Title: Helping pregnant smokers quit: Multi-centre RCT of electronic cigarettes vs usual care.
Funder: Department of Health and Social Care

Abstract: Background: Smoking in pregnancy remains an unresolved issue. A number of interventions failed to show efficacy. Electronic cigarettes (EC) are a promising new option, with a realistic chance of providing practical help to pregnant smokers and their children. No study has tested EC in this context so far. EC do not contain most of the chemicals responsible for health risks of smoking and those that are present are there at levels much lower than those present in cigarette smoke. The overall risks of EC use are estimated to be some 95% less than risks of smoking. Nicotine itself can have adverse affects on the foetus as shown in animal studies, although the only study that examined birth outcomes in a large cohort of women randomised to NRT or placebo detected no health risks. NRT is universally used by the UK pregnancy stop smoking services because pregnant smokers are consuming nicotine anyway and because the harm to foetus is also caused by other chemicals in tobacco smoke which are absent in NRT. The same logic applies to nicotine intake from EC. Regarding other chemicals in EC ‘vapour’, its main components are propylene glycol, which is approved for use in pregnancy (e.g. in asthma inhalers) and vegetable glycerol which has no known adverse effects. Some flavourings may over time affect the lungs, but to our knowledge, no chemicals other than nicotine have been identified in EC vapour that would be expected to affect the health of the foetus. The safety concerns are tempered by the fact that EC would be used as a replacement for cigarettes which pose well known dangers, and that in the trial setting, pregnant women would be closely monitored and that if there is any sign of an elevated risk, the trial can be stopped. Such a negative result would, in fact, be of significant value. EC are used by an increasing proportion of pregnant smokers. If such use involves risks, evidence of this would have important practical implications. Study design: Multi-centre RCT comparing usual care (behavioural support and nicotine patches) with the same behavioural support with EC instead. Usual care: Standard care across the Stop Smoking Services (SSS) ranges from advice by midwives through telephone support to standard SSS clinics to home visits by specialist advisors. Across these, interventions usually include behavioural support and provision of 16h nicotine patches for up to eight weeks. We propose to provide a representative intervention comprising of initial face-to-face advice by midwives followed by telephone counselling by SSS advisors with six weekly calls, accompanied by 16h nicotine patches. Experimental intervention: This will be the same as the control intervention, but instead of patches, participants will receive EC to use. Participants: Pregnant smokers (12 to 24 weeks gestation) who smoke daily and are interested in stopping smoking. Setting: Maternity services across the UK. Primary outcome: Prolonged smoking cessation, reported throughout pregnancy and validated by salivary cotinine and anabasine at end of pregnancy (36 weeks gestation to 4 weeks post-partum). Secondary outcomes: Changes in smoke intake and in nicotine intake indexed by salivary anabasine and cotinine levels, assessed for quitters currently using NRT/EC products and, and smokers currently using NRT/EC products; self-reported quit rates at 4 weeks and at end of pregnancy; 7-day point prevalence abstinence (end of pregnancy); use of NRT and EC throughout pregnancy. Safety outcomes: Adverse effects throughout pregnancy and birth and maternal safety outcomes at end of pregnancy and 3 months post-partum. Procedures and visits: Participants will attend a baseline visit with a research midwife, and would be randomised to either EC or Patch. A stop-smoking advisor would then post the relevant study product to the participant and call them to set a quit date. Weekly behavioural support phone calls will be conducted on the quit date, and for 4 weeks after. Patches or EC would be dispensed for up to 8 weeks. All participants would be followed-up at the end of pregnancy and 3 months post-partum. Sample size: Extrapolating from the results of existing EC studies and success rates in previous UK pregnancy trials, we estimate the quit rate at delivery in the control arm of 8% and in the intervention arm of 14%. 1,140 participants (570 in each condition) would provide 90% power (alpha=0.05, two-tailed test) to detect this difference. Data analysis: The primary outcome will use the Russell Standard (RS) criterion of abstinence with participants lost to follow-up classified as smokers. We would use a logistic regression model with a contrast for intervention versus control, adjusting for site and variables predictive of the outcome as fixed effect covariates. Note: RS is preferable to other imputations because in smoking cessation trials, missingness is not random – smokers who fail in their quit attempt typically avoid follow-up contact while those who succeed are keen to be followed up. We would include the Hedeker imputation, however, in secondary analysis. Project timetable: 48 months (M). 8 M to set up the study and obtain regulatory approvals, 26 M to enrol 1,140 participants; 10 M to complete follow ups, 4 M to analyse the data and write up the result.

Lay abstract: Smoking in pregnancy remains an unresolved issue. Quit rates in pregnant smokers are low and advice by doctors and nurses, even when combined with behavioural support and nicotine replacement treatment (NRT) has only limited efficacy. NRT has shown little effect most likely because pregnant women use them very little. Pregnant women also metabolise nicotine faster and standard NRT doses may be too slow and too low for them. Nicotine patches also do not allow dosing tailored to smokers’ needs. Electronic cigarettes (EC) may overcome these limitations. EC allow flexible dosing and have a faster effect than NRT. They also provide some of the sensations and enjoyment that smokers get from smoking. These characteristics should ensure better treatment adherence. It is estimated that in the UK half a million smokers switched from smoking to vaping (EC use) so far, with some 20,000 quitting smoking with the help of EC per year who would not have quit otherwise. There is thus a strong rationale for testing the efficacy of EC as a stop-smoking treatment for pregnant women. However, safety of such treatment needs to be addressed. EC do not contain most of the chemicals responsible for health risks of smoking and those that are present are there at levels much lower than those present in cigarette smoke. The overall risks of EC use are estimated to be some 95% less than risks of smoking. To our knowledge, no chemicals other than nicotine have been identified in EC vapour that would be expected to affect the health of the foetus. NRT is universally used by the UK pregnancy stop smoking services because pregnant smokers are consuming nicotine anyway and because the harm to foetus is also caused by other chemicals in tobacco smoke which are absent in NRT. The same logic applies to nicotine intake from EC. The safety concerns are tempered by the fact that EC would be used as a replacement for cigarettes which pose well known dangers. If there is any sign of an elevated risk, the trial can be stopped. If such use involves risks, evidence of this would have important practical implications. Regarding trial details, we propose to randomise 1,140 pregnant smokers to either an intervention representative of usual care (behavioural support provided by pro-active phone calls and accompanied by nicotine patches) or to the same support accompanied instead by EC. The two study arms would be compared in validated abstinence rates at end of pregnancy and in a number of other outcomes including adverse effects and birth and maternal outcomes. A positive result would provide a new, inexpensive, and practical tool to tackle an important and so far unresolved problem.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH;RESPIRATORY;STROKE