The trial results suggest that ECs are more effective than NPs in helping pregnant smokers quit, but lead to more continued use. Regarding EC safety, birth and safety outcomes were similar in the two study arms, but there were fewer cases of low birthweight in the EC arm. Here we discuss separately the study findings concerning effectiveness and those that concern EC safety.
Effect of e-cigarettes on smoking cessation
The measure that comprised the primary outcome required a biochemical validation of abstinence from smoking via salivary sampling. This required participants to read the instructions on the sampling kit posted to their address, provide a sample in sufficient quantity and mail the sample back to the study team. The compliance with this request was limited, with only about half of the eligible participants providing useable samples. It is possible that the timing of the sampling was particularly inconvenient for women in late pregnancy or with newborn babies. Future studies should consider other approaches. Due to this issue, the validated sustained abstinence rates were low. The difference favoured the EC arm, but it was not statistically significant.
Six times as many participants in the NP arm used ECs regularly during pregnancy than participants in the EC arm who used any form of NRT (18% vs. 3%). A pre-specified sensitivity analysis of the primary outcome that excluded abstainers who regularly used the non-allocated product showed a significantly higher abstinence rate in the EC arm (RR = 1.93, 95% CI = 1.14 to 3.26). When using the same adjustment for other abstinence outcomes, ECs were almost twice as effective as NPs across different outcome measures (RRs ranging from 1.89 to 2.03).
The two treatments thus did not differ significantly in the primary outcome, but the effect of ECs appears to have been masked by EC use in the NP study arm. When this was controlled for, ECs were superior to NPs. The difference between the two treatments in biochemically validated abstinence (7% vs. 4%) is low because of the saliva sampling problem, but the difference in self-reported 7-day PP abstinence at EOP (21% vs. 14%, or 20% vs. 10% with adjustment for contamination) suggests a clinically important effect.
Behaviour change trials that compare an old and a new treatment are at a risk that some participants who did not benefit from the old treatment join the trial to access the new treatment and if allocated to the old one, are disappointed and drop out. In this trial, similar proportions of participants had previous experience with NRT and ECs (just under 50%). They all stopped using the products and continued to smoke. Familiarity with the two products and the rate of previous failure with them was thus similar. Reassuringly, the proportions of participants in the two study arms who never set up a TQD were also similar in the two study arms. However, more participants in the NP arm never tried their allocated product (32% vs. 15%). This, however, seems to have been due to participants being keen to try ECs, rather than not wanting NPs, because NP use was higher than in the previous large UK Smoking, Nicotine and Pregnancy (SNAP) trial of nicotine versus placebo patches that recruited pregnant smokers in the same way and from largely the same locations.10,12,50–53
For any treatment to make an impact, clients must be willing to use it. In previous studies of pregnant smokers, treatment adherence was limited.12 For instance, in the SNAP trial behavioural support was rarely used and only 14% (72 out of 521) of participants in the NP arm requested further patches after the first 4-week supply.12 Here, the adherence to behavioural advice was also low. Almost a third of participants did not set up a TQD, and the response to support calls was low. In the NP arm, 23% of participants used their allocated products for at least 4 weeks. ECs had a higher initial appeal, with 40% of participants in the EC arm using their allocated product at 4 weeks. The two products further diverged during the follow-up period. At EOP, 6% and 34% were using their products in the NP and EC study arms, respectively. The contrast was even stronger among self-reported EOP abstainers, with 9% in the NP arm versus 57% in the EC arm using their allocated product at EOP. Interviews with trial participants suggested that positive beliefs about the necessity of vaping to achieve smoking cessation outweighed concerns about vaping.54 The difference at EOP could have been in part at least due to participants expecting that NPs are supposed to be used for only 3 months, although in this study, participants in both study arms were encouraged to use their products for as long as needed. They also needed to ask for a prescription for NRT, while this was not needed for ECs. On the other hand, participants were able to obtain NPs and any other NRT they asked for free of charge, but had to source EC supplies and pay for them themselves. The number of participants who switched to regular use of the non-allocated product can be considered another indication of treatment attractiveness. This was much more frequent in the NP arm. As in previous studies with general cohorts of smokers,39,55 ECs seem to be a more attractive option than NPs in this client group as well.
The higher rate of ongoing use of ECs compared to ongoing use of NRT raises the question of what effects this may have over time on participants who stopped smoking, as well as on those who became dual users. Smokers who switch to dual use can be expected to reduce their smoking and toxicant intake and so gain a degree of harm reduction.56–58 The effect on ex-smokers is less clear. It could be negative because EC use is likely to carry some health risks if used over an extended time,59 and for some vapers at least, the cost and/or compulsive nature of ongoing nicotine use is likely to be undesirable. Ongoing EC use, however, could also have some positive effects if it helps with reducing irritability39 and weight gain60 that can accompany cessation of nicotine use and possibly help with maintaining enjoyment that was previously derived from smoking.61 Perhaps the key issue is whether extended EC use facilitates or prevents relapse back to smoking. Future studies should examine quality of life, relapse risk and health outcomes in comparable ex-smokers who did and did not switch to EC use.
Regarding the type of EC products used by participants, refillable ECs were used almost exclusively. In the USA, pod-based ECs, such as JUUL™ (Juul Labs Inc., San Francisco, CA, USA), are now the most popular EC product.62 JUUL has a high nicotine content (59%) and provides nicotine in a way similar to cigarettes.63 The UK, however, is currently subject to European Union (EU) regulations that ban ECs with nicotine content above 20%. This means that pod products on sale in the EU provide only low nicotine levels that are unlikely to be helpful for smokers trying to stop smoking and that indeed did not become popular in the UK.63
As in previous studies,39,55 fruit flavour was the most popular EC flavour choice. The study also replicated an unexpected previous finding39 of EC users reducing nicotine content of their e-liquid over time. This could be the result of a conscious effort at weaning oneself off nicotine, but it could also be due to an improved vaping technique64 or using more effective EC devices.
Regarding treatment costs, it is worth noting that while ECs were more costly for participants, NRT was much more costly to treatment providers.
Safety of e-cigarettes compared to safety of nicotine patches
Existing data on safety of ECs in pregnancy come from observational studies. In two reports, infants of exclusive vapers had a higher risk of smallness for gestational age65 and a higher incidence of low birthweight and pre-term birth66 compared to non-smokers. The findings are difficult to interpret as most or all vapers had been smoking during early pregnancy, and no comparison is provided with ex-smokers who quit without using ECs. One study found birthweight of infants born to exclusive vapers matching that of infants of never-smokers, and significantly higher than in infants of smokers.67 A study of Neonatal Behavioural Assessment Scale scores reported a greater number of abnormal reflexes in infants of both smokers and EC users compared to non-smokers.68 This could be related to EC use, but as in the two studies above, the finding could reflect differences between smoking and non-smoking mothers, or tobacco exposure in early pregnancy.
In our study, AEs and pregnancy outcomes were similar in the two study arms, but there were more infants born with low birthweight (<2500 g) in the NP arm. The BF of 10.3 indicates strong evidence for the effect, though a possibility needs to be considered that as the two study arms were compared on a number of health outcomes, the finding could be an artefact of multiple testing. The most likely explanation of the finding is that participants in the EC arm reduced their smoking more than those randomised to NPs. The finding echoes the result from the SNAP trial mentioned earlier, where infants born to women randomised to NPs had better outcomes than those randomised to placebo patches.69 The secondary analyses could not explain this finding in terms of smoking cessation70 but smoking reduction was not measured and it is plausible that women on NPs reduced their smoking more than those on placebo patches. The potentially important implication of both of these findings is that the risks of negative birth outcomes in smokers is due to other chemicals in cigarette smoke rather than nicotine.
It is important to note that these results only concern effects of nicotine in later pregnancy. All study participants were smoking for at least the first 3 months of pregnancy and so were exposed to both nicotine and to other tobacco chemicals early on. The results do not rule out possible detrimental effects of nicotine during these early stages. However, they provide reassuring evidence that providing pregnant smokers with alternative nicotine delivery devices such as NRT or ECs does not generate any additional risks and is likely in fact to reduce the risk of low birthweight. In addition, a recent study looking at women who stopped smoking at various stages of their pregnancy showed that smoking during the second trimester or through the entire pregnancy is associated with a higher incidence of low birthweight.71 Our results suggest that nicotine is not implicated in these effects. If the effects of smoking in the first trimester are due to the same processes, nicotine on its own may not affect intrauterine growth.
Trial strengths
This was a large ‘real-world’ trial. The participants were representative of the population of pregnant smokers in the UK and the two interventions were delivered in a way that is economic and practicable and can be applied in routine care. The trial included detailed examinations of smoking behaviours as well as monitoring of product safety and of birth outcomes for both women and infants.
Trial limitations
Validation of smoking status via postal saliva sampling proved problematic. Almost half of eligible participants did not provide useable samples, which led to low primary outcome abstinence rates and reduced the study power. The trial results concern primarily NPs rather than NRT combinations. Although participants were encouraged to use additional NRT products, this was used only rarely. In non-pregnant smokers, combinations of patches with other NRT products were shown more effective than single NRT.72 Participants could only access ECs with a maximum of 20 mg/ml nicotine because EU regulations do not allow higher nicotine concentrations. The results may not generalise to modern ‘pod’ EC products with higher nicotine delivery.
Implications for health care
Although nicotine in late pregnancy may not have any detrimental effects on pregnancy outcomes, given the question marks regarding possible effects of continuing nicotine use on quality of life, health outcomes and risk of relapse, stopping smoking without nicotine-containing aids is preferable to switching to such products. However, where the choice is between using nicotine products such as NRT or EC, or continuing to smoke, nicotine product use would be the recommended option. Specialist SSSs should include EC starter packs among the treatment options offered to pregnant smokers. Such an offer is likely to reach more smokers and generate better smoking reduction at lower cost than the offer of NPs.
Recommendations for research
As noted earlier, future studies should avoid postal saliva sampling. Regarding use of non-allocated products, this is likely to continue to occur in future studies. Researchers should pre-specify how this will be controlled for. We opted for excluding abstainers who used the non-allocated products, but re-classifying them as non-abstainers could be a better approach, as discussed above. Future studies may also consider partially randomised patient preference design. The inclusion of long-term follow-up of the offspring would address concerns about effects of nicotine on later offspring development. Regarding more general research recommendations, in this field, long-term health effects of EC use are the main current research priority. Studies are needed that compare biomarkers or risks and eventually also long-term health outcomes, quality of life and relapse rates in comparable ex-smokers who either stopped smoking without switching to EC use, or stopped smoking and use ECs.
Conclusion
In the unadjusted primary analysis, there was insufficient evidence to confidently demonstrate that ECs are more effective in helping pregnant smokers quit than NPs. EC effects appear to have been masked by EC use in the NP arm. When this was controlled for, ECs were more effective than patches. Regarding product safety, ECs do not seem to pose more risks to birth outcomes that were assessed in this study than NPs and may reduce the incidence of low birth weight.
