Safety of e-cigarettes and nicotine patches as stop-smoking aids in pregnancy: Secondary analysis of the Pregnancy Trial of E-cigarettes and Patches (PREP) randomized controlled trial.

AIMS: The aim of this study was to examine the safety of e-cigarettes (EC) and nicotine patches (NRT) when used to help pregnant smokers quit. DESIGN: A recent trial of EC versus NRT reported safety outcomes in the randomized arms. We conducted a further analysis based on product use. SETTING: Twenty-three hospitals in England and a stop-smoking service in Scotland took part. PARTICIPANTS: The participants comprised 1140 pregnant smokers. INTERVENTIONS: We compared women using and not using EC and NRT regularly during pregnancy. MEASUREMENTS: Measurements included nicotine intake compared with baseline, birth weight, other pregnancy outcomes, adverse events, maternal respiratory symptoms and relapse in early abstainers. FINDINGS: Use of EC was more common than use of NRT (47.3% vs 21.6%, P < 0.001). Women who stopped smoking (abstainers) and used EC at the end-of-pregnancy (EOP) reduced their salivary cotinine by 45% [49.3 ng/ml, 95% confidence interval (CI) = -79.8 to -10]. Only one abstainer used NRT at EOP. In dual users, cotinine increased by 19% (24 ng/ml, 95% CI = 3.5-68). In women reporting a reduction of at least 50% in cigarette consumption, cotinine levels increased by 10% in those using nicotine products and by 9% in those who did not. Birth weights in dual users and exclusive smokers were the same (3.1 kg). Birth weight in abstainers using either nicotine product was higher than in smokers [3.3 kg, standard deviation (SD) = 0.7] versus 3.1 kg, SD = 0.6; difference = 0.15 kg, 95% CI = 0.05-0.25) and not different from abstainers not using nicotine products (3.1 kg, SD = 0.8). Abstainers and smokers using nicotine products had no worse pregnancy outcomes or more adverse events than abstainers and smokers not using them. EC users reported more improvements than non-users in cough [adjusted relative risk (aRR) = 0.59, 95% CI = 0.37-0.93] and phlegm (aRR = 0.53, 95% CI = 0.31-0.92), controlling for smoking status. EC or NRT use had no association with relapse. CONCLUSIONS: Regular use of e-cigarettes or nicotine patches by pregnant smokers does not appear to be associated with any adverse outcomes.

Helping pregnant smokers quit: a multi-centre randomised controlled trial of electronic cigarettes versus nicotine replacement therapy.

Background: Some pregnant smokers try e-cigarettes, but effectiveness and safety of such use are unknown. Objectives: To compare effectiveness and safety of nicotine patches and e-cigarettes in pregnancy. Design: A pragmatic multi-centre randomised controlled trial. Setting: Twenty-three hospitals across England, and a Stop Smoking Service in Scotland. Participants: One thousand one hundred and forty pregnant daily smokers (12-24 weeks' gestation) motivated to stop smoking, with no strong preference for using nicotine patches or e-cigarettes. Interventions: Participants in the e-cigarette arm were posted a refillable e-cigarette device with two 10 ml bottles of tobacco-flavoured e-liquid (18 mg nicotine). Participants in the nicotine patches arm were posted a 2-week supply of 15 mg/16-hour nicotine patches. Supplies were provided for up to 8 weeks. Participants sourced further supplies themselves as needed. Participants in both arms received support calls prior to their target quit date, on the quit date, and weekly for the next 4 weeks. Outcome measures: The primary outcome was validated prolonged abstinence at the end of pregnancy. Participants lost to follow-up or not providing biochemical validation were included as non-abstainers. Secondary outcomes included self-reported abstinence at different time points, treatment adherence and safety outcomes. Results: Only 55% of self-reported abstainers mailed back useable saliva samples. Due to this, validated sustained abstinence rates were low (6.8% vs. 4.4% in the e-cigarettes and nicotine patches arms, respectively, risk ratio = 1.55, 95% confidence interval 0.95 to 2.53; Bayes factor = 2.7). In a pre-specified sensitivity analysis that excluded abstainers using non-allocated products, the difference became significant (6.8% vs. 3.6%, risk ratio = 1.93, 95% confidence interval 1.14 to 3.26; Bayes factor = 10). Almost a third of the sample did not set a target quit date and the uptake of support calls was low, as was the initial product use. At end of pregnancy, 33.8% versus 5.6% of participants were using their allocated product in the e-cigarettes versus nicotine patches arm (risk ratio = 6.01, 95% confidence interval 4.21 to 8.58). Regular use of e-cigarettes in the nicotine patches arm was more common than use of nicotine replacement products in the e-cigarette arm (17.8% vs. 2.8%). Rates of adverse events and adverse birth outcomes were similar in the two study arms, apart from participants in the e-cigarette arm having fewer infants with low birthweight (<2500 g) (9.6% vs. 14.8%, risk ratio = 0.65, 95% confidence interval 0.47 to 0.90; Bayes factor = 10.3). Limitations: Low rates of validation reduced the study power. A substantial proportion of participants did not use the support on offer sufficiently to test its benefits. Sample size may have been too small to detect differences in less frequent adverse effects. Conclusions: E-cigarettes were not significantly more effective than nicotine patches in the primary analysis, but when e-cigarettes use in the nicotine patches arm was accounted for, e-cigarettes were almost twice as effective as patches in all abstinence outcomes. In pregnant smokers seeking help, compared to nicotine patches, e-cigarettes are probably more effective, do not pose more risks to birth outcomes assessed in this study and may reduce the incidence of low birthweight. Future work: Routine monitoring of smoking cessation and birth outcomes in pregnant women using nicotine patches and e-cigarettes and further studies are needed to confirm these results. Trial registration: This trial is registered as ISRCTN62025374 and Eudract 2017-001237-65. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 13. See the NIHR Journals Library website for further project information.

Like many other smokers in the UK, some pregnant smokers try to limit or stop smoking with the help of e-cigarettes. It is not known whether this helps with stopping smoking and whether using e-cigarettes has any bad effects on the baby. We recruited 1140 pregnant smokers who wanted to quit. A random half were given nicotine patches, which are commonly used to help smokers quit. The other half were given an e-cigarette. They also received six weekly phone calls to support them in stopping smoking. We then looked at how many in each group stopped smoking by the end of pregnancy. More women stopped smoking in the group that was given an e-cigarette, but the difference was small and could be due to chance. However, some of the women in the nicotine patch group who had successfully stopped smoking were using e-cigarettes rather than patches. When these (and women in the e-cigarette group who used patches) were not counted, e-cigarettes helped almost twice as many women stop smoking than patches. E-cigarettes were better than patches in preventing low birthweight (having babies who weigh less than 2.5 kg). Otherwise, women given patches and those given e-cigarettes (and their babies) had similar numbers of medical complications. For pregnant women who smoke and need help to quit, e-cigarettes are probably more helpful than nicotine patches, and do not pose any additional risks to women or their babies.

Electronic cigarettes versus nicotine patches for smoking cessation in pregnancy: a randomized controlled trial.

Nicotine replacement therapy, in the form of nicotine patches, is commonly offered to pregnant women who smoke to help them to stop smoking, but this approach has limited efficacy in this population. Electronic cigarettes (e-cigarettes) are also used by pregnant women who smoke but their safety and efficacy in pregnancy are unknown. Here, we report the results of a randomized controlled trial in 1,140 participants comparing refillable e-cigarettes with nicotine patches. Pregnant women who smoked were randomized to e-cigarettes (n = 569) or nicotine patches (n = 571). In the unadjusted analysis of the primary outcome, validated prolonged quit rates at the end of pregnancy in the two study arms were not significantly different (6.8% versus 4.4% in the e-cigarette and patch arms, respectively; relative risk (RR) = 1.55, 95%CI: 0.95-2.53, P = 0.08). However, some participants in the nicotine patch group also used e-cigarettes during the study. In a pre-specified sensitivity analysis excluding abstinent participants who used non-allocated products, e-cigarettes were more effective than patches (6.8% versus 3.6%; RR = 1.93, 95%CI: 1.14-3.26, P = 0.02). Safety outcomes included adverse events and maternal and birth outcomes. The safety profile was found to be similar for both study products, however, low birthweight (<2,500 g) was less frequent in the e-cigarette arm (14.8% versus 9.6%; RR = 0.65, 95%CI: 0.47-0.90, P = 0.01). Other adverse events and birth outcomes were similar in the two study arms. E-cigarettes might help women who are pregnant to stop smoking, and their safety for use in pregnancy is similar to that of nicotine patches. ISRCTN62025374.

Effectiveness of offering tailored text message, self-help smoking cessation support to pregnant women who want information on stopping smoking: MiQuit3 randomised controlled trial and meta-analysis.

AIMS: To test the efficacy of 'MiQuit', a tailored, self-help, text message stop smoking programme for pregnancy, as an adjunct to usual care (UC) for smoking cessation in pregnancy. DESIGN: Multicentre, open, two-arm, parallel-group, superiority randomised controlled trial (RCT) and a trial sequential analysis (TSA) meta-analysis combining trial findings with two previous ones. SETTING: Twenty-four English hospital antenatal clinics. PARTICIPANTS: A total of 1002 pregnant women who were ≥16 years old, were ≤25 weeks gestation and smoked ≥1 daily cigarette and accepted information on cessation with no requirement to set quit dates. INTERVENTIONS: UC or UC plus 'MiQuit': 12 weeks of tailored, smoking cessation text messages focussed on inducing and aiding cessation. MEASUREMENTS: Primary outcome: biochemically validated cessation between 4 weeks after randomisation and late pregnancy. SECONDARY OUTCOMES: shorter and non-validated abstinence periods, pregnancy outcomes and incremental cost-effectiveness ratios. FINDINGS: RCT: cessation was 5.19% (26/501) and 4.59% (23/501) in MiQuit and UC groups (adjusted odds ratio [adj OR] for quitting with MiQuit versus UC, 95% CI = 1.15 [0.65-2.04]); other abstinence findings were similar, with higher point estimates. Primary outcome ascertainment was 61.7% (309) and 67.3% (337) in MiQuit and UC groups with 71.1% (54/76) and 69.5% (41/59) abstinence validation rates, respectively. Pregnancy outcomes were similar and the incremental cost per quality-adjusted life year was -£1118 (95% CI = -£4806-£1911). More MiQuit group women reported making at least one quit attempt (adj OR [95% CI]) for making an attempt, 1.50 (1.07-2.09). TSA meta-analysis: this found no significant difference in prolonged abstinence between MiQuit and UC (pooled OR = 1.49, adjusted 95% CI = 0.62-3.60). CONCLUSIONS: Irrespective of whether they want to try quitting, when offered a tailored, self-help, text message stop smoking programme for pregnancy (MiQuit) as an adjunct to usual care, pregnant women are not more likely to stop smoking until childbirth but they report more attempts at stopping smoking.

Pre-notification and personalisation of text messages to increase questionnaire completion in a smoking cessation pregnancy RCT: an embedded randomised factorial trial.

BACKGROUND: Low response rates in randomised controlled trials can compromise the reliability of the results, so ways to boost retention are often implemented. Although there is evidence to suggest that sending a text message to participants increases retention, there is little evidence around the timing or personalisation of these messages.  Methods:  A two-by-two factorial SWAT (study within a trial) was embedded within the MiQuit-3 trial, looking at smoking cessation within pregnant smokers. Participants who reached their 36-week gestational follow-up were randomised to receive a personalised or non-personalised text message, either one week or one day prior to the telephone follow-up. Primary outcomes were completion rate of questionnaire via telephone. Secondary outcomes included: completion rate via any method, time to completion, and number of reminders required.  Results  In total 194 participants were randomised into the SWAT; 50 to personalised early text, 47 to personalised late text, 50 to non-personalised early text, and 47 to non-personalised late text. There was no evidence that timing of the text message (early: one week before; or late: one day before) had an effect on any of the outcomes. There was evidence that a personalised text would result in fewer completions via telephone compared with a non-personalised text (adjusted OR 0.44, 95% CI 0.22-0.87, p=0.02). However, there was no evidence to show that personalisation or not was better for any of the secondary outcomes.  Conclusion  Timing of the text message does not appear to influence the retention of participants. Personalisation of a text message may be detrimental to retention; however, more SWATs should be undertaken in this field.

Effectiveness and cost-effectiveness of a tailored text-message programme (MiQuit) for smoking cessation in pregnancy: study protocol for a randomised controlled trial (RCT) and meta-analysis.

BACKGROUND: Smoking in pregnancy is a major international public health problem. Self-help support (SHS) increases the likelihood of women stopping smoking in pregnancy and delivering this kind of support by text message could be a cost-effective way to deliver SHS to pregnant women who smoke. SHS delivered by text message helps non-pregnant smokers to stop but the currently available message programmes are not appropriate for use in pregnancy. A randomised controlled trial (RCT) has demonstrated the feasibility and acceptability of using a programme called 'MiQuit' to text SHS support to pregnant women who smoke. Another pilot RCT has shown that it would be feasible to run a larger, multi-centre trial within the UK National Health Service (NHS). The aim of this third RCT is to complete MiQuit's evaluation, demonstrating whether or not this is efficacious for smoking cessation in pregnancy. METHODS/DESIGN: This is a multi-centre, parallel-group RCT. Pregnant women aged over 16 years, of less than 25 weeks' gestation who smoke one or more daily cigarettes but smoked at least five daily cigarettes before pregnancy and who understand written English and are being identified in 24 English antenatal care hospitals. Participants are randomised to control or intervention groups in a 1:1 ratio stratified by gestation (< 16 weeks versus ≥ 16 weeks). All participants receive a leaflet on stopping smoking during pregnancy; they are also able to access standard NHS smoking cessation support. Intervention group women also receive the 12-week MiQuit programme of tailored, interactive text message, and self-help cessation support. Women are followed up by telephone at 4 weeks after randomisation and 36 weeks' gestation. The RCT will recruit 692 women (346 per group), enabling a 95% confidence interval for the difference in quit rates to be estimated within ± 3%. To determine whether or not MiQuit helps pregnant smokers to stop, intervention group quit rates from this trial will be combined with those from the two earlier trials in a Trial Sequential Analysis (TSA) meta-analysis to derive a pooled efficacy estimate. DISCUSSION: If effective, MiQuit will be a cheap, cost-effective method to help pregnant women to stop smoking. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03231553 . Registered on 20 July 2017.

Attitudes to E-Cigarettes and Cessation Support for Pregnant Women from English Stop Smoking Services: A Mixed Methods Study.

Smoking in pregnancy remains a public health problem. In the UK e-cigarettes are the most popular aid to quitting smoking outside of pregnancy, but we don't know the extent of e-cigarette use in pregnancy or how English Stop Smoking Services (SSS) respond to pregnant women who vape. In 2015 we surveyed SSS managers about cessation support for pregnant women and responses to clients who vaped. Subsequently we interviewed a sub-sample of managers to seek explanations for the SSS' position on e-cigarettes; interviews were thematically analysed. Survey response rate was 67.8% (72/106); overall managers reported 2.2% (range 1.4⁻4.3%) of pregnant clients were using e-cigarettes. Most SSS reported supporting pregnant women who already vaped, but would not recommend e-cigarette use; for women that were still smoking and not using e-cigarettes, 8.3% of SSS were likely/very likely to advise using e-cigarettes, with 56.9% of SSS unlikely/very unlikely to advise using them. Fifteen respondents were interviewed; interviewees were generally positive about the potential of e-cigarettes for cessation in pregnancy although concerns about perceived lack of evidence for safety were expressed and most wanted research on this. Clear guidance on e-cigarette use informed by pregnancy specific research will assist SSS to provide consistent evidence-based support.

Views on and experiences of electronic cigarettes: a qualitative study of women who are pregnant or have recently given birth.

BACKGROUND: Electronic cigarettes (ECs) are increasingly used for reducing or stopping smoking, with some studies showing positive outcomes. However, little is known about views on ECs during pregnancy or postpartum and previous studies have nearly all been conducted in the US and have methodological limitations, such as not distinguishing between smokers and ex/non-smokers. A greater understanding of this topic will help to inform both clinicians and EC interventions. We elicited views and experiences of ECs among UK pregnant or recently pregnant women. METHODS: We conducted semi-structured telephone interviews, using topic guides, with pregnant or recently pregnant women, who were current or recent ex-smokers. To ensure broad views of ECs were obtained, recruitment was from several geographical locations and via various avenues of recruitment. This included stop smoking services, antenatal and health visitor clinics, a pregnancy website and an informal network. Participants were 15 pregnant and 15 postpartum women, including nine current EC users, 11 ex-users, and 10 never-users. Five women who were interviewed in pregnancy were later interviewed in postpartum to explore if their views had changed. Audio data was transcribed verbatim and framework analysis was applied. RESULTS: Five main themes emerged: motivations for use (e.g., for stopping or reducing smoking), social stigma (e.g., avoiding use in public, preferring 'discrete' NRT), using the EC (e.g., mostly used at home); consumer aspects (e.g., limited advice available), and harm perceptions (e.g., viewed as less harmful than smoking; concerns about safety and addiction). CONCLUSIONS: ECs were viewed positively by some pregnant and postpartum women and seen as less harmful than smoking and useful as aids for reducing and stopping smoking. However, due to perceived social stigma, some women feel uncomfortable using ECs in public, especially during pregnancy, and had concerns about safety and nicotine dependence. Health professionals and designers of EC interventions need to provide women with up-to-date and consistent information and advice about safety and dependence, as well as considering the influence of social stigma.

Large multi-centre pilot randomized controlled trial testing a low-cost, tailored, self-help smoking cessation text message intervention for pregnant smokers (MiQuit).

AIMS: To estimate the effectiveness of pregnancy smoking cessation support delivered by short message service (SMS) text message and key parameters needed to plan a definitive trial. DESIGN: Multi-centre, parallel-group, single-blinded, individual randomized controlled trial. SETTING: Sixteen antenatal clinics in England. PARTICIPANTS: Four hundred and seven participants were randomized to the intervention (n = 203) or usual care (n = 204). Eligible women were < 25 weeks gestation, smoked at least one daily cigarette (> 5 pre-pregnancy), were able to receive and understand English SMS texts and were not already using text-based cessation support. INTERVENTION: All participants received a smoking cessation leaflet; intervention participants also received a 12-week programme of individually tailored, automated, interactive, self-help smoking cessation text messages (MiQuit). OUTCOME MEASUREMENTS: Seven smoking outcomes, including validated continuous abstinence from 4 weeks post-randomization until 36 weeks gestation, design parameters for a future trial and cost-per-quitter. FINDINGS: Using the validated, continuous abstinence outcome, 5.4% (11 of 203) of MiQuit participants were abstinent versus 2.0% (four of 204) of usual care participants [odds ratio (OR) = 2.7, 95% confidence interval (CI) = 0.93-9.35]. The Bayes factor for this outcome was 2.23. Completeness of follow-up at 36 weeks gestation was similar in both groups; provision of self-report smoking data was 64% (MiQuit) and 65% (usual care) and abstinence validation rates were 56% (MiQuit) and 61% (usual care). The incremental cost-per-quitter was £133.53 (95% CI = -£395.78 to 843.62). CONCLUSIONS: There was some evidence, although not conclusive, that a text-messaging programme may increase cessation rates in pregnant smokers when provided alongside routine NHS cessation care.

'Opt-out' referrals after identifying pregnant smokers using exhaled air carbon monoxide: impact on engagement with smoking cessation support.

BACKGROUND: In the UK, free smoking cessation support is available to pregnant women; only a minority accesses this. 'Opt-out' referrals to stop smoking services (SSS) are recommended by UK guidelines. These involve identifying pregnant smokers using exhaled carbon monoxide (CO) and referring them for support unless they object. METHODS: To assess the impact of 'opt-out' referrals for pregnant smokers on SSS uptake and effectiveness, we conducted a 'before-after' service development evaluation. In the 6-month 'before' period, there was a routine 'opt-in' referral system for self-reported smokers at antenatal 'booking' appointments. In the 6-month 'after' period, additional 'opt-out' referrals were introduced at the 12-week ultrasound appointments; women with CO≥4 ppm were referred to, and outcome data were collected from, local SSS. RESULTS: Approximately 2300 women attended antenatal care in each period. Before the implementation, 536 (23.4%) women reported smoking at 'booking' and 290 (12.7%) were referred to SSS. After the implementation, 524 (22.9%) women reported smoking at 'booking', an additional 156 smokers (6.8%) were identified via the 'opt-out' referrals and, in total, 421 (18.4%) were referred to SSS. Over twice as many women set a quit date with the SSS after 'opt-out' referrals were implemented (121 (5.3%, 95% CI 4.4% to 6.3%) compared to 57 (2.5%, 95% CI 1.9% to 3.2%) before implementation) and reported being abstinent 4 weeks later (93 (4.1%, 95% CI 3.3% to 4.9%) compared to 46 (2.0%, 1.5% to 2.7%) before implementation). CONCLUSIONS: In a hospital with an 'opt-in' referral system, adding CO screening with 'opt-out' referrals as women attended ultrasound examinations doubled the numbers of pregnant smokers setting quit dates and reporting smoking cessation.

The SNAP trial: a randomised placebo-controlled trial of nicotine replacement therapy in pregnancy--clinical effectiveness and safety until 2 years after delivery, with economic evaluation.

BACKGROUND: Smoking during pregnancy causes many adverse pregnancy and birth outcomes. Nicotine replacement therapy (NRT) is effective for cessation outside pregnancy but efficacy and safety in pregnancy are unknown. We hypothesised that NRT would increase smoking cessation in pregnancy without adversely affecting infants. OBJECTIVES: To compare (1) at delivery, the clinical effectiveness and cost-effectiveness for achieving biochemically validated smoking cessation of NRT patches with placebo patches in pregnancy and (2) in infants at 2 years of age, the effects of maternal NRT patch use with placebo patch use in pregnancy on behaviour, development and disability. DESIGN: Randomised, placebo-controlled, parallel-group trial and economic evaluation with follow-up at 4 weeks after randomisation, delivery and until infants were 2 years old. Randomisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio. Participants, site pharmacies and all study staff were blind to treatment allocation. SETTING: Seven antenatal hospitals in the Midlands and north-west England. PARTICIPANTS: Women between 12 and 24 weeks' gestation who smoked ≥ 10 cigarettes a day before and ≥ 5 during pregnancy, with an exhaled carbon monoxide (CO) reading of ≥ 8 parts per million (p.p.m.). INTERVENTIONS: NRT patches (15 mg per 16 hours) or matched placebo as an 8-week course issued in two equal batches. A second batch was dispensed at 4 weeks to those abstinent from smoking. PARTICIPANTS: self-reported, prolonged abstinence from smoking between a quit date and childbirth, validated at delivery by CO measurement and/or salivary cotinine (COT) (primary outcome). Infants, at 2 years: absence of impairment, defined as no disability or problems with behaviour and development. Economic: cost per 'quitter'. RESULTS: One thousand and fifty women enrolled (521 NRT, 529 placebo). There were 1010 live singleton births and 12 participants had live twins, while there were 14 fetal deaths and no birth data for 14 participants. Numbers of adverse pregnancy and birth outcomes were similar in trial groups, except for a greater number of caesarean deliveries in the NRT group. Smoking: all participants were included in the intention-to-treat (ITT) analyses; those lost to follow-up (7% for primary outcome) were assumed to be smoking. At 1 month after randomisation, the validated cessation rate was higher in the NRT group {21.3% vs. 11.7%, odds ratio [OR], [95% confidence interval (CI)] for cessation with NRT, 2.05 [1.46 to 2.88]}. At delivery, there was no difference between groups' smoking cessation rates: 9.4% in the NRT and 7.6% in the placebo group [OR (95% CI), 1.26 (0.82 to 1.96)]. Infants: at 2 years, analyses were based on data from 888 out of 1010 (87.9%) singleton infants (including four postnatal infant deaths) [445/503 (88.5%) NRT, 443/507 (87.4%) placebo] and used multiple imputation. In the NRT group, 72.6% (323/445) had no impairment compared with 65.5% (290/443) in placebo (OR 1.40, 95% CI 1.05 to 1.86). The incremental cost-effectiveness ratio for NRT use was £4156 per quitter (£4926 including twins), but there was substantial uncertainty around these estimates. CONCLUSIONS: Nicotine replacement therapy patches had no enduring, significant effect on smoking in pregnancy; however, 2-year-olds born to women who used NRT were more likely to have survived without any developmental impairment. Further studies should investigate the clinical effectiveness and safety of higher doses of NRT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07249128. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 54. See the NIHR Journals Library programme website for further project information.

Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trial.

BACKGROUND: The SNAP (Smoking and Nicotine in Pregnancy) trial compared nicotine replacement therapy (NRT) patches with placebo in pregnant smokers; although NRT doubled cessation rates in the first 4 weeks, by delivery no differences in maternal smoking or birth outcomes were noted. As a result, NRT used in standard doses during pregnancy is considered ineffective for smoking cessation. Subsequent effects of NRT on the children of treated mothers are unknown because no trials have investigated the effect of gestational NRT use beyond birth. To assess whether NRT use in pregnancy might cause harm to infants, we aimed to compare effects of NRT and placebo on infant development 2 years after delivery. METHODS: 1050 pregnant smokers aged 16-45 years, at 12-24 weeks' gestation, and smoking at least five cigarettes per day were recruited from seven hospitals in England between May 1, 2007, and Feb 26, 2010, and followed up until their infants were 2 years old. Participants were randomly assigned (1:1) to receive up to 8-weeks treatment with NRT (15 mg/16 h transdermal patches) or identically packaged and visually matched placebo patches (all patches manufactured by and purchased at market rate from United Pharmaceuticals, Amman, Jordan), issued as two 4-week supplies (521 for NRT group, 529 for placebo group) [Corrected]. Randomisation was stratified by site with participants, health-care professionals, and research staff masked to treatment allocation. The primary results for participants and infants at delivery were published in 2012; we present results from the trial cohort 2 years after birth. After delivery, questionnaires were posted to participants and, if there was no response, to family physicians. The primary outcome at 2 years was infants' survival without developmental impairment (ie, no disability or problems with behaviour or development). Treatment groups were compared on an intention-to-treat basis. The trial is registered with Controlled-Trials.com, number ISRCTN07249128. FINDINGS: Questionnaires were returned at 2 years for 891 (88%) of 1010 live singleton births (445 of (88%) 503 given NRT and 446 (88%) of 507 given placebo). Because of missing data, developmental outcomes, including four infant deaths, were documented for 888 of (88%) 1010 singleton infants; 445 (88%) of 503 infants in NRT group and 443 (87%) of 507 infants in placebo. In the NRT group, 323 (73%) of 445 infants had no impairment compared with 290 (65%) of 443 infants in the placebo group (odds ratio [OR] 1.40, 95% CI 1.05-1.86, p=0.023). At 2 years, 15 (3%) of 521 mothers in the NRT group and nine (2%) of 529 mothers in the placebo groups self-reported prolonged smoking abstinence since a quit date set in pregnancy (OR 1.71, 95% CI 0.74-3.94, p=0.20). Adverse events were not collected after delivery, but previously reported adverse pregnancy and birth outcomes were similar in the two groups. INTERPRETATION: Infants born to women who used NRT for smoking cessation in pregnancy were more likely to have unimpaired development. NRT had no effect on prolonged abstinence from smoking but did cause a temporary doubling of smoking cessation shortly after randomisation during pregnancy, which could explain findings. If findings are confirmed by subsequent research, this has potential implications for the management of smoking in pregnancy. FUNDING: National Institute for Health Research Health Technology Assessment Programme.