Assessing the efficacy of Nicotine Replacement Therapy for smoking cessation during pregnancy

Claire, Ravinder (2021) Assessing the efficacy of Nicotine Replacement Therapy for smoking cessation during pregnancy. PhD thesis, University of Nottingham.

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Smoking during pregnancy is the leading modifiable risk factor for poor maternal and infant health outcomes. Pregnancy-related health problems associated with smoking during pregnancy include complications during labour, increased risk of miscarriage, premature birth, stillbirth and low birthweight. Despite this, around 12% of pregnant women in the United Kingdom (UK), 13% in the United States and 20% in France continue to smoke during pregnancy. A Cochrane review of 136 studies found that nicotine replacement Therapy (NRT) is proven to be effective amongst non-pregnant smokers, however a Cochrane review of eight studies found its efficacy in pregnancy to be uncertain. It is unclear whether we can ascertain a conclusion from this review as it may be subject to error due to repetitive testing, furthermore there may be insufficient power in the meta-analyses. Trial Sequential Analysis (TSA) is a method which could overcome these issues. This thesis provides an overview of TSA and applies the method to a systematic review of NRT use in pregnancy. This thesis also presents an alternative use for TSA, where it can be used for trial sample size estimation.

In most studies investigating NRT use for smoking cessation in pregnancy, women are instructed to discontinue use of nicotine patches if they have even brief smoking lapses. This is due to concerns that concomitant smoking and NRT use could increase exposure to nicotine and potentially more tobacco smoke toxins if they smoke heavily when using NRT. In 2014, the ‘Study of Nicotine Patch in Pregnancy’ (SNIPP) trial, a large randomised controlled trial (RCT) investigating NRT used in pregnancy for smoking cessation reported that it did not increase either smoking cessation rates or birth weights. This study was unique as participants were told that they could continue using nicotine patches during smoking lapses. Using data from this trial, this thesis aims to explore whether concurrent smoking and NRT use resulted in changes in nicotine intake as well as smoking behaviour. This thesis also uses this trial to explore whether NRT use and changes in expired air carbon monoxide throughout pregnancy have an impact on birthweight.


Systematic review and meta-analysis

To determine the efficacy and safety of NRT for smoking cessation in later pregnancy, systematic review methods were used following standard Cochrane methods. The primary outcome was smoking cessation at the latest time point in pregnancy at which this was measured, and secondary outcomes were safety related. Meta-analyses were conducted where appropriate.

Trial Sequential Analysis

Trial sequential analysis was used to investigate whether there is sufficient evidence available to come to a firm conclusion on the efficacy of nicotine replacement therapy in pregnancy. Trial Sequential Analysis is a methodology that can be used in systematic reviews and meta-analyses to control random errors, and to assess whether further trials need to be conducted. We employ this method to the data from the systematic review, to assess whether there is sufficient evidence to conclude a clinically important treatment effect, no evidence of an effect, or lack of evidence.

This thesis goes on to explain an alternative use for Trial Sequential Analysis, where it can be used to estimate trial sample sizes for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using Trial Sequential Analysis to assess the intervention’s effects. Using feasibility and pilot trials of a behavioural smoking cessation intervention, data are combined to estimate the sample size that one or more future RCTs would need to recruit, to provide a more decisive answer regarding intervention benefit.

Analysis of the SNIPP trial

The final study in this thesis used data from 402 women recruited to the SNIPP trial. Paired t-tests, linear regression, interaction tests, and within-individual variability analysis techniques were employed to answer the following questions: (1) does concurrent smoking and NRT use result in changes in nicotine, and other indicators of smoking intensity?; (2) do these changes differ between NRT or placebo patch use?.


Systematic review and meta-analysis

Compared to placebo and non‐placebo controls, there was low‐certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). There was unclear evidence of an effect in placebo‐controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non‐placebo‐controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women).

Trial Sequential Analysis

The meta-analysis was not adequately powered to provide a strong conclusion, and TSA estimates that further placebo-controlled trials with approximately 10,741 participants in total are needed to arrive at a firm conclusion.

Analysis of the SNIPP trial

(1) In the nicotine patch group, there was no change in saliva cotinine concentrations between baseline and 2-weeks post quit date (ratio of geometric means = 0.94, 95% CI=0.83 to 1.07; p=0.37, Bayes factor=0.15). However, there was a reduction in reported number of daily cigarettes smoked (mean difference -6, 95% CI’s -7 to -5, p<0.001) and in CO concentrations (mean difference -3.0ppm, 95% CI’s -4.2 to -1.9, p<0.001). (2) These changes were not significantly different from changes in the placebo group except for cigarette consumption which reduced more in the placebo group (p=0.046).


• NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non‐placebo‐controlled RCTs were excluded from the analysis.

• According to TSA, there is uncertainty regarding the efficacy of NRT use for smoking cessation during pregnancy compared to control, and further placebo-controlled trials are needed to arrive at a firm conclusion.

• Although TSA suggests more research is required for a firm conclusion, the general trend appears that NRT as it has previously been trialled, may not be effective for smoking cessation in pregnant women. Further trials should focus on what can be done differently in future. For example, using higher dose NRT or encouraging better adherence to treatment may produce more positive outcomes.

• Our findings suggest that when pregnant women use nicotine patches as part of a quit attempt, but they also smoke, they smoke less than they did before the quit attempt started. This means that their exposure to the toxic products of burnt tobacco is reduced.

• Despite having similar cotinine exposure to that from cigarette smoking, pregnant women who use nicotine patches and smoke, smoke less and exhale less CO, so their exposure to other tobacco smoke toxins is likely to be lower too.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Coleman, Tim
Leonardi-Bee, Jo
Berlin, Ivan
Keywords: Smoking; Tobacco; Pregnancy; Systematic Review; Meta-analysis; Trial sequential analysis
Subjects: W Medicine and related subjects (NLM Classification) > WM Psychiatry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 64650
Depositing User: Claire, Ravinder
Date Deposited: 04 Aug 2021 04:40
Last Modified: 04 Aug 2021 04:40

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