette smoke

Electronic nicotine dispensing systems

e-cigarette or vaping product use-associated lung injury

Food and Drug Administration

Gas chromatography with a flame ionisation detector

Gas chromatography-mass spectrometry

Granulocyte–macrophage colony-stimulating factor

High performance liquid chromatography

Human umbilical vein endothelial cells

Interleukin

Interferon γ

Liquid chromatography-mass spectrometry

Monocyte chemoattractant protein-1

Matrix metallopeptidase 9

α7 Nicotinic acetylcholine receptor

Nickel‐chromium alloy

Nitric oxide

Propylene glycol

Regulated on activation, normal T cell expressed and secreted

Reactive oxygen species

Severe acute respiratory syndrome coronavirus 2

Stainless‐steel atomizer

Tetrahydrocannabinol

Tumour necrosis factor-α

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Acknowledgements

The authors gratefully acknowledge Dr. Cruz González, Pulmonologist at University Clinic Hospital of Valencia (Valencia, Spain) for her thoughtful suggestions and support.

This work was supported by the Spanish Ministry of Science and Innovation [Grant Number SAF2017-89714-R]; Carlos III Health Institute [Grant Numbers PIE15/00013, PI18/00209]; Generalitat Valenciana [Grant Number PROMETEO/2019/032, Gent T CDEI-04/20-A and AICO/2019/250], and the European Regional Development Fund.

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Marques, P., Piqueras, L. & Sanz, MJ. An updated overview of e-cigarette impact on human health. Respir Res 22 , 151 (2021). https://doi.org/10.1186/s12931-021-01737-5

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Latest Cochrane Review finds high certainty evidence that nicotine e-cigarettes are more effective than traditional nicotine-replacement therapy (NRT) in helping people quit smoking

A Cochrane review  has found the strongest evidence yet that e-cigarettes, also known as ‘vapes’, help people to quit smoking better than traditional nicotine replacement therapies, such as patches and chewing gums.

New evidence published today in the Cochrane Library finds high certainty evidence that people are more likely to stop smoking for at least six months using nicotine e-cigarettes, or ‘vapes’, than using nicotine replacement therapies, such as patches and gums. Evidence also suggested that nicotine e-cigarettes led to higher quit rates than e-cigarettes without nicotine, or no stop smoking intervention, but less data contributed to these analyses. The updated Cochrane review includes 78 studies in over 22,000 participants – an addition of 22 studies since the last update in 2021.

Smoking is a significant global health problem. According to the World Health Organisation (WHO), in 2020, 22.3% of the global population used tobacco, despite it killing up to half of its users. Stopping smoking reduces the risk of lung cancer, heart attacks and many other diseases. Though most people who smoke want to quit, many find it difficult to do so permanently. Nicotine patches and gum are safe, effective and widely used methods to help individuals quit.

E-cigarettes heat liquids with nicotine and flavourings, allowing users to ‘vape’ nicotine instead of smoking. Data from the review showed that i f six in 100 people quit by using nicotine replacement therapy, eight to twelve would quit by using electronic cigarettes containing nicotine. This means an additional two to six people in 100 could potentially quit smoking with nicotine containing electronic cigarettes.

Dr Jamie Hartmann-Boyce, Associate Professor at the University of Oxford, Editor of the Cochrane Tobacco Addiction Group, and an author of the new publication, said:

“Electronic cigarettes have generated a lot of misunderstanding in both the public health community and the popular press since their introduction over a decade ago. These misunderstandings discourage some people from using e-cigarettes as a stop smoking tool. Fortunately, more and more evidence is emerging and provides further clarity. With support from Cancer Research UK, we search for new evidence every month as part of a living systematic review. We identify and combine the strongest evidence from the most reliable scientific studies currently available. For the first time, this has given us high-certainty evidence that e-cigarettes are even more effective at helping people to quit smoking than traditional nicotine replacement therapies, like patches or gums.”

In studies comparing nicotine e-cigarettes to nicotine replacement treatment, significant side effects were rare. In the short-to-medium term (up to two years), nicotine e-cigarettes most typically caused throat or mouth irritation, headache, cough, and feeling nauseous. However, these effects appeared to diminish over time.

Dr Nicola Lindson, University Research Lecturer at the University of Oxford, Cochrane Tobacco Addiction Group’s Managing Editor, and author of the publication said:

“ E-cigarettes do not burn tobacco; and as such they do not expose users to the same complex mix of chemicals that cause diseases in people smoking conventional cigarettes. E-cigarettes are not risk free, and shouldn’t be used by people who don’t smoke or aren’t at risk of smoking. However, evidence shows that nicotine e-cigarettes carry only a small fraction of the risk of smoking. In our review, we did not find evidence of substantial harms caused by nicotine containing electronic cigarettes when used to quit smoking. However, due to the small number of studies and lack of data on long-term nicotine-containing electronic cigarette usage – usage over more than two years – questions remain about long-term effects.”

The researchers conclude that more evidence, particularly about the effects of newer e-cigarettes with better nicotine delivery than earlier ones, is needed to assist more people quit smoking. Longer-term data is also needed.

Michelle Mitchell, chief executive at Cancer Research UK, said:

“We welcome this report which adds to a growing body of evidence showing that e-cigarettes are an effective smoking cessation tool. We strongly discourage those who have never smoked from using e-cigarettes, especially young people. This is because they are a relatively new product and we don’t yet know the long term health effects. While the long term effects of vaping are still unknown, the harmful effects of smoking are indisputable – smoking causes around 55,000 cancer deaths in the UK every year. Cancer Research UK supports balanced evidence-based regulation on e-cigarettes from UK governments which maximises their potential to help people stop smoking, whilst minimising the risk of uptake among others.”

• Read the full Cochrane review and plain language summary 
• Learn more about Cochrane Tobacco Addition Group
• Science Media Centre: Expert reaction to cochrane review on electronic cigarettes for smoking cessation

 Hartmann-Boyce J, Lindson N, Butler AR, McRobbie H, Bullen C, Begh R, Theodoulou A, Notley C, Rigotti NA, Turner T, Fanshawe TR, Hajek P. Electronic cigarettes for smoking cessation. Cochrane Database of Systematic Reviews 2022, Issue 11. Art. No.: CD010216. DOI: 10.1002/14651858.CD010216.pub7

This work was supported by Cancer Research UK [A ref. A29845]

To speak to a team member about this project please contact Dr. Hartmann-Boyce, [email protected] or Dr. Lindson, [email protected] .

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• Published: 22 October 2022

A systematic review of the effects of e-cigarette use on lung function

• Lucy Honeycutt 1 ,
• Katherine Huerne 1 , 2 ,
• Alanna Miller 1 ,
• Erica Wennberg 1 ,
• Kristian B. Filion 1 , 3 ,
• Roland Grad 1 , 4 ,
• Andrea S. Gershon 5 ,
• Carolyn Ells   ORCID: orcid.org/0000-0002-4593-454X 1 , 2 , 4 ,
• Genevieve Gore 6 ,
• Andrea Benedetti 3 , 7 ,
• Brett Thombs 1 , 3 , 8 &
• Mark J. Eisenberg   ORCID: orcid.org/0000-0002-1296-0661 1 , 3 , 9  

npj Primary Care Respiratory Medicine volume  32 , Article number:  45 ( 2022 ) Cite this article

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• Epidemiology

Given the increasing use of e-cigarettes and uncertainty surrounding their safety, we conducted a systematic review to determine the effects of e-cigarettes on measures of lung function. We systematically searched EMBASE, MEDLINE, and PsycINFO databases via Ovid, the Cochrane CENTRAL database, and the Web of Science Core from 2004 until July 2021, identifying 8856 potentially eligible studies. A total of eight studies (seven studying immediate effects and one long-term effects, 273 total participants) were included. The risk of bias was assessed using the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) and Cochrane risk of bias tools. These studies suggest that vaping increases airway resistance but does not appear to impact forced expiratory volume in one second (FEV 1) , forced vital capacity (FVC), or FEV 1 /FVC ratio. However, given the limited size and follow-up duration of these studies, larger, long-term studies are required to further determine the effects of e-cigarettes on lung function.

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Introduction.

The first electronic cigarette (e-cigarette) was patented and marketed in 2004 1 . Since then, e-cigarette use (or “vaping”) has grown exponentially across the globe 2 . As the use of vaping devices evolves with policy, the consequences of vaping on health are becoming an increasingly important public health issue. E-cigarettes are being studied for harm reduction in individuals who use cigarettes and as a smoking cessation aid, as they are believed to be less harmful to health than smoking 3 . However, there is increasing evidence demonstrating adverse respiratory effects of vaping compared to vaping abstinence. In particular, an outbreak of E-Cigarette and Vaping-Associated Lung Illness (EVALI) brought the short-term respiratory consequences of vaping into question, especially if cannabis or THC-containing products are used 4 . Other short-term respiratory changes that have been linked to vaping include increased airway resistance 5 , breathing difficulty 6 , and transient lung inflammation 7 . Vaping has also been associated with chronic respiratory conditions such as asthma 8 and chronic bronchitis 9 . Despite these reports, the short- and long-term respiratory safety of vaping is still largely unknown. Several small studies have examined the effects of e-cigarettes on lung function, including measures such as forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC), and airway resistance. However, no evidence syntheses have been completed on this topic. Therefore, we conducted a systematic review to determine the effects of vaping on measures of lung function.

Our systematic review was conducted following a protocol developed prior to initiating the review, which was registered on the PROSPERO register of systematic reviews ( CRD42021227121 ) 10 . This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 11 .

Search strategy and study selection

Using a search strategy (Supplementary Tables 1 – 5 ) developed by an experienced health sciences librarian (G.G.), we systematically searched EMBASE, MEDLINE, and PsycINFO databases via Ovid, the Cochrane CENTRAL database, and the Web of Science Core from 2004 (the year of the first e-cigarette patent) until July 12, 2021. We additionally conducted a gray literature search by searching the websites of key governmental and public health organizations (the World Health Organization, Health Canada, the US Centers for Disease Control and Prevention, the US Food and Drug Administration, the Canadian Center on Substance Use and Addiction, the European Centre for Disease Prevention and Control, and the European Public Health Association). Additional articles were identified by manually searching the reference lists of included publications as well as SCOPUS and Google Scholar (first ten pages). Articles were included if they reported quantitative primary data on changes in lung function associated with vaping, defined as the use of any device that functions by transforming an e-liquid to an aerosol using metal coils, among human participants of any age. Studies of cells and those conducted in animals were excluded. Studies using heat-not-burn devices were also excluded, as these do not meet the above definition of vaping. Eligible studies included randomized controlled trials (RCTs), non-randomized studies of interventions (NRSIs), and cohort studies; cross-sectional studies and case reports were excluded. We included studies that used non-users of both vaping devices and conventional cigarettes as a comparison group and those that used a pre- and post-design in which individuals acted as their own controls. Inclusion was not restricted by language or country of publication. Abstracts and conference proceedings were included if sufficient data could be extracted from these publications.

Search results were downloaded from databases into reference management software (EndNote X9) or manually added (e.g., for gray literature results). Duplicates were removed in EndNote and entries were uploaded to Covidence (Veritas Health Innovation, Melbourne, Australia), a systematic review software. Two reviewers (L.H. and K.H.) independently screened the titles and abstracts of all identified publications for eligibility. Citations considered potentially eligible by either reviewer, based on the pre-specified review inclusion/exclusion criteria (Supplementary Table 6 ), were retrieved for full-text screening and assessed for inclusion. The reasons for exclusion after full-text review were annotated in Covidence and any disagreements were resolved by consensus or a third reviewer (A.H-L.).

Data extraction

Two independent reviewers (L.H and K.H.) extracted methodological, demographic, and outcome data from included studies in duplicate; disagreements were detected in Covidence and were resolved by consensus or, if necessary, by a third reviewer (A.H-L.). Extracted data included study characteristics (first author, journal, year of publication, years(s) of data collection, funding, data source, study design, recruitment strategy, duration of follow-up, country of origin, sample size); population characteristics (sex, gender, age, race, ethnicity, socioeconomic status, dose/frequency of e-cigarette use, conventional cigarette smoking status, smoked cannabis use); and vaping behavior, including the type of vaping device used (e.g., disposable e-cigarette vs. pod device such as JUUL), vaping products used (e.g., nicotine cartridges exclusively vs. THC cartridges exclusively vs. dual use of nicotine and THC products), and source of the vaping product (informal [i.e., friends, family members, or dealers] vs. commercial [i.e., vape shops, stores, dispensaries]).

Initially, extracted outcomes of primary interest were respiratory signs and symptoms, as these are important to patients and are the early signs of respiratory disease. Secondary outcomes included: findings on lung function; Computed tomography (CT) findings of emphysema, airway remodeling, and small airway loss; respiratory-related quality of life and exercise limitations; incidence and/or prevalence of respiratory disease as well as exacerbations of previous respiratory disease; and health care resource use including respiratory disease-related ambulatory care, emergency department visits, and hospitalization. Given the limited number of studies available and the heterogeneity of the data extracted from these studies, no meta-analysis was conducted.

Risk of bias

The risk of bias in included publications was assessed independently by two reviewers (L.H. and K.H.), and discrepancies were resolved by consensus or, if necessary, by a third reviewer (A.H-L.). The risk of bias of included non-randomized studies (pre-post studies, NRSI with non-vaping reference group, cohort study) was assessed using the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool 12 . The ROBINS-I tool evaluates intervention-specific outcomes for a study through seven domains which assess the risk of bias pre-intervention, at-intervention, and post-intervention. For each outcome of interest extracted from an included study, the risk of bias within each domain was reported as “low”, “moderate”, “serious”, or “critical”. Included RCTs were assessed using the Cochrane Collaboration’s Tool for Assessing Risk of Bias (ROB V1) 13 . Similar to ROBINS-I, this tool evaluates the risk of bias through the assessment of five domains; for each outcome of interest extracted from an included study, the risk of bias for each domain was reported as “low risk of bias”, “high risk of bias”, or “unclear risk of bias.” All eligible publications were included in the qualitative synthesis regardless of their assessed risk of bias.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

As our search did not identify studies which focused on the broad outcomes detailed above, we chose to limit our focus to studies on lung function. Our database searches identified 14,307 potentially eligible studies (Fig. 1 ). After duplicates were removed, 8856 titles and abstracts were assessed. After this initial screening, 44 full texts were retrieved and reviewed in further detail, yielding eight studies eligible for inclusion.

PRISMA flow diagram of included studies assessing the effect of e-cigarettes on lung function.

Study and participant characteristics

Of the eight included studies (273 total participants), seven 14 , 15 , 16 , 17 , 18 , 19 , 20 involved short-term exposure to e-cigarettes with immediate outcome assessment, and the remaining study followed vapers and non-vapers over 3.5 years 21 (Table 1 ). This prospective cohort study examined 21 participants (12 nonsmokers and nine vapers) at means of 12 (standard deviation: 1), 24 (2), and 42 (2) months after baseline 21 . Of the seven short-term studies, four were NRSIs (three pre-post studies 14 , 15 , 16 and one NRSI with a non-vaping reference group 20 ) and three were RCTs 17 , 18 , 19 . Among these seven studies, two included 70–80 participants 14 , 15 and five included 10–30 participants 16 , 17 , 18 , 19 , 20 . Exposures varied in terms of e-cigarettes, e-liquids, and vaping session timings. Most studies did not expand on their definition of “non-smoker/non-vaper” 15 , 16 , 18 , 19 , 20 , 21 , but two studies clarified that these participants were never-smokers 14 , 17 . One of these two studies further elaborated that participants had no exposure to tobacco products or e-cigarettes 17 . Few studies gave detailed information on the type of e-cigarette used. Three studies reported a specific brand or product (Blu 17 , eGo 16 , Joytech elips-C series 18 , Puff bar 20 ). Polosa et al. listed some of the various e-cigarettes used by participants throughout the longitudinal study, including standard refillable (eGo style products) and more advanced refillable (Provari, Innokin, Joytech, eVIC, Avatar Puff) 21 . The remaining studies did not report a specific brand, though one study described the e-cigarette used as a “1 st generation e-cigarette popular in Greece” 15 . All studies clarified whether the e-cigarettes used during the study contained nicotine.

The included RCTs ( n  = 3) 17 , 18 , 19 had an unclear risk of bias, with each study demonstrating an unclear risk of bias in 3+ domains (Table 2 ). This was primarily due to missing information in the manuscripts required to make an adequate judgment, such as a lack of detail surrounding randomization. The risk associated with the blinding of participants and personnel was judged to be low for all 3 included RCTs. These studies were not blinded, and one was placebo-controlled. However, it was judged that this lack of blinding would not influence measures of lung function. Of the included non-randomized studies ( n  = 5) 14 , 15 , 16 , 20 , 21 , four 14 , 15 , 16 , 20 were judged to be at moderate risk of bias and one 21 was found to have a serious risk of bias (Table 3 ). The most consistent source of bias in these studies was bias due to confounding, with only one 16 study judged to have a low risk of bias due to confounding. Of the remaining four studies, three 14 , 15 , 20 were found to have a moderate risk of bias due to confounding and one 21 was found to be at serious risk of bias due to confounding, with important confounding variables not accounted for in the design or analysis.

Effects of E-cigarette use on lung function

Seven studies 14 , 15 , 16 , 17 , 18 , 19 , 20 reported immediate measures of lung function after short-term exposure to e-cigarettes (Table 4 ), including FEV 1 , FVC, and FEV 1 /FVC. Two studies, Boulay et al. and Staudt. et al. suggested no changes in FEV 1 or FEV 1 /FVC after vaping among nonsmokers 17 , 19 . Kizhakke Puliyakote et al. observed lower baseline FEV 1 and FEV 1 /FVC values among nonsmokers compared to vapers 20 . Coppeta et al. found a decrease in FEV 1 and FEV 1 /FVC among nonsmokers after 1 min of vaping; however, these values returned to baseline after 15 min 16 .

Airway resistance and specific airway conductance after 10 min of vaping were measured in two 14 , 15 of the seven short-term studies (Table 4 ). Both Palamidas et al. 2013 and 2017 suggested that vaping increased airway resistance and decreased specific airway conductance among nonsmokers and smokers with and without respiratory disease. Oxygen saturation was assessed in four studies 15 , 17 , 19 , 20 . Three studies suggested no changes after vaping, with only Palamidas et. al. 2017 suggesting decreased oxygen saturation following vaping among smokers with and without asthma 15 .

Long-term changes (3.5 years) in lung function measurements were assessed in only one small ( n  = 21) study (Polosa 2017) 21 . This study suggested that FEV 1 , FVC, FEV 1 /FVC, and forced mid-expiratory flow (FEF 25-75 ) did not change over time among vapers and non-vapers (Table 5 ).

This systematic review was designed to determine the effect of vaping on measures of lung function. We found that there were only eight studies in the literature assessing this issue, all of which were small, and only one examined longer-term outcomes (3.5 years follow-up). In general, these studies suggest that there are no acute changes associated with vaping. However, airway resistance and conductance may be influenced by e-cigarettes, with two studies reporting changes in these values in multiple population subgroups. It is important to note that there were few studies available for this systematic review and that most of these studies focused on the acute effects of vaping; therefore, these results are suggestive but not definitive, and future research must be conducted in this area. Furthermore, three of the included studies had an unclear risk of bias, four had a moderate risk of bias, and one had a serious risk of bias, which further limits the interpretation of this review’s findings.

In addition to the limitations above, this review lacks subgroup analyses or a meta-analysis. This is due to the heterogeneity of the included studies, both in terms of study design and outcomes. Few studies were eligible for this review due to the variation in study designs and definitions of e-cigarettes and smoking status. For example, some studies included both conventional cigarette smokers and nonsmokers in their definition of “non-vapers” and did not analyze data separately based on conventional smoking status. Other studies used a “sham” vaping session for controls where either an e-cigarette with an empty cartridge (i.e., without e-liquid) or second-hand smoke were used. More commonly, studies were conducted on smokers only, without nonsmokers as a comparison group. Future studies could analyze subgroups based on both smoking and vaping status to allow for a more detailed quantitative analysis.

E-cigarettes are becoming more popular for recreational use and are being studied for harm reduction among smokers as a smoking cessation aid, as they are believed to be less harmful to health than smoking. However, there are limited data available and virtually no long-term studies assessing how prolonged e-cigarette use could impact lung function. As the use of vaping devices evolves and becomes more widespread, the health consequences of vaping are becoming an increasingly important public health issue. This is a knowledge gap that must be addressed. Knowledge of the safety of e-cigarettes, particularly their long-term safety, will inform public health policy and e-cigarette regulations, as well as the guidance clinicians, offer to their patients on smoking harm reduction. For these policies, regulations, and guidelines to be developed, we must understand how e-cigarettes can influence one’s health. This includes establishing the effects of e-cigarettes on clinical outcomes such as respiratory symptoms (cough, dyspnea), measures of lung function, and risk of developing respiratory disease. Further research is required to elucidate the short- and long-term consequences of vaping to determine whether e-cigarettes are truly a “safer” alternative to traditional cigarettes for smoking cessation or for recreational use. Future studies should be long-term, have large sample sizes, and may include different types of e-cigarettes as well as conventional cigarettes for comparison. In addition, it is important for future research to include clinical outcomes as described above. This will allow for better translation of the research findings to help inform clinical decision-making.

Data availability

No additional data were available, as this study is a knowledge synthesis that relied on aggregate, published results available in the public domain. Any inquiries should be directed to the corresponding author.

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Acknowledgements

The authors would like to thank Jenna Glidden and Andrea Hebert-Losier for their assistance with study screening, data abstraction, and risk of bias assessment. The authors would also like to thank Francesca Frati, who peer-reviewed the search strategy. This work was funded by the Canadian Institutes for Health Research (#HEV-172891). The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication. Dr. Filion is supported by a Senior Research Scholar award from the Fonds de recherche du Québec – Santé and a William Dawson Scholar award from McGill University. Dr. Thombs was supported by a Tier 1 Canada Research Chair.

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Lucy Honeycutt, Katherine Huerne, Alanna Miller, Erica Wennberg, Kristian B. Filion, Roland Grad, Carolyn Ells, Brett Thombs & Mark J. Eisenberg

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G.G. performed the search. L.H. and K.H. screened studies, extracted data, and performed a risk of bias assessment of included studies. L.H. drafted the manuscript. All authors contributed to the study design and interpretation of results, revised the manuscript for important intellectual content, and approved the final version of the manuscript. M.J.E. supervised the study and is the guarantor.

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Honeycutt, L., Huerne, K., Miller, A. et al. A systematic review of the effects of e-cigarette use on lung function. npj Prim. Care Respir. Med. 32 , 45 (2022). https://doi.org/10.1038/s41533-022-00311-w

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Latest Cochrane Review finds high certainty evidence that nicotine e-cigarettes are more effective than traditional nicotine-replacement therapy (NRT) in helping people quit smoking

17 November 2022

Research led by the University of Oxford, and funded by Cancer Research UK, has found the strongest evidence yet that e-cigarettes, also known as ‘vapes’, help people to quit smoking better than traditional nicotine replacement therapies, such as patches and chewing gums.

New evidence published today in the Cochrane Library finds high certainty evidence that people are more likely to stop smoking for at least six months using nicotine e-cigarettes, or ‘vapes’, than using nicotine replacement therapies, such as patches and gums. Evidence also suggested that nicotine e-cigarettes led to higher quit rates than e-cigarettes without nicotine, or no stop smoking intervention, but less data contributed to these analyses. The updated Cochrane review includes 78 studies in over 22,000 participants – an addition of 22 studies since the last update in 2021.

Smoking is a significant global health problem. According to the World Health Organisation (WHO), in 2020, 22.3% of the global population used tobacco, despite it killing up to half of its users. Stopping smoking reduces the risk of lung cancer, heart attacks and many other diseases. Though most people who smoke want to quit, many find it difficult to do so permanently. Nicotine patches and gum are safe, effective and widely used methods to help individuals quit.

E-cigarettes heat liquids with nicotine and flavourings, allowing users to ‘vape’ nicotine instead of smoking. Data from the review showed that if six in 100 people quit by using nicotine replacement therapy, eight to twelve would quit by using electronic cigarettes containing nicotine. This means an additional two to six people in 100 could potentially quit smoking with nicotine containing electronic cigarettes.

Dr Jamie Hartmann-Boyce, Associate Professor at the University of Oxford, Editor of the Cochrane Tobacco Addiction Group, and an author of the new publication, said: “Electronic cigarettes have generated a lot of misunderstanding in both the public health community and the popular press since their introduction over a decade ago. These misunderstandings discourage some people from using e-cigarettes as a stop smoking tool. Fortunately, more and more evidence is emerging and provides further clarity. With support from Cancer Research UK, we search for new evidence every month as part of a living systematic review. We identify and combine the strongest evidence from the most reliable scientific studies currently available.

For the first time, this has given us high-certainty evidence that e-cigarettes are even more effective at helping people to quit smoking than traditional nicotine replacement therapies, like patches or gums.”

In studies comparing nicotine e-cigarettes to nicotine replacement treatment, significant side effects were rare. In the short-to-medium term (up to two years), nicotine e-cigarettes most typically caused throat or mouth irritation, headache, cough, and feeling nauseous. However, these effects appeared to diminish over time.

Dr Nicola Lindson, University Research Lecturer at the University of Oxford, Cochrane Tobacco Addiction Group’s Managing Editor, and author of the publication said: “E-cigarettes do not burn tobacco; and as such they do not expose users to the same complex mix of chemicals that cause diseases in people smoking conventional cigarettes. E-cigarettes are not risk free, and shouldn’t be used by people who don’t smoke or aren’t at risk of smoking. However, evidence shows that nicotine e-cigarettes carry only a small fraction of the risk of smoking. In our review, we did not find evidence of substantial harms caused by nicotine containing electronic cigarettes when used to quit smoking. However, due to the small number of studies and lack of data on long-term nicotine-containing electronic cigarette usage – usage over more than two years – questions remain about long-term effects.”

The researchers conclude that more evidence, particularly about the effects of newer e-cigarettes with better nicotine delivery than earlier ones, is needed to assist more people quit smoking. Longer-term data is also needed.

Michelle Mitchell, chief executive at Cancer Research UK, said: “We welcome this report which adds to a growing body of evidence showing that e-cigarettes are an effective smoking cessation tool. We strongly discourage those who have never smoked from using e-cigarettes, especially young people. This is because they are a relatively new product and we don’t yet know the long term health effects.“

“While the long term effects of vaping are still unknown, the harmful effects of smoking are indisputable – smoking causes around 55,000 cancer deaths in the UK every year. Cancer Research UK supports balanced evidence-based regulation on e-cigarettes from UK governments which maximises their potential to help people stop smoking, whilst minimising the risk of uptake among others.”

This work was supported by Cancer Research UK [A ref. A29845]

Notes to Editors:

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010216.pub7/full

doi: 10.1002/14651858.CD010216.pub7 Lead authors: Associate Professor at the Nuffield Department of Primary Care Health Sciences, University of Oxford and Editor of the Cochrane Tobacco Addiction Group, Dr Jamie Hartmann-Boyce and Senior Researcher at the Nuffield Department of Primary Care Health Sciences, University of Oxford and Managing Editor of the Cochrane Tobacco Addiction Group, Dr Nicola Lindson.

To speak to a team member about this project please contact Dr. Hartmann-Boyce, [email protected] or Dr. Lindson, [email protected] .

About Cochrane Cochrane is a global independent network of researchers, professionals, patients, carers, and people interested in health. Cochrane produces reviews which study all the best available evidence generated through research and make it easier to inform decisions about health. These are called systematic reviews. Cochrane is a not-for profit organization with collaborators from more than 130 countries working together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. Our work is recognized as representing an international gold standard for high-quality, trusted information. Find out more at cochrane.org

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NIH-funded studies show damaging effects of vaping, smoking on blood vessels

Combining e-cigarettes with regular cigarettes may increase health risks.

Long-term use of electronic cigarettes, or vaping products, can significantly impair the function of the body’s blood vessels, increasing the risk for cardiovascular disease. Additionally, the use of both e-cigarettes and regular cigarettes may cause an even greater risk than the use of either of these products alone. These findings come from two new studies supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH).  

The findings, which appear today in the journal  Arteriosclerosis, Thrombosis, and Vascular Biology , add to growing evidence that long-term use of e-cigarettes can harm a person’s health. Researchers have known for years that tobacco smoking can cause damage to blood vessels. However, the effects of e-cigarettes on cardiovascular health have been poorly understood. The two new studies – one on humans, the other on rats – aimed to change that.

“In our human study, we found that chronic e-cigarettes users had impaired blood vessel function, which may put them at increased risk for heart disease,” said Matthew L. Springer, Ph.D., a professor of medicine in the Division of Cardiology at the University of California in San Francisco, and leader of both studies. “It indicates that chronic users of e-cigarettes may experience a risk of vascular disease similar to that of chronic smokers.” 

In this first study, Springer and his colleagues collected blood samples from a group of 120 volunteers that included those with long-term e-cigarette use, long-term cigarette smoking, and those who didn't use. The researchers defined long-term e-cigarette use as more than five times/week for more than three months and defined long-term cigarette use as smoking more than five cigarettes per day.

They then exposed each of the blood samples to cultured human blood vessel (endothelial) cells in the laboratory and measured the release of nitric oxide, a chemical marker used to evaluate proper functioning of endothelial cells. They also tested cell permeability, the ability of molecules to pass through a layer of cells to the other side. Too much permeability makes vessels leaky, which impairs function and increases the risk for cardiovascular disease.

The researchers found that blood from participants who used e-cigarettes and those who smoked caused a significantly greater decrease in nitric oxide production by the blood vessel cells than the blood of nonusers. Notably, the researchers found that blood from those who used e-cigarettes also caused more permeability in the blood vessel cells than the blood from both those who smoked cigarettes and nonusers. Blood from those that used e-cigarettes also caused a greater release of hydrogen peroxide by the blood vessel cells than the blood of the nonusers. Each of these three factors can contribute to impairment of blood vessel function in people who use e-cigarettes, the researchers said.

In addition, Springer and his team discovered that e-cigarettes had harmful cardiovascular effects in ways that were different from those caused by tobacco smoke. Specifically, they found that blood from people who smoked cigarettes had higher levels of certain circulating biomarkers of cardiovascular risks, and the blood people who used e-cigarettes had elevated levels of other circulating biomarkers of cardiovascular risks.

“These findings suggest that using the two products together, as many people do, could increase their health risks compared to using them individually,” Springer said.  “We had not expected to see that.”

In the second study, the researchers tried to find out if there were specific components of cigarette smoke or e-cigarette vapor that were responsible for blood vessel damage. In studies using rats, they exposed the animals to various substances found in tobacco smoke or e-cigarettes. These included nicotine, menthol (a cigarette additive), the gases acrolein and acetaldehyde (two chemicals found in both tobacco smoke and e-cigarette vapors), and inert carbon nanoparticles to represent the particle-like nature of smoke and e-cigarette vapor.

Using special arterial flow measurements, the researchers demonstrated that blood vessel damage does not appear to be caused by a specific component of cigarette smoke or e-cigarette vapor. Instead, they said, it appears to be caused by airway irritation that triggers biological signals in the vagus nerve that somehow leads to blood vessel damage, possibly through an inflammatory process. The vagus is a long nerve extending from the brain that connects the airway to the rest of the nervous system and plays a key role in heart rate, breathing, and other functions. The researchers showed that detaching the nerve in rats prevented blood vessel damage caused by tobacco smoke, demonstrating its key role in this process. 

“We were surprised to find that there was not a single component that you could remove to stop the damaging effect of smoke or vapors on the blood vessels,” Springer said. “As long as there’s an irritant in the airway, blood vessel function may be impaired.”   

The finding has implications for efforts to regulate tobacco products and e-cigarettes, as it underscores how difficult it is to pinpoint any one ingredient in them that is responsible for blood vessel damage. “What I like to tell people is this: Just breathe clean air and avoid using these products,” Springer said.

Lisa Postow, Ph.D., an NHLBI program officer in NHLBI’s Division of Lung Diseases, agreed that the study results “provide further evidence that exposure to e-cigarettes could lead to harmful cardiovascular health effects.” She added that more data is needed to fully understand the health effects of e-cigarettes. The NIH and others are continuing to explore this area.

Research reported in the e-cigarette study was funded by NHLBI grants U54HL147127, P50HL120163, and R01HL120062 and the U.S. Food and Drug Administration Center for Tobacco Products (FDA CTP); and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. Research reported in the cigarette smoke/-vagal nerve study was supported by NHLBI grants R01HL120062 and U54HL147127 and FDA CTP and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. For additional funding details, please see the full journal articles.

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit www.nhlbi.nih.gov .   

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Chronic e-cigarette use impairs endothelial function on the physiological and cellular levels. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.121.317749

Impairment of Endothelial Function by Cigarette Smoke is not Caused by a Specific Smoke Constituent, but by Vagal Input from the Airway. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.122.318051

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NIH-funded studies show damaging effects of vaping, smoking on blood vessels

Combining e-cigarettes with regular cigarettes may increase health risks     

Long-term use of electronic cigarettes, or vaping products, can significantly impair the function of the body’s blood vessels, increasing the risk for cardiovascular disease. Additionally, the use of both e-cigarettes and regular cigarettes may cause an even greater risk than the use of either of these products alone. These findings come from two new studies supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH).  

The findings, which appear today in the journal Arteriosclerosis, Thrombosis, and Vascular Biology , add to growing evidence that long-term use of e-cigarettes can harm a person’s health. Researchers have known for years that tobacco smoking can cause damage to blood vessels. However, the effects of e-cigarettes on cardiovascular health have been poorly understood. The two new studies – one on humans, the other on rats – aimed to change that.

“In our human study, we found that chronic e-cigarettes users had impaired blood vessel function, which may put them at increased risk for heart disease,” said Matthew L. Springer, Ph.D., a professor of medicine in the Division of Cardiology at the University of California in San Francisco, and leader of both studies. “It indicates that chronic users of e-cigarettes may experience a risk of vascular disease similar to that of chronic smokers.” 

In this first study, Springer and his colleagues collected blood samples from a group of 120 volunteers that included those with long-term e-cigarette use, long-term cigarette smoking, and those who didn't use. The researchers defined long-term e-cigarette use as more than five times/week for more than three months and defined long-term cigarette use as smoking more than five cigarettes per day.

They then exposed each of the blood samples to cultured human blood vessel (endothelial) cells in the laboratory and measured the release of nitric oxide, a chemical marker used to evaluate proper functioning of endothelial cells. They also tested cell permeability, the ability of molecules to pass through a layer of cells to the other side. Too much permeability makes vessels leaky, which impairs function and increases the risk for cardiovascular disease.

The researchers found that blood from participants who used e-cigarettes and those who smoked caused a significantly greater decrease in nitric oxide production by the blood vessel cells than the blood of nonusers. Notably, the researchers found that blood from those who used e-cigarettes also caused more permeability in the blood vessel cells than the blood from both those who smoked cigarettes and nonusers. Blood from those that used e-cigarettes also caused a greater release of hydrogen peroxide by the blood vessel cells than the blood of the nonusers. Each of these three factors can contribute to impairment of blood vessel function in people who use e-cigarettes, the researchers said.

In addition, Springer and his team discovered that e-cigarettes had harmful cardiovascular effects in ways that were different from those caused by tobacco smoke. Specifically, they found that blood from people who smoked cigarettes had higher levels of certain circulating biomarkers of cardiovascular risks, and the blood people who used e-cigarettes had elevated levels of other circulating biomarkers of cardiovascular risks.

“These findings suggest that using the two products together, as many people do, could increase their health risks compared to using them individually,” Springer said.  “We had not expected to see that.”

In the second study, the researchers tried to find out if there were specific components of cigarette smoke or e-cigarette vapor that were responsible for blood vessel damage. In studies using rats, they exposed the animals to various substances found in tobacco smoke or e-cigarettes. These included nicotine, menthol (a cigarette additive), the gases acrolein and acetaldehyde (two chemicals found in both tobacco smoke and e-cigarette vapors), and inert carbon nanoparticles to represent the particle-like nature of smoke and e-cigarette vapor.

Using special arterial flow measurements, the researchers demonstrated that blood vessel damage does not appear to be caused by a specific component of cigarette smoke or e-cigarette vapor. Instead, they said, it appears to be caused by airway irritation that triggers biological signals in the vagus nerve that somehow leads to blood vessel damage, possibly through an inflammatory process. The vagus is a long nerve extending from the brain that connects the airway to the rest of the nervous system and plays a key role in heart rate, breathing, and other functions. The researchers showed that detaching the nerve in rats prevented blood vessel damage caused by tobacco smoke, demonstrating its key role in this process. 

“We were surprised to find that there was not a single component that you could remove to stop the damaging effect of smoke or vapors on the blood vessels,” Springer said. “As long as there’s an irritant in the airway, blood vessel function may be impaired.”   

The finding has implications for efforts to regulate tobacco products and e-cigarettes, as it underscores how difficult it is to pinpoint any one ingredient in them that is responsible for blood vessel damage. “What I like to tell people is this: Just breathe clean air and avoid using these products,” Springer said.

Lisa Postow, Ph.D., an NHLBI program officer in NHLBI’s Division of Lung Diseases, agreed that the study results “provide further evidence that exposure to e-cigarettes could lead to harmful cardiovascular health effects.” She added that more data is needed to fully understand the health effects of e-cigarettes. The NIH and others are continuing to explore this area.

Research reported in the e-cigarette study was funded by NHLBI grants U54HL147127, P50HL120163, and R01HL120062 and the U.S. Food and Drug Administration Center for Tobacco Products (FDA CTP); and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. Research reported in the cigarette smoke/-vagal nerve study was supported by NHLBI grants R01HL120062 and U54HL147127 and FDA CTP and grant P50CA180890 from the National Cancer Institute at the NIH and FDA CTP. For additional funding details, please see the full journal articles.

Study: Chronic e-cigarette use impairs endothelial function on the physiological and cellular levels. Arteriosclerosis, Thrombosis, and Vascular Biology.  DOI: 10.1161/ATVBAHA.121.317749

Study:  Impairment of Endothelial Function by Cigarette Smoke is not Caused by a Specific Smoke Constituent, but by Vagal Input from the Airway. Arteriosclerosis, Thrombosis, and Vascular Biology. DOI: 10.1161/ATVBAHA.122.318051

About the National Heart, Lung, and Blood Institute (NHLBI):  NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit  www.nhlbi.nih.gov .

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  www.nih.gov .

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• E-Cigarette Cessation

First US trial of varenicline for e-cigarette cessation shows positive results

The first U.S. trial of varenicline for e-cigarette cessation shows promising results and warrants larger-scale trials, the researchers say.

Researchers from Yale Cancer Center and MUSC Hollings Cancer Center  published the results of their clinical trial of varenicline to help adults to stop using e-cigarettes in the American Journal of Preventive Medicine on May 16.

The results showed a significant disparity between the placebo group and the group receiving the medication. “We had a 15% difference in quit rates, with those in the medication group having a quit rate of 45%,” said Lisa Fucito, Ph.D ., lead author and director of the Tobacco Treatment Service at the Yale Cancer Center and Smilow Cancer Hospital.

Benjamin Toll, Ph.D. , director of the Tobacco Treatment Program  at MUSC Health and senior author on the study, said that the researchers designed the trial to mimic real-world conditions as much as possible – from the people who enrolled in the trial to the type of support they would likely receive from primary care providers.

The publication of their results closely follows publication of a trial of cytisinicline for e-cigarette cessation. The two drugs work similarly. However, varenicline is already on the market in the U.S. in generic versions while cytisinicline has not yet received FDA approval and is not currently available for use by patients.

“People can get to very high levels of nicotine exposure with these e-cigarette products, and they can use them near constantly throughout the day. So, the question we all have is, ‘Can any pharmacotherapy stand up to this challenge?’” Lisa Fucito, Ph.D.

Varenicline, perhaps better known by the brand name Chantix, is FDA-approved to help adults to stop smoking traditional cigarettes. But, despite the growing numbers of people who use e-cigarettes, there are no approved medication options to help them to stop using e-cigarettes.

“People can get to very high levels of nicotine exposure with these e-cigarette products, and they can use them near constantly throughout the day. So, the question we all have is, ‘Can any pharmacotherapy stand up to this challenge?’” Fucito said.

It’s a question of logistics. People who smoke cigarettes have to get a cigarette from the pack and light it. It’s easy to track use. There are also natural stopping points – when the cigarette is finished, it must be snuffed out, and when the pack is used up, it must be thrown away and a new one purchased and opened before the person can smoke again.

E-cigarettes, however, can last for 5,000 or more puffs, making them harder to track intake but easier to use. Toll said he has patients who describe keeping their e-cigarettes under their pillows so they can vape right before going to sleep and then again immediately upon waking in the morning.

Previous studies have shown that a majority of people using e-cigarettes want to quit. But it’s been unclear whether products used to stop smoking traditional combustible cigarettes would also work for e-cigarettes.

“We need more pharmacotherapy treatments to help address the really strong physical dependence that can develop from e-cigarette use. People undergo significant withdrawal when they try to stop, and that withdrawal is so unpleasant and hard to manage with just behavioral support alone,” Fucito said.

A recent Italian study married pharmacotherapy with intense weekly behavioral counseling sessions, and the trial of cytisinicline also included weekly 10-minute sessions with trained counselors.

In this study, however, the researchers wanted to see how well the pharmacotherapy could work given typical health care conditions – meaning, the patient would likely get a brief discussion with a primary care provider along with a prescription and information about resources for quitting but no follow-up counseling sessions.

To recreate this, they developed a self-guided cessation booklet for patients, with practical tools and tips for quitting. A licensed health care provider also met with each patient to inform them of how to use the medication, offer brief advice and instruct them to set a quit date for one to two weeks after starting the medication.

“We took a much lighter touch to reflect the behavioral support that you’d likely experience if you went to your doctor and asked for help with quitting e-cigarettes,” Fucito said.

“If you have a former smoking history, one of the worries in the field is that you’re going to go back to smoking when you quit vaping. And we did not find that.” Benjamin Toll, Ph.D.

The study also included some patients with histories of depression. This was significant because Chantix, at one point, had a “black box warning” after reports linking the drug to psychiatric side effects. That warning was dropped in 2016 after a very large study showed the drug to be safe, but Toll and Fucito said the stigma of the warning remains in the minds of both health care providers and the general public.

“There’s still some hesitancy to prescribe this very safe – now generic – drug, and it really shouldn't be that way,” Toll said.

None of the participants in this study experienced serious side effects, although a larger study would be needed to verify this finding. Most of the side effects were along the lines of nausea, insomnia or vivid dreams.

Another piece of good news – those who stopped vaping didn’t boomerang back to cigarettes.

“If you have a former smoking history, one of the worries in the field is that you’re going to go back to smoking when you quit vaping,” Toll said. “And we did not find that.”

On the other hand, one potential challenge that the researchers uncovered in the results indicated that people without a cigarette smoking history – in other words, those who have only ever used e-cigarettes – might have a harder time quitting. That could be because that group is more likely to use e-cigarettes continuously throughout the day, therefore getting more nicotine into their systems.

Larger trials are needed to delve into these questions. But this trial, at least, should give health care providers some confidence in prescribing varenicline for patients trying to stop using e-cigarettes.

“We want people to come back to this medication,” Fucito explained. “There are people who need help now and are likely to struggle to quit e-cigarettes on their own because the technology facilitates nicotine use on a level that we’ve never seen before.”

Research reported in this press release was supported through internal department funds from Fucito and Toll. In addition, investigators were supported during this study by NIH grants: P30CA138313 for NLB, AMP, MJC, KMG, and BAT; P30CA016359 for LMF; and K23DA045957 for SRB. The research was also supported by an American Heart Association (AHA) grant, 20YVNR35460041, to SKS and SOM. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Outstanding Performance

The National Cancer Institute renewed MUSC Hollings Cancer Center's NCI designation, awarding the center its best score ever of “outstanding performance.”

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Vaping: what we know and what we don’t about e-cigarettes

26 April 2021

This article was originally published in April 2021, but was updated in November 2023  

It’s been a decade or so since e-cigarettes (commonly known as ‘vapes’) first gained popularity in the UK. Since then, the types of devices available and the number of people using them has risen sharply.  

And as the popularity of vaping has grown, so has the debate around it. It’s important to note that this information relates to legal e-cigarettes – this means vapes that are registered with the UK Medicines and Healthcare products regulatory authority (MHRA) and follow UK regulations.  

The big selling point for e-cigarettes is that they’re a way to help people stop smoking and reduce harm from the biggest cause of cancer in the world, tobacco. According to the Office for National Statistics , the level of smoking in the UK in 2022 was the lowest it had been since 2011. This follows the same trend as smoking rates in 2021, where it was suggested that the decrease could be partly due to the rise in vaping.   

But it’s a balancing act. Most e-cigarettes contain nicotine, which is the addictive chemical in tobacco. It’s important to make sure that people who have never smoked, particularly young people, don’t start to use them.  

While it may be hard to remember a time before vaping, in the grand scheme of research, there hasn’t been enough time yet to get the whole picture. And there’s still a lot more we need to understand about e-cigarettes.  

Linda Bauld, Professor of Public Health at the University of Edinburgh, says, “These are still relatively new products. But a huge amount of research has been done. It’s a far more sophisticated discussion now than it was in the early years.”  

Here are the big questions around e-cigarettes, what we know and what we still need to find out.  

Is vaping safe?  

There are a lot of mixed messages out there when it comes to e-cigarettes, with many headlines suggesting that vaping is just as bad or worse than smoking.  

In fact,  research so fa r shows  that vaping legal e-cigarettes is far less harmful than smoking .  

What are e-cigarettes/vapes?  

E-cigarettes (also known as vapes) heat a liquid so that it becomes vapour and people can breathe it in. They usually contain nicotine which is the addictive chemical found in cigarettes.   

Some studies have shown harmful effects of e-cigarette vapour. However, these are usually conducted on animals or cells in the lab, rather than in people. And the concentrations of e-cigarette vapour used are often much higher than people would be exposed to in real life.  

Whilst these studies are useful to explore the potential effects of e-cigarettes, they shouldn’t be used to estimate real-world impact in humans.  

The tone of the debate may also depend on where you live. In 2019, the US saw an outbreak of several thousand cases o f a respiratory illness called ‘EVALI’ (‘e-cigarette or vaping product use-associated lung injury’) and nearly 70 deaths linked to the use of vaping products. But again, headlines can be misleading, as the outbreak was actually caused by contaminants in illegal products and not to regular vaping. There was no similar outbreak in the UK, and the chemicals of concern are banned here.  

However, if you do vape, it is important to make sure that you buy your vaping products from a reputable source, as there has been a rise in illicit and unregulated vaping products being sold across the world.   

The  best evidence available  in humans shows  e-cigarettes are far less harmful than smoking.  For example, one study found significantly lower levels of exposure to harmful chemicals in people who switch ed from smoking to vaping compared with those who continued to smoke. These levels were similar to people using nicotine replacement therapy (NRT). There’s also no good evidence that second-hand e-cigarette vapour is harmful to bystanders.  

But e-cigarettes are a relatively new product. For this reason, there isn’t enough research yet into long-term use, or into their effects in people who have never smoked.   

“In people who vape, the vast majority are smokers or ex-smokers. So unpicking the relationship between those two risks is really tough” says Bauld. “Definitive answers about safety may still take many years to identify”.  

In short, there’s a lot more to learn. Cancer Research UK is funding research into e-cigarettes to help to answer some of the outstanding questions.  

But what researchers have had time to observe, over decades, is the huge amounts of research showing that tobacco is extremely harmful. Which is why experts can be confident that e-cigarettes are far less harmful than tobacco. This is broadly agreed by researchers and public health bodies.  

Do e-cigarettes help people to stop smoking?  

There’s  growing evidence  from around the world that e-cigarettes can help people stop smoking. In England, a study that looked at e-cigarette use and smoking cessation across the population estimated that  e-cigarettes may have helped around an additional 50-70,000 people  in England in 2017 to quit for the long term.  

Research shows  the best way to stop smoking is through free support from stop smoking services. We now have evidence that e-cigarettes combined with support from stop smoking services are also effective in helping people to stop smoking.    

Bauld says that smoking is still the largest preventable cause of cancer and is linked to 15 different types. “Supporting smokers to quit and young people to not start is a really important cancer prevention priority. So, if e-cigarettes can provide support for individuals as an aid to smoking cessation, then that’s of interest to cancer researchers.”  

But there’s still a lot we need to find out. For example, we need to know more about the role that different types of devices, nicotine concentrations and flavours play in helping people to stop smoking.  

Although smoking rates in the UK continue to fall,  levels in the most deprived populations  are still much higher than in the least deprived, so experts are especially interested in whether e-cigarettes could help reduce this inequality.  Recent research  has suggested that people from lower socioeconomic groups might be more likely to use e-cigarettes, but it’s not yet clear whether this means e-cigarettes are improving smoking cessation rates in these communities.  

Does vaping in young people lead to smoking?  

Another question which often makes the headlines is around youth vaping and whether e-cigarettes are causing people to start smoking – the so-called ‘gateway effect’.  

Overall, there’s no strong evidence for a gateway effect in the UK. Although experimentation with e-cigarettes among young people has increased in recent years, the latest data show that regular vaping in young people in Britain remains very low.   

Some research   shows  that young people who use e-cigarettes are more likely to smoke later on. But it’s a tricky relationship to untangle, as young people who smoke are also more likely to vape. Experts have suggested that some young people are generally more likely to engage in ‘risky’ behaviours – like alcohol, drug use or smoking and vaping. Therefore, studies examining smoking and vaping in young people don’t necessarily show that vaping leads them to start smoking, but that they may be likely to do both anyway.  

And the good news is that smoking rates and the perceptions around the acceptability of smoking have declined in young people, even since the introduction of e-cigarettes. So, it doesn’t seem like e-cigarettes have interfered with the promising drop in levels of smoking in young people.  

Currently, the evidence doesn’t suggest that many young people who have never smoked are vaping regularly, or that vaping is causing more young people in the UK to start smoking. But, vaping in young people is something we’re concerned about and are watching the evidence on closely.  

Is it OK to smoke and vape at the same time?  

There’s currently  no good evidence  that using both cigarettes and e-cigarettes is worse than just smoking. But there’s no safe level of smoking, so people need to switch completely from smoking to vaping.  

And there are still unanswered questions here. It may be that some people go through a period where they both smoke and vape to help them quit, but right now we don’t know how long this transition period is, or how it varies from person to person.  

Experts need to find out what causes people to switch from vaping and smoking to just vaping and how they can support people to do this.  

Getting answers  

Highlighting some of the main gaps in the current research, Bauld says that we don’t know enough about how people use e-cigarettes over time – including how use patterns change and if and when people stop using them. “We have some studies, but they’re really quite limited. We also don’t know enough about the impact of long-term use of these devices on health.”  

At Cancer Research UK, we fund lots of research into the role of e-cigarettes in smoking cessation and their use in young people, which complements research across the world to answer these big questions. And we work with policymakers to advocate for regulations that match the rapidly-evolving research in the area and engage with the public to ensure they receive accurate information.  

Large, long-term studies examining topics such as harms, youth use, use patterns over time, use of flavours and effectiveness in smoking cessation are needed.  

And to get the answers we need about the effects of different regulations, these studies need to be conducted across the world. This will allow governments and health bodies to develop laws that protect young people from vaping, but also allow e-cigarettes to continue to be used to help people stop smoking.  

There’s a lot we still need to know, but the evidence has come a long way so far. And all this evidence is why at Cancer Research UK, we recommend people who smoke consider using e-cigarettes as an option to help them quit, and why people who have never smoked, including children and young people, shouldn’t start to vape.  

Thank you for sharing us this awareness, Grateful.

I believe vaping does help to stop smoking but vaping itself is very addictive. Although vaping is better than smoking cigarettes it’s better to use other methods of nicotine replacement therapy as these are used with a view to cutting down and eventually stopping. I say this with personal experience. I think if people want to stop vaping they will still need to use other forms of nicotine replacement.

Interesting review of research on cancer risk and vaping but without looking at cardiovascular risk. Is the level of nicotine in vapers more or less than that found in smokers?

Thanks for your question. Studies show that levels of nicotine in people who switch to vaping compared with those who continue to smoke are similar. Nicotine is the chemical that makes cigarettes and e-cigarettes addictive, but it’s not responsible for the harmful effects of smoking – it doesn’t cause cancer and is not a significant health hazard for people without heart conditions. You can read more about the potential cardiovascular benefits of switching from smoking to vaping on the British Heart Foundation’s website .

Best wishes,

Katie, Cancer Research UK

My husband had knowledge when he worked in a business with Glycol. His thoughts are the Glycol product being used in E-Cigarettes can’t be anything but harmful to the lungs. Is there any information about this.

Thanks for your question. Propylene glycol and vegetable glycerine are used to make the e-liquids for e-cigarettes. As with other research on safety, we still need more long-term data. However Public Health England have concluded that studies in animals have generally been reassuring that it does not pose a significant risk to health.

I think this assessment is flawed in numerous ways. See for example: US evidence shows using cigarettes and e-cigarettes worse than either on the respiratory system

Reddy KP, Schwamm E, Kalkhoran S, et al. Respiratory Symptom Incidence among People Using Electronic Cigarettes, Combustible Tobacco, or Both. Am J Respir Crit Care Med. 2021 Apr 15

Excellent news. Vaping needs to be encouraged.

A fair, balanced assessment, thanks CRUK, Alice, and Linda Bauld

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July 17, 2023

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Current evidence identifies health risks of e-cigarette use, long-term research needed

by American Heart Association

Research increasingly reveals health risks of e-cigarette use, and more studies are needed about the long-term impact e-cigarettes may have on the heart and lungs, according to a new scientific statement from the American Heart Association published in the journal Circulation .

The statement, "Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products," details the latest usage data and trends, identifies current health impacts, highlights existing basic and clinical scientific evidence surrounding e-cigarettes and recommends research priorities to further understand the short- and long-term health effects of e-cigarette use.

Vaping products, also known as e-cigarettes, are battery-operated systems that heat a liquid solution, or e-liquid, to create an aerosol that is inhaled into the lungs. Most e-liquid formulations deliver nicotine, which has been established as having negative health effects as well as strong addictive properties.

The products may also contain other substances, most commonly tetrahydrocannabinol (THC), the psychoactive element of cannabis, as well as methamphetamine, methadone or vitamins. The liquids also include humectants (hygroscopic carriers such as propylene glycol and vegetable glycerol) that act as solvents and create a water aerosol or vapor, flavoring agents, cooling agents such as menthol and sweeteners, in addition to metals from the heating coil and other chemicals.

"E-cigarettes deliver numerous substances into the body that are potentially harmful, including chemicals and other compounds that are likely not known to or understood by the user. There is research indicating that nicotine-containing e-cigarettes are associated with acute changes in several hemodynamic measures, including increases in blood pressure and heart rate ," said the volunteer chair of the scientific statement writing committee Jason J. Rose, M.D., M.B.A., an associate professor of medicine at the University of Maryland School of Medicine in Baltimore.

"There has also been research indicating that even when nicotine is not present, ingredients in e-cigarettes, particularly flavoring agents, independently carry risks associated with heart and lung diseases in animals. Negative effects of e-cigarettes have been shown through in vitro studies and in studies of individuals exposed to chemicals in commercially available products."

The writing committee points to the significance of the clinical diagnosis of "E-cigarette, or Vaping, product use Associated Lung Injury" (EVALI). EVALI was first recognized as a condition by the U.S. Centers for Disease Control and Prevention in 2019, when approximately 2,800 hospitalizations occurred among e-cigarette users in less than a year. This is cited in the statement as one example that emphasizes the lack of knowledge surrounding the risks of e-cigarettes and their ingredients.

In the case of the EVALI hospitalizations, vitamin E acetate has been implicated as the ingredient likely causing illness. This substance is used as a thickening agent in some e-cigarette liquids.

Studies gauging the specific impact e-cigarettes have on heart attacks and strokes are limited. Much research on e-cigarette use has been conducted in people who have also used or were currently using traditional cigarettes. Additionally, large survey studies have focused on younger adults who have a low occurrence of heart attacks and strokes. The writing committee says longer-term studies of e-cigarettes users of all ages are needed, including among people who already have cardiovascular disease.

One recent analysis of the adult Population Assessment of Tobacco and Health (PATH) study found a statistically significant association between former or current e-cigarette use at the time participants enrolled in the study and the development of incident respiratory disease (chronic obstructive pulmonary disease/COPD, chronic bronchitis, emphysema or asthma) within the next two years. The PATH Study, an ongoing study that started in 2013, is one of the first large tobacco research efforts undertaken by the National Institutes of Health and the U.S. Food and Drug Administration.

Additional studies cited in the statement indicate a rapid increase since 2010 in the number of people who had ever used e-cigarettes or were currently using the devices, and most of those users were current or former traditional cigarette smokers. In addition, by 2016, data from the Behavioral Risk Factor Surveillance System indicated about 1.2 million adults in the U.S. who had never smoked combustible cigarettes before were currently using e-cigarettes.

The writing committee noted that e-cigarettes are reported to be the most commonly used tobacco product among youth, particularly high school and middle school students. The statement cites data showing that almost three out of four young people using e-cigarettes exclusively report using flavored e-cigarette products. This high rate of use by youth makes it critical to assess the short- and long-term health effects of these products, according to the statement.

"Young people often become attracted to the flavors available in these products and can develop nicotine dependence from e-cigarette use. There is significant concern about young people assuming e-cigarettes are not harmful because they are widely available and marketed to an age group that includes many people who have never used any tobacco products," Rose said.

"The long-term risks of using e-cigarettes are unknown, but if the risks of chronic use are like combustible cigarettes, or even if the risks are reduced but still present, we may not observe them for decades. What is equally concerning is that studies show that some youth who use e-cigarettes go on to use other tobacco products, and there is also a correlation between e-cigarette use and substance use disorders."

Given the established, high health risks of smoking combustible cigarettes, e-cigarette products have been evaluated as smoking cessation tools. The writing committee examined the limited research in this area and concluded that any benefits e-cigarettes may offer to help people stop smoking or stop using tobacco products needs to be clearly balanced alongside the products' known and unknown potential health risks, including the known risk of long-term dependence on these products.

"E-cigarette companies have suggested that their products are a way to quit smoking traditional cigarettes. There is no strong evidence to support this beyond any short-term benefit. The lack of long-term scientific safety data on e-cigarette use, along with the potential for the addiction to e-cigarette products seen among youth, are among the reasons the American Heart Association does not recommend e-cigarette use for cessation efforts," said Rose Marie Robertson, M.D., FAHA, the Association's deputy chief science and medical officer and co-director of the Association's Tobacco Center of Regulatory Science.

"It's also important to note that e-cigarette products are not approved by the U.S. Food and Drug Administration (FDA) for tobacco cessation. The Association recommends a combination of multiple-episode cessation counseling accompanied by personalized nicotine replacement therapy with FDA-approved doses and formulations, as well as medications to help control cravings, to help people who smoke combustible cigarettes with cessation. And all of this needs to be undertaken with the understanding that quitting often takes many tries, and any failures should be seen as just episodes to learn from on the road to finally beating a powerful addiction for good."

The scientific statement writing committee emphasizes a critical need for additional knowledge and research, specifically:

• Future research should focus on gaining knowledge about serious and potentially long-term effects of e-cigarettes on the heart, blood vessels and lungs.
• Studies are needed that include patients with pre-existing cardiopulmonary disease, such as coronary artery disease or chronic obstructive pulmonary disease , to evaluate and compare outcomes among e-cigarette users in comparison to traditional smokers, and those who use e-cigarettes along with traditional cigarettes (referred to as dual users) and nonsmokers.
• More in-depth research is needed about the common chemical ingredients in e-cigarettes and the effects they independently have on pulmonary and cardiac health.
• Clinical studies are needed to study the risks and potential benefits of e-cigarettes as alternatives to traditional combustible cigarettes.
• Since the long-term health impact of e-cigarettes may take decades to emerge, more molecular and laboratory studies are needed in the interim to help determine the biological implications of e-cigarette use .

"Because e-cigarettes and other vaping systems have only been in the U.S. for about 15 years, we do not yet have enough information on their long-term health effects, so we must rely on shorter term studies, molecular experiments and research in animals to try to assess the true risk of using e-cigarettes," Jason Rose added. "It is necessary for us to expand this type of research since the adoption of e-cigarettes has grown exponentially, especially in young people, many of whom may have never used combustible cigarettes."

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New research shows e-cigarette use up sharply among younger adults in U.S. during EVALI outbreak and COVID-19 pandemic

American Cancer Society

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Credit: American Cancer Society

ATLANTA, April 18, 2023 – A new study by researchers at the American Cancer Society (ACS) shows almost three-quarters of a million more adults in the United States, ages 18-29 years, used e-cigarettes between 2019-2021 during the period that spanned the EVALI outbreak (E-cigarette or vaping product use–associated lung injury) and COVID-19 pandemic. Scientists report the year-on-year increase was primarily among adults who never smoked cigarettes. The study was published today in the American Journal of Preventive Medicine (AJPM).

“Unfortunately, these numbers show we’re moving in the wrong direction concerning e-cigarette use in this vulnerable population,” said Dr. Priti Bandi , scientific director, cancer risk factors & screening surveillance research at the American Cancer Society and lead author of the study. “Our research finding is concerning as it may point to an increase in nicotine addiction risk for young adults, potentially contributing to progression to combustible tobacco products, and may also increase exposure to unknown toxicants, carcinogens, and the risk of respiratory diseases.”

Researchers pooled data from the National Health Interview Survey from 2019, 2020, and 2021 to estimate current e-cigarette use prevalence, adjusted prevalence difference between survey years, and population counts, by age group and cigarette smoking status (persons who currently, formerly, or never smoked).

The study results showed between 2019 and 2021, e-cigarette use prevalence increased from 8.8% in 2019 to 10.2% in 2021 among younger U.S. adults ages 18-29 years. Of note, among those young adults who never smoked cigarettes, e-cigarette use jumped from 4.9% in 2019 to 5.2% in 2020 to 6.4% in 2021. This group of young adults constituted 53% (2.68 million) of younger adults who used e-cigarettes in 2021, increasing by 0.71 million persons from 2019. The study also showed among middle-aged and older U.S. adults, e-cigarette prevalence was similar in 2019 and 2021 irrespective of combustible cigarette smoking status. People who formerly smoked cigarettes constituted the largest population proportion of people who use e-cigarettes among adults older than 30 years in 2021 (51.1%, 3.1 million).

“E-cigarette use is not harmless at any age. It may have serious health risks, including negative short-term effects on airways and blood vessels, and we do not know the long-term effects of their use,” Bandi said. “We must address the rise in e-cigarette use among younger adults who never smoked cigarettes and, at the same time, help those who may have switched from cigarettes to e-cigarettes to stop using these devices completely.” “It’s clear Big Tobacco’s strategy is to addict future generations to its products with e-cigarettes, putting the health of the country at risk,” said Lisa Lacasse , president, American Cancer Society Cancer Action Network (ACS CAN), the advocacy affiliate of the American Cancer Society. “Policymakers at the local, state, and federal levels must take action now to protect the public, especially youth, from this predatory industry. E-cigarettes must be regulated like all other tobacco products, and we urge the FDA to complete and enforce the premarket review process for all new tobacco products, including e-cigarettes.”

Resources from the ACS on how to quit e-cigarettes can be found here . Information on cigarette smoking cessation can be found here .     Dr. Ahmedin Jemal is senior author of the study. Other ACS authors include: Jessica Star , Adair K. Minihan , Dr. Minal Patel , and Dr. Nigar Nargis .

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What is new in electronic-cigarettes research?

Brian p. jenssen.

a Department of Pediatrics, University of Pennsylvania School of Medicine and PolicyLab and the Center for Pediatric Clinical Effectiveness, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Karen M. Wilson

b Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA

Purpose of review

Electronic cigarettes (e-cigarettes) and other vaping devices have seen extraordinary growth in use in the past 10 years, and companies are accelerating their development of new products and marketing efforts. In turn, researchers have increased their efforts to determine how e-cigarettes affect health, how marketing these products impacts adolescents and how the use of e-cigarettes may affect adolescents’ use of other tobacco products. Products like Juul were not on the market 2 years ago; thus, frequent updates on the topic are essential.

Recent findings

Studies have begun to demonstrate that users of the newer pod systems are exposed to high levels of nicotine, as well as other chemicals. These products are highly marketed, with a strong emphasis on how adolescents can use them surreptitiously. This is concerning to researchers, and other studies have continued to demonstrate that teens who use e-cigarettes are more likely to go on to use combusted tobacco. Further research has also failed to demonstrate that e-cigarettes are useful for people wishing to quit smoking combusted tobacco.

E-cigarettes and vaping systems are not safe products and should not be used by adolescents.

EMERGING ELECTRONIC CIGARETTE PRODUCTS

Electronic cigarettes (e-cigarettes), in general, use an electric impulse to heat a nicotine containing liquid to the point where it aerosolizes but does not burn. The use of e-cigarettes is called ‘Vaping’. It is promoted by the industry as an alternative to smoking; however, studies have not shown that they are effective for smoking cessation. The industry has long used marketing techniques that are appealing to adolescents and young adults, such as cartoons and hyper-sexual imagery. These products are also marketed in a variety of flavors, which are far more appealing to youth than a tobacco-flavored product. The industry has been rapidly innovative, from the cigarette-like products introduced in the early 2000s ( Fig. 1 ) to the ‘mods’ or modified tank systems ( Fig. 2 ) [ 1 ]. Recently, the industry has developed e-cigarette products that are more technologically advanced. These products are designed to look like electronic devices, car fobs, coffee cups, credit cards, mobile phones or even tic-tac boxes [ 2 ]. Quite distressing to pediatricians are the vaping devices designed to look like asthma inhalers; versions are used to aerosolize marijuana leaf (PUFFiT), or nicotine (QuickNIC). Companies have also developed low vapor and low odor products specifically to facilitate public use.

First generation e-cigarette.

Tank system or ‘Mod’.

The JUUL e-cigarette ( Fig. 3 ) was introduced in 2015; by 2016, reports were emerging about its prevalence of use among adolescents. JUUL pods contain 59 mg/ml of nicotine, which is a significantly higher concentration than the standard e-cigarette liquid. A study completed in June 2018 found 148000 videos on YouTube when searching on ‘JUUL’ [ 2 ], including 15 000 from ‘JUUL at school’, 1040 from ‘JUUL in school bathroom’ and 6840 from ‘JUUL in class’. A variety of suggested techniques for hiding the aerosol plume includes inhaling more deeply (and increasing nicotine absorption), swallowing the aerosol, exhaling under clothing or into a napkin or paper towel. The study also found YouTube videos detailing how to hide JUUL pods. One video demonstrated the use of a Sharpie marker ( Fig. 4 ) [ 2 ].

JUUL with pods. Permission: Susanne Tanski, MD, MPH.

Hiding JUUL in a Sharpie. Source: Ramamurthy et al. [ 2 ].

A recent study evaluated the exposure to nicotine by adolescents who used JUUL and other vape pod systems, using urine samples and teen-reported use of e-cigarettes [ 3■ ]. In this sample of 506 teens, ages 12–21 years, 7.7% were daily pod users; JUUL was the most popular brand (80%). Bo (36%), Phix (18%) and Suorin (12%) were also popular. The preferred flavors were menthol/mint (24%), fruit (21%) and candy/desserts (18%). The median urinary cotinine of exclusive pod users ( N = 22) in this study was 244.8 ng/ml – an amount higher than has been reported in studies of exclusive combusted tobacco users [ 4 ]. Urinary cotinine varied by the type of pod used: the median urinary cotinine of exclusive JUUL users was 135 ng/ml, compared with 508 ng/ml for exclusive Bo users and 906 ng/ml for exclusive Phix users. This study highlights the high levels of nicotine that adolescents are exposed to when they use these vape pod systems.

ADOLESCENT EXPOSURE TO TOXIC CHEMICALS FROM ELECTRONIC-CIGARETTES

E-cigarettes are promoted as a ‘reduced harm’ product that leads to far less exposure to toxic chemicals than with combusted cigarettes. However, few studies have examined the actual exposures e-ciga-rette users have. In another study, 67 e-cigarette-only users were evaluated and compared to dual users (N=16) and nontobacco using controls ( N = 20). In comparison to the above study, these e-cigarette-only users had a wide range of urinary cotinine levels (0–864 ng/ml), with a median of 0, suggesting that many users were not exposed to the same degree of nicotine. Further, the study team found that the e-cigarette-only users, compared with controls, had higher levels of the volatile organic compounds (VOCs) acrylonitrile (1.3 vs. Ong/mg), acrolein (254 vs. 193ng/mg), propylene oxide (29 vs. 14ng/mg), acrylamide (67 vs. 42 ng/mg) and crotonaldehyde (149 vs. 130ng/mg) [ 5■ ]. Fruit flavor use was also associated with increased levels of acrylonitrile (10 vs. 2ng/mg). Adolescents who used both tobacco and e-cigarettes had VOC levels up to three times higher than those who used only e-cigarettes. This suggests that even in the absence of high nicotine levels in these products, users are exposed to toxic chemicals – chemicals identified as carcinogenic – created by the vaping of the humectant or flavors. Adolescents should never use e-cigarette or vaping products.

ELECTRONIC-CIGARETTE USE AMONG YOUTH AND PROGRESSION TO TRADITIONAL CIGARETTE USE

In January 2018, the National Academies of Sciences, Engineering, and Medicine (NASEM, formerly known as the Institute of Medicine), with support from the Center for Tobacco Products of the Food and Drug Administration (FDA), published an expert committee report of the scientific evidence about e-cigarettes and public health. The report, titled the Public Health Consequences of E-Cigarettes, provides both an overview and in-depth analysis of the evidence, recommends ways to improve the research and highlights gaps that are priority focus areas for future work [ 6 ].

For youth and young adults, there is substantial evidence that e-cigarette use increases the risk of ever using combustible tobacco cigarettes [ 6 , 7 ]. Further, for e-cigarette users who have also ever used combustible tobacco cigarettes, there is moderate evidence that e-cigarette use increases the frequency and intensity of subsequent combustible tobacco cigarette smoking [ 6 ]. These conclusions are based on substantial evidence from several separate, well-designed, longitudinal studies [ 8 – 15 ]. Adolescents and young adults (aged 14–30) who have used e-cigarettes are 3.6 times more likely to report using cigarettes at follow-up, compared to those who had not, according to a recent meta-analysis [ 7 ]. In addition, adolescents who use e-cigarettes appear to have fewer social and behavioral risk factors than conventional cigarette users [ 10 – 12 , 14 ].

These findings raise significant concern that e-cigarettes have the potential to addict a new generation to nicotine and tobacco, slowing or reversing the decline in adolescent cigarette smoking that has occurred over the past 20 years. Data have begun to influence policy, with the FDA recently acknowledging adolescent e-cigarette use as an epidemic. ‘E-cigs have become an almost ubiquitous — and dangerous — trend among teens,’ FDA Commissioner Scott Gottlieb, M.D., said in a statement in September 2018. ‘The disturbing and accelerating trajectory of use we’re seeing in youth, and the resulting path to addiction, must end’ [ 16 ].

ELECTRONIC-CIGARETTES FOR SMOKING CESSATION FOR ESTABLISHED SMOKERS

Health claims that e-cigarettes are effective smoking cessation aids are not currently supported by scientific evidence. According to the NASEM report, there is limited evidence regarding the ability of e-cigarettes to promote smoking cessation [ 6 ]. In particular, with a limited number of small, randomized controlled trials, there is insufficient evidence on the effectiveness of e-cigarettes as cessation aids compared with no treatment or to FDA-approved smoking cessation treatments [ 6 ]. A more recent large-scale, randomized controlled trial found that the use of free e-cigarettes does not result in higher rates of sustained abstinence than traditional smoking-cessation aids and does not increase abstinence rates among smokers who are also offered information and motivational text messages [ 17 ].

The overall evidence from observational trials is mixed [ 6 ]. When compared to randomize controlled trials, it is inherently more difficult to draw conclusions about the relationship between cause and effect because of the potential for selection bias and unmeasured confounding. Two systematic reviews that included cohort studies published between 2013 and 2015 in meta-analyses each found a negative association between e-cigarette use and cessation, meaning e-cigarette users have lower rates of successful quitting compared to never e-cigarette users [ 18 , 19 ]. The NASEM report identified that more recent prospective longitudinal studies report that daily or very frequent e-cigarette use may be associated with cessation, whereas intermittent use may not [ 6 ]. Given the current state of the science, smokers interested in quitting should seek and be referred to evidence-based, safe and effective treatments, including nicotine replacement therapy, behavioral counseling and additional pharmacotherapy [ 20 ].

For established smokers, e-cigarettes may reduce health risks for the individual user compared to the risk of continued combustible tobacco use [ 6 ]. However, tobacco, when used as intended, causes disease, disability and death [ 21 ], and discussions and messaging about individual tobacco products must placed in a larger public health context. Even if e-cigarettes themselves pose less risk to the user than other tobacco products, they still represent a significant public health burden in need of further regulation, particularly if they cause more adolescents and adults to begin harmful combustible tobacco use or prevent fewer people from quitting tobacco use [ 6 ].

AREAS FOR FURTHER RESEARCH

The NASEM report closed with a call for action: ‘More and better research is needed to help clarify whether e-cigarettes will prove to reduce harm—or induce harm—at the individual and the population levels.’[ 6 ] As the e-cigarette market grows, there is continued need for research to inform regulatory standards and understand the effects of use and exposure across the lifespan [ 6 ]. Additional research is needed to understand the trajectory of addiction among youth and the progression to combustible tobacco products [ 22 ]. Studies are needed to determine whether and, if so, how e-cigarettes may be effective for smoking cessation [ 6 ]. Finally, research is needed to evaluate effective counter-messaging and public health interventions, especially regarding preventing adolescent e-cigarette initiation.

New research in 2018 is strongly pointing to the potential for e-cigarette products to exposure their users to toxic chemicals, the likelihood of addicting adolescents to nicotine and possible future combusted tobacco use and the continued failure of rigorous studies to show that these products are effective for smoking cessation. The FDA has delayed the implementation of tighter regulations on e-cigarette products, but this year has recognized the dangers of adolescent exposure and targeted companies such as JUUL for their appeal to teens. Pediatricians and other healthcare practitioners that provide care to young adults and adolescents should continue to stress the dangers of using these products to patients and their parents as well as advocate for restrictions on the purchase and use of these products by teens.

• Recent evidence highlights the high levels of nicotine that adolescents are exposed to when they use vape pod system e-cigarettes, such as JUUL.
• Even in the absence of high nicotine levels in these products, users are exposed to toxic chemicals – chemicals identified as carcinogenic – created by the vaping of the humectant or flavors.
• For youth and young adults, there is substantial evidence that e-cigarette use increases the risk of ever using combustible tobacco cigarettes.
• According to the National Academy of Science report on the public health consequences of e-cigarettes, there is limited evidence regarding the ability of e-cigarettes to promote smoking cessation.
• Pediatricians and other healthcare practitioners that provide care to young adults and adolescents should continue to stress the dangers of using these products to patients and their parents as well as advocate for restrictions on the purchase and use of these products by teens.

Acknowledgements

Financial support and sponsorship

Solicited Review.

We confirm that our article has not been published in its current form or a substantially similar form (in print or electronically; including on a website), that it has not been accepted for publication elsewhere, and that it is not under consideration by another publication.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

■ of special interest

■■ of outstanding interest

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Do E-Cigarette Retail Licensure Laws Reduce Tobacco Use?

E-cigarette licensure laws (ELLs) require retailers to obtain a state license to sell e-cigarettes over the counter. This study is the first to comprehensively explore the effect of ELL adoption on youth and adult tobacco product use. Using data from the State Youth Risk Behavior Survey (YRBS) and a difference-in-differences approach, we find no evidence that ELL adoption reduces overall youth ENDS use. The precision of our estimates allows us to rule out, with 95 percent confidence, ELL-induced prior-month youth ENDS use declines of more than 3.4 percent. The pattern of null findings persists when we examine ELLs that impose (1) higher penalties for retailer non-compliance, (2) higher renewable licensure fees, and (3) criminal as compared to civil penalties. However, we do uncover evidence that adoption of ELLs with higher penalties associated with a modest reduction in ENDS use among Black teens. We conclude that ELLs have only limited success in curbing access to ENDS.

Dr. Sabia acknowledges research support for this work from the Center for Health Economics & Policy Studies (CHEPS) at San Diego State University (SDSU), which has received grants from the Charles Koch Foundation. This study was funded, in part, with a grant from the Foundation for a Smoke- Free World, Inc. ("FSFW'), a U.S. nonprofit 501(c)(3) private foundation. This study is, under the terms of the grant agreement with FSFW, editorially independent of FSFW. The contents, selection and presentation of facts, as well as any opinions expressed herein, are the sole responsibility of the authors and under no circumstances should they be regarded as reflecting the positions of FSFW. FSFW's mission is to end smoking in this generation. Dr. Sabia also acknowledges research support from a subcontract by Georgia State University in 2023 – via a grant received from the National Institute on Drug Abuse of the National Institutes of Health under Award Number R01DA045016 – to support exploratory work on this project. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Institutes of Health. We thank Erik Nesson and Chad Cotti for sharing their ENDS tax data with us. We thank Anthony Chuo and Christian Pryfogle for outstanding research assistance. All errors are the authors’. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.

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The analytic sample size was 1693 in 2016, 1818 in 2017, 2028 in 2018, 1783 in 2019, 1673 in 2020, and 1433 in 2021. The trend test P values were P  < .001 for exclusive e-cigarette use from 2016 to 2021, P  < .001 for exclusive cigarette use from 2017 to 2021, and P  = .38 for dual use from 2016 to 2021. Error bars indicate 95% CIs.

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Wen X , Liu L , Moe AA, et al. Use of E-Cigarettes and Cigarettes During Late Pregnancy Among Adolescents. JAMA Netw Open. 2023;6(12):e2347407. doi:10.1001/jamanetworkopen.2023.47407

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Use of E-Cigarettes and Cigarettes During Late Pregnancy Among Adolescents

• 1 Division of Behavioral Medicine, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo
• 2 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor
• 3 Rochester Institute of Technology, Rochester, New York
• 4 Behavioral Health and Health Policy, Westat, Rockville, Maryland
• 5 Center for Tobacco Products, Food and Drug Administration, Silver Spring, Maryland
• 6 Department of Communication, College of Arts and Sciences, University of Louisville, Louisville, Kentucky
• 7 Department of Health Behavior, Roswell Park Comprehensive Cancer Center, Buffalo, New York
• 8 New York Medical College, Valhalla

Question   What are the trends, determinants, and association with small-for-gestational-age (SGA) birth of e-cigarette use among pregnant adolescents?

Findings   This cohort study using 2016-2021 data on 10 428 adolescents from the Pregnancy Risk Assessment Monitoring System in the US found that pregnant adolescents have increasingly used e-cigarettes, with the highest use among White adolescents. Adolescent use of cigarettes during pregnancy was a risk factor for SGA birth; however, adolescent use of e-cigarettes or dual use of e-cigarettes and cigarettes was not associated with SGA birth.

Meaning   This study suggests that e-cigarette use during late pregnancy among adolescents was not statistically significantly associated with a high risk of SGA birth.

Importance   Pregnant adolescents sometimes use cigarettes; however, little is known about e-cigarette use among pregnant adolescents, a population with increased health vulnerability.

Objective   To examine yearly trends, sociodemographic and pregnancy-related determinants, and the association with small-for-gestational-age (SGA) birth of e-cigarette and/or cigarette use during late pregnancy among adolescents.

Design, Setting, and Participants   This cohort study used existing data from the 2016-2021 Pregnancy Risk Assessment Monitoring System on 10 428 US adolescents aged 10 to 19 years who had a singleton birth with complete data on e-cigarette or cigarette use and SGA birth.

Exposure   Adolescents reported e-cigarette and cigarette use during the last 3 months of pregnancy.

Main Outcomes and Measures   SGA birth (birth weight below the 10th percentile for the same sex and gestational duration) was determined from birth certificates. Multivariable logistic regression was used to compare the odds of SGA birth across pregnant adolescents who exclusively used e-cigarettes, exclusively used cigarettes, used e-cigarettes and cigarettes, or did not use either.

Results   Of the 10 428 pregnant adolescents, 72.7% were aged 18 or 19 years; 58.9% self-identified as White and 23.3% as Black; and 69.8% were non-Hispanic. The weighted prevalence of exclusive e-cigarette use during late pregnancy increased from 0.8% in 2016 to 4.1% in 2021, while the prevalence of exclusive cigarette use decreased from 9.2% in 2017 to 3.2% in 2021. The prevalence of dual use fluctuated, ranging from 0.6% to 1.6%. White pregnant adolescents were more likely than those who self-identified as another race and ethnicity to use e-cigarettes (2.7% vs 1.0% for American Indian or Alaska Native adolescents, 0.8% for Asian or other race adolescents, 0.6% for Black adolescents, and 0.7% for multiracial adolescents). Compared with those who did not use either product, adolescents who exclusively used e-cigarettes (16.8% vs 12.9%; confounder-adjusted odds ratio [AOR], 1.68 [95% CI, 0.89-3.18]) or who used cigarettes and e-cigarettes (17.6% vs 12.9%; AOR, 1.68 [95% CI, 0.79-3.53]) had no statistically significant difference in risk of SGA birth. However, adolescents who exclusively used cigarettes had a more than 2-fold higher risk of SGA birth (24.6% vs 12.9%; AOR, 2.51 [95% CI, 1.79-3.52]).

Conclusions and Relevance   This cohort study suggests that pregnant adolescents increasingly used e-cigarettes, with the highest use among White adolescents. Results from this analysis found that, unlike cigarette use, e-cigarette use during late pregnancy was not statistically significantly associated with an increased risk of SGA birth among adolescents. Due to the uncertainty of this nonsignificant association, future research could benefit from a larger sample size.

Cigarette smoking sometimes occurs among pregnant adolescents; 4.5% of people who gave birth in the US in 2021 smoked cigarettes during pregnancy, with the highest prevalence among young adults aged 20 to 24 years (5.8%) or 25 to 29 years (5.1%), followed by adolescents aged 15 to 19 years (4.3%). 1 E-cigarettes are another major tobacco or nicotine product used by US adolescents. 2 , 3 According to the 2022 National Youth Tobacco Survey, 3.3% of middle school students and 14.1% of high school students used e-cigarettes that year, 2 although it is unclear how common e-cigarette use is among pregnant adolescents.

Nicotine, carbon monoxide, and other chemicals in combustible cigarettes may contribute to the maternal smoking–related risk to the fetus. 4 , 5 E-cigarettes are noncombustible and do not generate some of the toxic chemicals present in tobacco smoke, including carbon monoxide. 6 For this reason, some pregnant people who smoke cigarettes before pregnancy use e-cigarettes as a smoking cessation aid to reduce nicotine intake and/or to reduce harm to the fetus. 7 However, average nicotine delivery from e-cigarettes is comparable to that of combustible cigarettes. 8 In addition, despite being 1 to 2 orders of magnitude lower than levels from combustible cigarette products, trace levels of certain toxicants, including formaldehyde, acetaldehyde, nickel, and lead, are present in e-cigarettes. 9 The presence of those toxicants in emissions from e-cigarettes may explain, at least in part, why e-cigarette use during pregnancy is associated with adverse birth outcomes, such as low birth weight, preterm birth, and small-for-gestational-age (SGA) birth among people who gave birth, including adolescents and adults 10 and adults aged 18 years or older. 11

SGA birth, defined as birth weight below the 10th percentile for the same sex and gestational duration, is a public health concern in the US and globally. 12 - 15 Between 2012 and 2016, the prevalence of SGA birth was as high as 12.1% in the US. 16 SGA infants are at an increased risk for adverse health outcomes, including postnatal growth failure, 17 neurodevelopmental impairment, 18 short stature, 19 and type 2 diabetes. 20

One study showed that infants of adolescents who smoked were 3.1 times more likely to be SGA compared with infants of adolescents who did not smoke cigarettes. 21 Compared with adults who have given birth, adolescents may be more vulnerable to smoking-related health risks due to the biological and psychosocial factors pertaining to adolescent pregnancies. One prior study showed that infants of adolescents (aged 12-18 years) who smoked during pregnancy had a greater reduction in birth weight than infants of adults who smoked during pregnancy (−202 g vs −158 g per pack per day). 22 Despite existing findings on the adverse health effects of cigarette smoking among pregnant adolescents, little is known about e-cigarette use among this population with increased health vulnerability.

Therefore, using a large US national pregnancy monitoring system, we aimed to fill the aforementioned research gaps by examining exclusive e-cigarette use, exclusive cigarette use, and dual use of e-cigarettes and cigarettes during pregnancy among adolescents. We focused on yearly trends in use from 2016 to 2021, sociodemographic and pregnancy-related determinants, and a potential health outcome of pregnancy (SGA birth).

In this cohort study, we conducted a secondary data analysis using Phase 8 of the US Pregnancy Risk Assessment Monitoring System (PRAMS; 2016-2021). The PRAMS is an ongoing state-level, population-based surveillance system first administered in 1987. 23 It applies a mixed-mode approach of birth certificates, mailed surveys, and telephone surveys to collect information on maternal behaviors, attitudes, and experiences before, during, and shortly after (2-6 months) pregnancy. This information is all collected retrospectively after live birth and documentation of SGA status is available. Approximately 83% of all US births are covered by the PRAMS, including 47 states, the District of Columbia, New York City, Puerto Rico, and the Great Plains Tribal Chairman’s Health Board. 23 The deidentified PRAMS data were provided by the Centers for Disease Control and Prevention. This secondary data analysis was approved as non–human participants research by the University at Buffalo institutional review board and did not require informed consent from study participants. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

The total sample size of the Phase 8 PRAMS from 2016 to 2021 was 242 573 (eFigure in Supplement 1 ). First, given the significantly distinct developmental and health outcomes associated with multiple births, we excluded these data and focused solely on singleton births. Then we applied the age criterion for adolescence (10-19 years) defined by the World Health Organization. 24 , 25 Among these adolescents, we included only those with complete data on e-cigarette and cigarette use during the last 3 months of pregnancy (late pregnancy). Furthermore, we restricted the analytic sample to adolescents who had complete data on SGA birth.

For e-cigarette use during late pregnancy, participants were asked the following question, “During the last 3 months of your pregnancy, on average, how often did you use e-cigarettes or other electronic nicotine products?” with response options of (1) more than once a day, (2) once a day, (3) 2 to 6 days a week, (4) 1 day a week or less, and (5) did not use e-cigarettes or other electronic nicotine products then. The questionnaire included a note that defined e-cigarettes as follows: “E-cigarettes (electronic cigarettes) and other electronic nicotine vaping products (such as vape pens, e-hookahs, hookah pens, e-cigars, e-pipes) are battery-powered devices that use nicotine liquid rather than tobacco leaves, and produce vapor instead of smoke.” We dichotomized responses into e-cigarette use (options 1, 2, 3, or 4) or nonuse (option 5) during late pregnancy to ensure sufficient statistical power for further analyses on determinants of e-cigarette use as well as its association with SGA birth. For cigarette use during late pregnancy, participants were asked the following question, “In the last 3 months of your pregnancy, how many cigarettes did you smoke on an average day?” with response options of (1) 41 cigarettes or more, (2) 21 to 40 cigarettes, (3) 11 to 20 cigarettes, (4) 6 to 10 cigarettes, (5) 1 to 5 cigarettes, (6) less than 1 cigarette, and (7) did not smoke then. Similar to e-cigarette use, we dichotomized responses into cigarette use (options 1-6) or nonuse (option 7) during late pregnancy for further analyses.

Based on e-cigarette and cigarette use status during late pregnancy, we further categorized participants into 4 mutually exclusive groups: adolescents who did not use either e-cigarettes or cigarettes, those who exclusively used e-cigarettes, those who exclusively used cigarettes, and those who used both e-cigarettes and cigarettes (dual use).

Using data from birth certificates, the percentiles of birth weight by sex and gestational duration were calculated using the natality files for singleton births from the National Center for Health Statistics. 26 We defined SGA birth as birth weight below the 10th percentile for the same sex and gestational duration, according to the cutoff point proposed by the World Health Organization. 27 , 28 This definition of SGA has been applied in previous research using the PRAMS data. 29

Based on the relevant literature, 30 - 33 we considered the following sociodemographic and pregnancy-related characteristics as potential determinants of e-cigarette use during late pregnancy: age (10-17 years and 18 or 19 years), race (American Indian or Alaska Native, Asian or other race [no further information was provided for the category of “other race”], Black, multiracial, White), ethnicity (Hispanic or non-Hispanic), marital status (unmarried or married), type of health insurance (Medicaid, private insurance, self-pay, or other), prepregnancy hypertension (yes or no), prepregnancy diabetes (yes or no), prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and the child’s birth year (2016-2021). In addition, these characteristics were considered as potential confounders in the associations between e-cigarette use and risk of SGA birth, given that they also have been reported to be associated with SGA in previous research. 34 - 37

Race and ethnicity were included due to known disparities in the prevalence of nicotine product use 30 , 33 and adverse birth outcomes. 37 , 38 Race and ethnicity were obtained from birth certificates. Due to small sample sizes, we combined the American Indian and Alaska Native categories into a single category. Similarly, the Asian and other race categories were combined into a separate single category. Additional information on selection of potential determinants can be found in the eMethods in Supplement 1 .

Information on the descriptive analysis can be found in the eMethods in Supplement 1 . We used logistic regression models to examine whether the prevalence of e-cigarette and/or cigarette use significantly varied between 2016 and 2021. We used χ 2 tests for categorical variables (eg, race) and a linear regression model for BMI, a continuous variable, to identify significant sociodemographic and pregnancy-related determinants of e-cigarette and/or cigarette use. Similarly, χ 2 tests were used to compare the risk of SGA birth by categorical sociodemographic and pregnancy-related characteristics. For prepregnancy BMI (continuous), we compared its mean between SGA birth and non-SGA births using a linear regression model. We also used χ 2 tests to compare the risk of SGA birth across the 4 tobacco use groups. Then, we fitted multivariable binary logistic regression models to estimate the associations between e-cigarette and/or cigarette use with the risk of SGA birth. We calculated crude odds ratios (ORs) and confounder-adjusted ORs (AORs) and 95% CIs of SGA birth for adolescents who exclusively used e-cigarettes, exclusively used cigarettes, or used both cigarettes and e-cigarettes compared with adolescents who did not use either product (reference group). The confounders included in the adjusted model were maternal age, race, ethnicity, marital status, health insurance, prepregnancy BMI, prepregnancy diabetes, prepregnancy hypertension, and the child’s birth year, based on the literature on factors associated with nicotine product use and risk of SGA birth. 30 - 37

To study the possible effect modification of prepregnancy BMI or the child’s birth year in the association of e-cigarette and/or cigarette use with the risk of SGA birth, we added interaction terms between prepregnancy BMI or the child’s birth year and e-cigarette or cigarette use to subsequent regression models. We focused on these 2 potential effect modifiers because previous research showed that the magnitude of the association between cigarette smoking during pregnancy and risk of SGA birth among pregnant adolescents who were underweight or normal weight was more striking than among those who were overweight or obese 39 and because e-cigarette devices have substantially changed through the recent years and thus the potential association of maternal use of e-cigarette products during pregnancy with fetal growth may have been changing with the child’s birth year as well. In a sensitivity analysis to evaluate the robustness of our analytic results, we additionally excluded 36 adolescents (0.4%) who initiated the use of e-cigarettes (n = 25) or cigarettes (n = 11) during pregnancy so that the results could be interpreted as continuous use during pregnancy.

All data analyses were performed using SAS, version 9.4 (SAS Institute Inc). We defined statistical significance as 2-sided P  < .05. Sampling weights were used in the statistical analysis to reduce potential selection bias due to nonrandom sampling, noncoverage, and nonresponse. 23

In the original PRAMS sample of 242 573 births, 229 176 were singletons (eFigure in Supplement 1 ). Among these singletons, 10 746 were birthed by adolescents aged 10 to 19 years. Among these adolescents, 10 451 had complete data on e-cigarette and cigarette use during late pregnancy and 10 428 of these had complete data on SGA birth (the final analytic sample). Table 1 shows the sociodemographic and pregnancy-related characteristics of the 10 428 pregnant adolescents in the analytic sample. Among them, 27.3% were aged 10 to 17 years and 72.7% were aged 18 or 19 years, 58.9% self-identified as White and 23.3% as Black, 69.8% were non-Hispanic, 91.6% were unmarried, and 78.5% had Medicaid insurance. The children’s birth years were evenly distributed from 2016 to 2021, with approximately 17% of the sample occurring each year.

As shown in Table 2 , 1.5% of the total sample exclusively used e-cigarettes, 7.3% exclusively used cigarettes, 1.2% used cigarettes and e-cigarettes, and the remaining 90.1% did not use either product during late pregnancy. Among those who reported exclusive e-cigarette use, 34.9% used e-cigarettes 1 day per week or less and 29.9% used e-cigarettes more than once a day ( Table 1 ). Among those who reported exclusive cigarette use, 49.2% used 1 to 5 cigarettes per day and 22.1% used 6 to 10 cigarettes per day.

In 2021, the prevalence of use during late pregnancy among adolescents was highest for exclusive e-cigarette use (4.1%), followed by exclusive cigarette use (3.2%), and lowest for dual cigarette and e-cigarette use (1.1%) ( Figure ). The prevalence of exclusive e-cigarette use increased significantly from 0.8% in 2016 to 4.1% in 2021 ( P  = .001 for the trend test). Statistically significant pairwise comparisons for e-cigarette use included 2021 vs 2016, 2021 vs 2017, and 2021 vs 2018. In contrast, the prevalence of exclusive cigarette use gradually decreased from 9.2% in 2017 to 3.2% in 2021 ( P  < .001 for the trend test). Statistically significant pairwise comparisons for cigarette use included 2020 vs 2017, 2020 vs 2018, 2021 vs 2016, 2021 vs 2017, 2021 vs 2018, and 2021 vs 2019. The prevalence of dual use of cigarettes and e-cigarettes varied across the years, with a range from 0.6% to 1.6% ( P  = .38 for the trend test). There were no significant pairwise comparisons for dual use between any 2 years.

Adolescents aged 18 or 19 years had a higher prevalence of exclusive e-cigarette use (2.0% vs 1.5%), exclusive cigarette use (7.4% vs 5.0%), and dual use (1.3% vs 0.7%) compared with those aged 10 to 17 years ( Table 2 ). White adolescents had the highest prevalence of exclusive e-cigarette use (2.7%) and exclusive cigarette use (9.8%), whereas Black adolescents had the lowest prevalence of exclusive e-cigarette use (0.6%) and Asian or other race adolescents had the lowest prevalence of exclusive cigarette use (1.2%). Compared with Hispanic adolescents, non-Hispanic adolescents had a higher prevalence of exclusive e-cigarette use (2.2% vs 1.1%), exclusive cigarette use (8.9% vs 1.9%), and dual use (1.6% vs 0.2%). Compared with unmarried adolescents, married adolescents were less likely to exclusively use e-cigarettes (1.4% vs 1.9%) or cigarettes (6.3% vs 6.8%). Adolescents with Medicaid insurance were more likely than adolescents with other health insurance to exclusively use cigarettes (7.1% vs 5.2%) and use both e-cigarettes and cigarettes (1.4% vs 0.6%).

In the total sample, 13.9% of children were born SGA ( Table 2 ). Being unmarried (14.0% vs 10.7% being married) and a lower prepregnancy BMI were significant risk factors for SGA. Compared with adolescents who did not use either product, those who exclusively used e-cigarettes appeared to have no significantly different odds of SGA birth (16.8% vs 12.9%; crude OR, 1.37 [95% CI, 0.73-2.56]; AOR, 1.68 [95% CI, 0.89-3.18]) ( Table 3 ). Similarly, those who used both e-cigarettes and cigarettes appeared to have no significant difference in the odds of SGA birth from those who did not use either product (17.6% vs 12.9%; crude OR, 1.45 [95% CI, 0.71-2.96]; AOR, 1.68 [95% CI, 0.79-3.53]). However, adolescents who exclusively used cigarettes had a more than 2-fold higher odds of SGA birth than those who did not use either product (24.6% vs 12.9%; crude OR, 2.21 [95% CI, 1.61-3.04]). After adjustment for confounders, exclusive cigarette use remained a risk factor for SGA birth (AOR, 2.51 [95% CI, 1.79-3.52]).

Prepregnancy BMI was inversely associated with the risk of SGA birth, with a higher BMI associated with a lower risk of SGA birth (AOR, 0.96 [95% CI 0.94-0.98] per kg/m 2 increment) ( Table 4 ). However, prepregnancy BMI did not modify the associations between e-cigarette and/or cigarette use and SGA. Similarly, the child’s birth year was not a significant effect modifier. Finally, results did not change meaningfully in our sensitivity analysis by excluding the 36 adolescents who initiated the use of e-cigarettes or cigarettes during pregnancy.

We found that the prevalence of e-cigarette use among US pregnant adolescents increased steadily from 2016 to 2021. This trend paralleled the increasing prevalence of e-cigarette use among all adolescents across similar years. 40 , 41 Our finding that White adolescents were more likely than other racial groups to use e-cigarettes and cigarettes during late pregnancy was consistent with previous research in the general adolescent population. 42 Another risk factor for cigarette use and dual use in our study sample was having Medicaid insurance (an indicator of low household income). This finding adds to the existing evidence on the high prevalence of smoking among adolescents with low socioeconomic status. 43 In addition, we found that married adolescents were less likely than unmarried adolescents to exclusively use cigarettes or use both cigarettes and e-cigarettes, which was supported by the literature showing that being married was a protective factor against cigarette use and dual use during pregnancy among adults. 11

We found that the risk of SGA birth was more than 2-fold higher among adolescents who exclusively used cigarettes during late pregnancy than those who did not. This finding was consistent with previous research showing that maternal cigarette use during pregnancy was a risk factor for SGA birth. 44 Nicotine, carbon monoxide, and other harmful chemicals in cigarettes may contribute to this association. 4 For instance, carbon monoxide, which is present in cigarettes but not in most e-cigarettes, can cause fetal hypoxia and thus lead to fetal growth restriction. 5

A novel finding from our analysis was the statistically nonsignificant association between adolescent e-cigarette use during late pregnancy and the risk of SGA birth. This finding might be associated with the fact that e-cigarettes contain little carbon monoxide and potentially lower nicotine concentrations compared with cigarettes. Cigarettes produce 0.8 to 1.7 mg of carbon monoxide and 81.5 to 187.7 μg of nicotine per puff. 45 - 48 However, e-cigarettes usually do not produce carbon monoxide above the limit of detection, 49 and the estimated amount of nicotine is 0 to 52 mg/mL. 50 Still, previous studies indicated that e-cigarette use during pregnancy may be a risk factor for SGA birth among adults (aged ≥18 years) 51 and among adolescents and adults. 29 For example, Cardenas et al 51 found that adult mothers who used e-cigarettes during pregnancy had a several times higher risk of SGA birth than mothers who did not use e-cigarettes. The reasons for the seeming inconsistency with our observed nonsignificant association among adolescents are unknown, but there are several plausible explanations. First, adolescents may have a shorter duration and a lower cumulative amount of e-cigarette use than older adults. It has been reported that most US adolescents begin using e-cigarettes in middle school and high school, 52 - 54 so it is possible that the adolescents in our sample had not been using e-cigarettes for very long. As a result, their exposure to e-cigarettes might influence them and their offspring less, compared with adults. Second, our statistical power might have been insufficient to detect significant associations due to the relatively small number of adolescents in the PRAMS sample who exclusively used e-cigarettes or used both e-cigarettes and cigarettes.

This study has some limitations. First, self-reported e-cigarette and cigarette use measures were subject to recall bias, and the prevalence might have gone underreported due to social stigma, especially given that respondents completed the surveys retrospectively during the 2- to 6-month postpartum period. Second, the sample sizes for adolescents who used e-cigarettes (n = 152 [1.5%, weighted]) or both e-cigarettes and cigarettes (n = 125 [1.2%, weighted]) during pregnancy were relatively small, which might widen the 95% CIs in our estimated risk of SGA birth among them; therefore, caution is needed to interpret those results. Third, information on e-cigarette and cigarette use during the first and second trimesters of pregnancy was not available in the PRAMS; thus, we could not examine the potential association of the timing of exposure during pregnancy with SGA births. 55 , 56 This limitation also did not allow us to distinguish individuals who used e-cigarettes and/or cigarettes throughout pregnancy from individuals who used these products only during the third trimester. Fourth, there was a lack of information on secondhand smoke exposure during pregnancy, which also could have a negative association with fetal growth and might have been an unmeasured confounder. 57 Fifth, information on specific e-cigarette devices used by the participants was not available in the PRAMS. Given the changes in the tobacco product market, it could be difficult to draw conclusions on specific products over time. Sixth, we did not control for use of other substances, such as cannabis, due to a large amount of missing data. Thus, we could not distinguish whether individuals used electronic delivery devices to vape nicotine, cannabis, or both substances. Use of all these products can occur among adolescents 58 and potentially have different associations with fetal growth. 59 This limitation is particularly important in interpreting the results for individuals who use both nicotine and cannabis. Our estimated OR for cigarette use might be overestimated, given the reported associations of cannabis use with SGA and low birth weight. 60 , 61 Seventh, we dichotomized e-cigarette and cigarette use (use vs nonuse) due to limited sample sizes of the original frequency categories. This simplified approach created a heterogeneous use group with considerable variability in use frequency and did not allow us to examine the potential dose-response association with risk of SGA birth. Eighth, maternal diet quality could have a substantial association with fetal growth, 62 , 63 but it was not considered in our analysis due to lack of information.

In this cohort study of US pregnant adolescents, there was an increase in e-cigarette use and a decrease in cigarette use during late pregnancy from 2016 to 2021. In this population with a potentially higher risk of SGA birth, exclusive cigarette use was a risk factor for SGA birth. Exclusive e-cigarette use and dual use of cigarettes and e-cigarettes did not seem to be statistically significantly associated with SGA birth in our analysis, but this finding should be interpreted with caution given the low prevalence of use and the limited sample size. Considering the uncertainty of this nonsignificant association, future research using a larger sample size may be beneficial.

Accepted for Publication: October 30, 2023.

Published: December 13, 2023. doi:10.1001/jamanetworkopen.2023.47407

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Wen X et al. JAMA Network Open .

Corresponding Author: Xiaozhong Wen, MD, PhD, Division of Behavioral Medicine, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 3435 Main St, G56 Farber Hall, Buffalo, NY 14214 ( [email protected] ).

Author Contributions: Dr Wen and Ms Liu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wen, Liu, Ormond, Stanton, Ruybal, Hart, Vargees.

Acquisition, analysis, or interpretation of data: Wen, Liu, Moe, Ormond, Shuren, Scott, Ozga, Stanton, Hart, Goniewicz, Lee.

Drafting of the manuscript: Wen, Liu, Moe, Ormond, Shuren, Scott, Ruybal, Hart, Goniewicz, Lee.

Critical review of the manuscript for important intellectual content: Wen, Liu, Moe, Shuren, Ozga, Stanton, Ruybal, Hart, Goniewicz, Lee, Vargees.

Statistical analysis: Wen, Liu, Shuren, Scott, Lee.

Obtained funding: Wen.

Administrative, technical, or material support: Wen, Ormond, Ozga, Stanton, Ruybal, Hart.

Supervision: Wen, Vargees.

Conflict of Interest Disclosures: Dr Goniewicz reported receiving grants from Pfizer, personal fees from Johnson & Johnson, the World Health Organization, and the Campaign for Tobacco-Free Kids outside the submitted work. No other disclosures were reported.

Funding/Support: Research reported in this publication was supported by the National Institute of Drug Abuse and the Food and Drug Administration Center for Tobacco Products through grant R21 DA053638 (Dr Wen). The authors’ efforts on this project were also supported by the Center for Coordination of Analytics, Science, Enhancement, and Logistics in Tobacco Regulatory Science (grant U54DA046060-01 [Dr Stanton]), the National Heart, Lung, and Blood Institute and Food and Drug Administration Center for Tobacco Products (grant U54HL120163 [Dr Hart]), and the American Heart Association (grant 20YVNR35500014 [Dr Hart]). The content is solely the responsibility of the authors.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Department of Health and Human Services or any of its affiliated institutions or agencies.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We appreciate the Pregnancy Risk Assessment Monitoring System (PRAMS) Working Group and the Centers for Disease Control and Prevention for providing the original PRAMS data set and technical support.

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