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Title: The use of medicinal nicotine in pregnancy for smoking cessation
Author: Vaz, Luis Reeves
ISNI:       0000 0004 5369 6988
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2015
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Background Smoking during pregnancy is the leading preventable cause of poor birth outcomes for mothers and babies. In 2010, 26% of women smoked during or in the 12 months prior to pregnancy, and 12% smoked throughout pregnancy. 120 trials of nicotine replacement therapy (NRT) have shown that it is effective for smoking cessation in non-pregnant smokers. However, the 9 trials conducted in pregnant smokers, provide no evidence that NRT helps pregnant smokers to stop. In 2012, a large randomised controlled trial (RCT) investigating NRT used in pregnancy for smoking cessation reported that it initially doubled smoking cessation rates, but found no evidence that it enhanced cessation throughout pregnancy. Trial participants reported low adherence to NRT. One possible reason for this is that nicotine metabolism is much faster in pregnancy and so the doses of NRT which have been trialled in pregnancy may not sufficiently treat women’s nicotine withdrawal symptoms. This study not only found that children of mothers in the intervention arm had better developmental outcomes at 2 years of age, but also that a dose-response relationship existed between reported higher NRT use and the latter. Using data from this trial, this thesis aims to further explore factors driving/associated with both higher adherence to NRT in pregnancy and improved birth outcomes, and to raise hypotheses about ways in which NRT may be used effectively to help pregnant smokers attempting to quit. Methods The studies reported in this thesis used data from 1,050 pregnant women recruited to the Smoking, Nicotine and Pregnancy (SNAP) trial. Linear and logistic regressions, mediation analysis, factor analysis and structural equation modelling techniques were employed to answer the following questions: (1) which factors are associated with smoking cessation in pregnancy?; (2) which factors, if any, mediate the negative influence of social disadvantage on cessation in pregnancy?; (3) is greater NRT use is associated with poor birth outcomes?; (4) is adherence to NRT associated with greater odds of cessation?; (5) what are the characteristics associated with the rate of nicotine metabolism and does more rapid metabolism of nicotine reduce a woman’s chances of achieving cessation? Results (1) Within a trial of NRT used for smoking cessation, pregnant women who were more educated (Odds Ratio (OR) at one month post-quit date (one month): 1.82, 95%CI: 1.24-2.67, p=0.002/OR at delivery: 1.89, 95%CI: 1.16-3.07, p=0.010) and less nicotine dependent (OR for baseline cotinine at one month: 0.94, 95%CI: 0.91-0.96, p<0.001/OR for baseline cotinine at delivery: 0.96, 95%CI: 0.92-0.99, p=0.010) / (OR for HSI at one month: 0.50, 95%CI: 0.32-0.76, p=0.001/OR for HSI at delivery: 0.43, 95%CI: 0.23-0.79, P=0.006) were more likely to achieve cessation. (2) There was evidence that the observed relationship between social disadvantage and cessation was mediated by women’s nicotine dependence (17.1% of the effect of social disadvantage on cessation), but not by them living with partners who smoked. (3) In an analysis investigating the relationship between use of NRT in pregnancy and birth outcomes, greater reported use of NRT was not associated with either better or worse birth outcomes, either in a-priori analyses using birth weight (β: -0.46, 95%CI: -3.58 to 2.66, p=0.773) and being born small for gestational age (SGA) (OR: 1.01, 95%CI: 0.99 to 1.03, p=0.184), or in exploratory analyses using all other SNAP trial birth outcomes. (4) In the first ever detailed analysis of the phenomenon of adherence with NRT in pregnancy, women who adhered more completely had lower pre-treatment cotinine concentrations (β: -0.08, 95%CI: -0.15- -0.01, p=0.020), lower heaviness of smoking index (β: -0.27, 95%CI: -0.50- -0.05, p<0.001) and were more likely to have been assigned to active rather than placebo NRT (β: 0.51, 95%CI: 0.29-0.72, p<0.001). Greater adherence with NRT was positively and significantly associated with increased odds of smoking cessation (Adjusted OR at one month: 1.11, 95%CI: 1.08-1.13, p<0.001/Adjusted OR at delivery: 1.06, 95%CI: 1.03-1.09, p<0.001), but there was no treatment allocation (i.e. nicotine or placebo)-adherence interaction with respect to cessation (LRT p=0.151). Analyses could not exclude the possibility that the observed adherence-cessation relationship was caused by women who relapsed to smoking consequently also stopping use of NRT. It also remains unclear whether the adherence-cessation relationship may be due the characteristics of individuals who are more likely to adhere (i.e. women who are prone to following instructions to use NRT, might also be more likely to follow instructions to not smoke). (5) In another novel analysis, pregnant women who metabolised nicotine more quickly had reduced odds of cessation (OR at one month: 0.87, 95%CI: 0.76-0.99, p=0.043/OR at delivery: 0.79, 95%CI: 0.66-0.94, p=0.008); however, there was no evidence that NRT was more effective in slower metabolisers. Conclusions Having higher levels of education and lower levels of nicotine dependence were associated with cessation. Nicotine dependence mediates the negative effect social disadvantage has on achieving smoking cessation in pregnancy. Greater reported use of NRT in pregnancy neither harms the foetus nor protects it from the harms of smoking, with respect to birth weight and SGA, but there is insufficient evidence to draw similar inferences for all birth outcomes. Adherence is associated with better smoking cessation outcomes, and women who exhibit greater adherence have differing characteristics compared to those that adhere less. It was not possible to determine whether or not these better outcomes were a function of women’s characteristics or if they were attributable to the treatment they received. The rate of nicotine metabolism appears to be important in determining whether or not pregnant smokers will manage to successfully stop smoking, but there was no evidence that NRT effectiveness was influenced by nicotine metabolism. Quitting smoking during pregnancy is important for both the mother and the child’s health outcomes. Socially disadvantaged women are less likely to achieve cessation but this thesis provides the first evidence to suggest that these odds may be improved by addressing nicotine dependence; NRT provides an eminently treatable way of doing this. This thesis’s findings suggest that use of NRT is at least as safe as continued smoking with respect to birth outcomes, although probably safer. This thesis also provides the first evidence on the associations between individual pieces of NRT and cessation in pregnancy, as well as the first evidence on nicotine metabolism’s association with cessation in pregnancy. Overall, NRT provides a promising way to increase the odds of cessation for disadvantaged pregnant smokers, however, there is a need for further research and the work in this thesis should provide a spur to investigate the effects that adherence to NRT and an individuals’ metabolism may have on NRT effectiveness in pregnancy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WM Psychiatry