Discussion
The current study shows that even a relatively high daily dose of nicotine, adjusted for baseline saliva cotinine levels and administered with a relatively high self reported compliance rate for a median of 105 days during the second and third trimester did not increase abstinence rates. The complete abstinence rate from quit date up to end of pregnancy was low (5.5% and 5.1%), and this was lower than the 21% and 19% (relative risk 1.1%, 95% confidence interval 0.7% to 1.8%) found in the most similarly designed previous study, but with a substantially shorter exposure. The nicotine substitution rate in the nicotine patch group showed that abstinence was unrelated to the level of nicotine substitution, suggesting that factors other than nicotine replacement may determine abstinence in pregnant smokers.
A probable consequence of the lack of efficacy for abstinence observed in this study is that compared with placebo the transdermal nicotine patch did not increase birth weight and other birth characteristics. The nicotine patch did not significantly reduce craving for tobacco, withdrawal symptoms, and number of cigarettes smoked.
The point difference in the frequency of at least one serious adverse event among mothers was 4% ( Table 5 ). A significant difference (at P≤0.05) would have required 882 women per group, therefore we cannot draw firm conclusions about differences in serious adverse events. More non-gynaecological-obstetric adverse effects were observed with use of the nicotine patch, with the greatest difference for skin reactions.
Diastolic blood pressure increased significantly in the nicotine patch group compared with placebo patch group. Previous studies on NRT in pregnant smokers did not report on blood pressure so this should be considered as a preliminary finding that needs confirmation. However, nicotine may increase diastolic blood pressure, and this effect on blood pressure is mediated by peripheral nicotinic receptors in the sympathetic nervous system.
The median length of prescription was longer in the nicotine patch group than in the placebo patch group. This could be considered as an intermediate sign of efficacy if it paralleled the main or secondary outcomes, which was not the case. However, because more non-serious adverse reactions occurred in the nicotine patch group, it is likely that the longer median length of prescription (visit attendance) in that group is a consequence of perception of non-serious adverse reactions with the active drug treatment—that is, the presence of non-serious adverse reactions may have suggested to participants that they were receiving the active treatment and might have increased attendance.
Most of the relapses occurred by week 2 after quit date. The dose adjustment schedule aimed, in case of insufficient initial tailoring, to rectify the initial dose of nicotine if the therapeutic response was insufficient (relapse), either by increasing the dose (to increase the likelihood of abstinence) or maintaining it (to prevent relapse), both aiming to enhance abstinence rates in the following months. However, even this schedule did not increase the efficacy of the nicotine patches.
Strengths and Weaknesses of This Study
The strengths of this study include the individualised adjustment of daily nicotine dose according to saliva cotinine levels while smoking and potentially resulting in a close to 100% nicotine substitution rate. The formula we used allowed concomitant cigarette use to be compensated for by increasing the daily dose of nicotine. The adjustment might also have avoided under-dosing or overdosing. Compared with previous studies the duration of treatment was longer and higher daily doses of nicotine were administered, leading to an overall higher exposure to nicotine. The self reported compliance rate was higher than previously reported probably because of the relatively frequent face to face visits. We used a licenced nicotine patch, a warranty of validated bioavailabilty, which allowed the findings of the nicotine patches to be generalised to clinical practice. The placebo patches were manufactured by the same company, with specific quality control guidelines to ensure double blinding. The study, unlike previous smoking cessation trials in pregnant smokers, reports on craving for tobacco, withdrawal symptoms, and blood pressure.
Study limitations were that treatment started only after the end of the first trimester; if effective, starting treatment earlier may have resulted in better outcomes, as smoking cessation at less than 15 weeks’ gestation provides similar birth outcomes to those in non-smokers. However, studies in animals have shown that nicotine is a developmental neurotoxicant, particularly during the early phase of pregnancy, and owing to a lack of safety data in humans, we avoided nicotine being administered during the first trimester. Participants were women seeking smoking cessation treatment in pregnancy, who consumed at least five cigarettes a day; therefore the results are difficult to generalise to other pregnant smokers. The trial's population was a highly tobacco dependent group. Generalisability of the results to a less dependent population of pregnant smokers should be done with caution.
The observed difference in the rate of complete abstinence (nicotine patch 5.5%, placebo patch 5.1%) was less than planned and cannot be considered as clinically significant; 49 242 pregnant smokers in each group would be needed to provide a significant difference. Moreover, the point prevalence rate was also low and far from a statistically significant difference. No effect of nicotine patch in improving craving or withdrawal symptoms was observed. Because between intervention differences occur mainly during the first month, in randomised, controlled smoking cessations studies using NRT, lack of difference in the time to relapse during the early phase of the trial also confirms the lack of efficacy. We would have needed to randomise 1939 women by group for the observed 50 g difference in birth weight to become significantly different.
Our primary smoking cessation outcome was stringent and we assumed that women who missed a visit were smoking. This definition might have reduced the overall abstinence rate in both groups. However, in this sample no women who missed one appointment were abstinent at other visits.
Implications for Clinicians and Policy Makers and Unanswered Questions and Future Research
Efficacy. Because NRT were licenced for smoking cessation in France in 1997, the current trial was conducted to confirm their hypothesised efficacy. One well powered but short exposure study and meta-analyses of previous trials using standard NRT doses for a shorter period than the present study concluded that NRTs are not effective in pregnant smokers.
The current findings show that relatively long and high dose exposure using an individualised dosage regimen did not increase complete or point prevalence abstinence rates or time to relapse and thus confirms the lack of efficacy of NRT in pregnant smokers and consequently the lack of improvement of birth characteristics. As in several previous studies, craving for tobacco declined progressively but without a difference between the groups. These are disappointing results and should encourage efforts to evaluate new approaches that are both drug and non-drug related. In the absence of evidence based drug interventions, behavioural support remains the core intervention to help pregnant smokers to quit.
Uncertainty exists about whether results would be different in a less dependent population of pregnant smokers, and whether other forms of NRT, such as transdermal NRT started before or during the first weeks of pregnancy, would yield superior results. Data from 3880 pregnant smokers attending stop smoking services in England have shown that two weeks’ abstinence during four weeks of treatment using combination NRT was higher than with no treatment or with single NRT, single NRT being no different from no treatment; however, the odds of success declined each month. The promising efficacy of combination NRT should be assessed in controlled trials, along with pregnancy and perinatal outcomes.
Safety
The current study shows that the nicotine patch may increase diastolic blood pressure at the end of pregnancy, which may potentially lead to unfavourable pregnancy outcomes. A median 8 mm Hg end of pregnancy difference in otherwise healthy women can be considered clinically important. Transposing this to the large population of pregnant smokers using nicotine patches, these data suggest that diastolic blood pressure can be a clinical concern. Future studies should confirm or refute this finding. Fewer than 2000 pregnant smokers were exposed to NRT in randomised, controlled smoking cessation studies. This number is too low to make a judgment about the safety of NRT. Future studies should monitor the safety of NRT in pregnancy.