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Use of ‘higher dose’ nicotine replacement therapy (NRT) for smoking cessation in pregnancy: investigating the role of nicotine metabolism and treatment adherence

Project title

Use of ‘higher dose’ nicotine replacement therapy (NRT) for smoking cessation in pregnancy: investigating the role of nicotine metabolism and treatment adherence

Project reference


Final report date

09 November 2015

Project start date

01 October 2012

Project end date

01 October 2015

Project duration

3 years

Project keywords

Pregnancy; Nicotine; Metabolism; Adherence; Smoking; Cessation; NRT

Lead investigator(s)
  • Dr Sue Cooper, Faculty of Medicine & Health Sciences, University of Nottingham
NIHR School Collaborators
  • Dr Tim Coleman, Faculty of Medicine & Health Sciences, University of Nottingham
  • Ms Katharine Bowker, Faculty of Medicine & Health Sciences, University of Nottingham (PhD Student)
  • Professor Sarah Lewis, Faculty of Medicine & Health Sciences, University of Nottingham (Supervisor and Statistician) 
  • Professor Jim Thornton, Faculty of Medicine & Health Sciences, University of Nottingham (Obstetrician)

Project objectives


The overarching aim is to investigate the use of nicotine replacement therapy (NRT) in pregnancy, including individuals’ reasons for discontinuing this, and any contribution that changes in women’s nicotine metabolic rates across pregnancy progresses might have on stopping NRT treatment early.


The specific, measurable objectives are within a cohort of pregnant smokers who use NRT during a quit attempt to:

  1. describe women’s patterns of NRT use (e.g. regular and daily, intermittent and sporadic);
  2. describe pregnant women’s nicotine metabolic rates (NMR) at different times during pregnancy and investigate any changes in individual’s NMR as pregnancy progresses;
  3. compare ‘pre-treatment’ (whilst smoking) cotinine levels with ‘on-treatment’ (on NRT) ones and investigate the level of nicotine substitution obtained whilst using higher dose NRT.

And, in women who use NRT for at least 2 weeks prior to stopping this, to:

  1. describe women’s nicotine withdrawal symptoms experienced whilst using NRT and whether or not these change as pregnancy progresses;
  2. compare women’s nicotine withdrawal symptoms experienced immediately prior to NRT discontinuation with symptoms experience in earlier pregnancy whilst using NRT;
  3. describe women’s perceptions of why they discontinue of NRT (used at any dose), with a particular focus on those who use NRT every day for at least 2 weeks prior to stopping.

Changes to project objectives

The original proposal was for studies that were going to be undertaken within a PhD. Once the student started she developed the proposal further, and throughout the PhD the research evolved meaning that the studies and some of the original objectives changed slightly. Studies conducted in the PhD using this funding are described in the 'brief summary' section below, along with the objectives that these explored.

Objective 5 was not explored as the longitudinal study we conducted (study two below) measured nicotine metabolism in continuing smokers, rather than women using NRT. Measuring nicotine metabolism was essential in order to understand how this could influence NRT use and so we prioritised this objective. However, objective 5 could be explored in future research to investigate the relationship between changing nicotine metabolism, NRT use and nicotine dependency.

Brief summary

The project consisted of three studies, each with a specific aim:

  1. Study one: to compare cotinine levels in pregnant women whilst smoking and when using NRT (Objective 3 and partially explored objective 1);
  2. Study two: to describe the longitudinal pattern of pregnant women’s nicotine metabolism, as measured by the nicotine metabolite ratio (NMR) (Objective 2);
  3. Study three: to understand pregnant smokers’ reasons for non-adherence to NRT during a quit attempt (Objective 6 and partially explored objectives 1 and 4).

Study One


Data were analysed from 33 pregnant participants from the NRT arm of a randomised control trial who had stopped smoking and were still using 15mg/16hr nicotine patches 1 month after quitting. Salivary cotinine levels when smoking at baseline were compared with levels on NRT at 1 month.


Cotinine levels were lower than those achieved from smoking (median of 98.5ng/ml while smoking and 62.8ng/ml while using NRT and remaining abstinent, p = 0.045). Participants with the highest cotinine measurements when smoking also tended to have the steepest reduction in cotinine levels while using NRT. This was most noticeable among participants with baseline cotinine levels more than 150ng/ml (n = 9) who had a greater reduction in median cotinine levels (median difference −134.8ng /ml [95% CI = −144.5 to −125.9]) than those with a baseline cotinine level under 150ng/ml (n = 24; median difference −27.9ng/ml [95% CI = −49.35 to −1.75]).


The study found evidence that, in pregnant women, the level of nicotine substitution provided by standard dose NRT patches was lower than that generated by smoking. This disparity may partially explain why standard dose NRT used by pregnant women has not been shown to be effective. The lower cotinine levels may be indicative of insufficient levels of nicotine from NRT, so it may not provide high enough levels of nicotine to alleviate nicotine withdrawal symptoms. This could be one explanation as to why pregnant women often do not adhere to NRT and return to smoking.

Study Two


101 pregnant smokers recruited from hospital antenatal clinics were asked to provide saliva samples at 8-14 weeks (n=98), 18-22 weeks (n=65), 32-36 weeks gestation (n=47), 4 weeks postpartum (n=44) and 12 weeks postpartum (n=47). Nicotine metabolite ratio (NMR) was measured using the ratio of cotinine to its primary metabolite trans-3'-hydroxycotinine. Multi-level modelling was used to detect any overall difference in NMR between time points. The 12 week postpartum NMR was compared with the NMRs collected antenatally and 4 weeks postpartum.


NMR changed over time (p=0.0006). Compared with NMR at 12 weeks postpartum, NMR was significantly higher at 18-22 weeks (26% higher, 95% CI 12% to 38%) and 32-36 weeks (23% higher, 95% CI 9% to 35%). There was no significant difference between the 8-14 weeks gestation or 4 weeks postpartum NMR and 12 weeks postpartum.


The rate of nicotine metabolism is faster in pregnancy compared to postpartum, falling between birth and 1 month after delivery, at which point it appears to stabilise, presumably returning to non-pregnant levels by this point. This is also the first study to show that metabolism is increased from 18 to 22 weeks of pregnancy onwards. This finding could help explain why NRT has, to date, been found ineffective in pregnancy; as nicotine metabolism increases during pregnancy, so the dose of nicotine in NRT may become insufficient at providing therapeutic levels of nicotine.

Study Three


Qualitative study which involved semi-structured telephone interviews with 14 pregnant smokers who had recently been prescribed NRT, but self-reported low NRT adherence or discontinuing treatment prematurely. Thematic analysis was used to analyse data.


There were four main themes identified; expectations of NRT, experience of using NRT, safety concerns and experience of using e-cigarettes. Most women smoked regularly while using NRT and many used NRT to cut down their cigarette intake rather than to quit abruptly. Some women were concerned that using NRT instead of smoking could actually increase their nicotine intake and nicotine dependency or cause greater harm to the fetus. Although not a prior aim of the work, this study highlighted the views of pregnant women towards using e-cigarettes when pregnant. The majority of women had heard about e-cigarettes and reported smokers in their communities were using them as a measure to cut down or quit smoking. Women were curious about the potential benefits of using e-cigarettes in pregnancy and some women in the study had used e-cigarettes during their current quit attempt in order to help them stop smoking. Women who were not using e-cigarettes during their quit attempt reported feeling wary and uncertain about their safety.


Many women underused NRT but simultaneously smoked. Challenging negative perceptions about NRT and educating women further about the risks of smoking may encourage them to use NRT products as recommended. These findings add to the research surrounding the efficacy of NRT during pregnancy by providing insight into how pregnant women use NRT during a quit attempt and how this may influence adherence. It may assist health professionals to support pregnant smokers by increasing their understanding about the differing ways in which women use NRT and help them address concerns women may have about the safety of NRT.

Overall, this project supports the hypothesis that NRT at standard doses may be ineffective in pregnancy due to increased metabolism. The use of NRT in pregnancy is also influenced by women underutilising NRT as a result of simultaneously smoking and not understanding the safety of NRT in relation to continued smoking. The findings from this project will enable the development of future interventions to increase adherence during pregnancy and has highlighted the need to investigate the effectiveness of NRT at higher levels.

Plain English summary


Nicotine replacement therapy (NRT) helps non-pregnant smokers to stop smoking, but there is no evidence that NRT, used at standard dose, can help pregnant smokers to quit. We know that the rate of nicotine metabolism (the speed the body breaks down and gets rid of nicotine) increases during pregnancy. However, we don’t know when this change begins, when it reduces again after birth or if the amount of nicotine obtained from NRT is lower than that obtained from smoking. The nicotine dose delivered by NRT might not be enough to reduce withdrawal symptoms and so women might stop using NRT early and go back to smoking. Also, little is known about the experiences of women who do not use their NRT as prescribed during pregnancy. A combination of such reasons may help explain why NRT does not appear to be effective during pregnancy.


We found that pregnant women get less nicotine from standard dose NRT patches than from smoking. Women’s nicotine metabolism has increased by the time they are 18-22 weeks pregnant, but after having their baby it drops again and seems to stabilise by 1 month after birth, presumably returning to non-pregnant levels by this point. When we asked women about how they used their NRT during pregnancy many told us that they continued to smoke regularly while using NRT. Some of them smoked as they felt NRT did not alleviate their cravings, whereas others intentionally used NRT to substitute a proportion of their cigarette intake (i.e. to cut down rather than quit). Also some women did not use their NRT as it had been prescribed because of side effects or they were concerned about the safety.


NRT is probably not effective during pregnancy for a complex mix of reasons. Pregnant women probably don’t receive as much nicotine as they need to get rid of their cravings. Aside from increased metabolism, women often don’t even use their NRT as prescribed or recommended, due to a lack of understanding about the relative safety of NRT, or due to the experience of side effects. Some women also report using NRT to help them cut down rather than quit smoking. To help pregnant women to quit, we need to develop ways to help women use NRT more effectively, perhaps by giving higher doses to help achieve this and by encouraging them to use it as prescribed.


Published articles

  1. K Bowker, S Lewis, T Coleman, L Vaz, S Cooper. Comparison of cotinine levels in pregnant women whilst smoking and when using Nicotine Replacement Therapy. Nicotine and Tobacco Research. 2014; 16(6):895-8. doi: 10.1093/ntr/ntu029.
  2. K Bowker, S Lewis, T Coleman, S Cooper. Changes in the rate of nicotine metabolism across pregnancy: a longitudinal study. Addiction. 2015; 110(11): 1827-32. doi: 10.1111/add.13029.
  3. K Bowker, K Campbell, S Lewis, T Coleman, F Naughton, S Cooper. Understanding pregnant smokers’ adherence to Nicotine Replacement Therapy during a quit attempt: a qualitative study. Nicotine and Tobacco Research 2015. doi: 10.1093/ntr/ntv205.

Public involvement

We initially sought the opinion of a lay person who smoked in their previous pregnancy, and whom we have involved in other research studies. She provided feedback on the Participant Information Sheet, consent form and questionnaires. We also liaised with the Nottingham Research Design Service, who put us in contact with patients and members of the public who might be willing to provide email or written opinions of study documents. We received feedback from six members of the public who reviewed the following study documents: letters to participants, PIS, consent forms, and screening and baseline questionnaires.

Participant involvement was very valuable and ensured that the language and information we gave participants was appropriate and easily understood.


Study One, research implications

Using existing data from a large RCT, this study found lower nicotine substitution levels after using NRT compared to smoking. However, as this study measured nicotine substitution only once, at 1 month following a quit date, we could not explore variation in substitution over time. This study also explored whether nicotine substitution was associated with smoking cessation, however the sample size was very small and is likely to have been underpowered. Further research is required to understand nicotine substitution during pregnancy as it may affect the efficacy of NRT:

  • Using a large prospective cohort of pregnant women who use NRT, frequent measurements of cotinine levels generated in women who are adherent and smoking abstinent may provide more insight into whether substitution levels change with gestation. If nicotine substitution levels decrease with gestation, this would support the hypothesis that there is a relationship between nicotine substitution and increased nicotine metabolism. Within such a study, associations between nicotine substitution and smoking cessation at differing time points within pregnancy, delivery and the postpartum could be explored. This would increase understanding as to whether there is a relationship between nicotine substitution and smoking cessation during pregnancy and help to distinguish what nicotine substitution levels are most efficacious. However, as adherence to NRT is often low during pregnancy sample sizes would need to be sufficiently large in order to ensure adequate power to detect associations.

Study Two, research implications

This study established that nicotine metabolism increases during pregnancy, so it may mean that the dose of nicotine in standard dose NRT is too low to alleviate nicotine cravings. In order to test this hypothesis future work trialling higher dose NRT is required; if proven effective this could explain why standard dose NRT is not effective during pregnancy. It could be that low nicotine substitution and increased nicotine metabolism may affect the efficacy of NRT by adversely affecting adherence. A study comprising of the following may be required:

  • An RCT using higher dose NRT with a placebo or standard dose NRT could determine if higher dose nicotine is more effective for smoking cessation during pregnancy. Higher dose NRT may consist of either higher dose nicotine patches or providing women with dual therapy NRT (i.e. a patch plus a short-acting NRT product); each would provide higher levels of nicotine, but dual therapy would be more flexible. By obtaining frequent cotinine measurements, the level of nicotine substitution after using higher dose NRT could be determined and associations with smoking cessation could be explored. In order to determine whether nicotine metabolism is associated with adherence this would require measuring adherence rates among women allocated to the higher dose group and comparing with the control group.

Study Three, research implications and clinical implications

This study described the experience of using NRT among pregnant smokers that were non-adherent during a quit attempt. Although low adherence may be the result of increased nicotine metabolism and inadequate nicotine substitution, this qualitative study has highlighted some potential implications for clinical practice and research:

  • Some women used NRT to cut down cigarettes rather than to stop smoking abruptly. Until future work is conducted to determine the safety and efficacy of this method during pregnancy, health professionals should still advise women to quit abruptly rather than cutting down first. However, an increased awareness among health professionals about concomitant smoking during a quit attempt may help them support women who relapse during a quit attempt.
  • Often women continued to smoke during their quit attempt because they were concerned about the safety of using NRT. Therefore, health professionals may need to offer pregnant women more reassurance about the safety of using NRT compared to continued smoking.
  • Women were aware and some were interested in the role of e-cigarettes from smoking cessation during pregnancy. E-cigarettes may enable women to self-titrate their nicotine levels to ensure adequate nicotine substitution levels. However, further research is required to explore both the safety and efficacy of using e-cigarettes during pregnancy in order to determine whether they have a legitimate role to play in smoking cessation. To develop this area we have recently started a qualitative study to further investigate pregnant and postnatal women’s attitudes to e-cigarettes.

Prior to a higher dose NRT trial, overall the work in this project has shown that there is a need to develop an intervention to ensure pregnant smokers receive an adequate dose of NRT, and that improves their adherence. Therefore, the findings from this project have been used to help investigate, develop and test this in an NIHR Programme Grant for Applied Research. A Stage 1 application was submitted by Professor Tim Coleman in October 2015: "Improving effectiveness of nicotine replacement therapy for smoking cessation in pregnancy through better adherence and adequate dosing."

The student who conducted this work (Katharine Bowker) for her PhD has written, submitted and has just successfully defended her thesis with minor corrections. She has also written and published 3 academic papers in high impact specialist journals (listed above), showing that this project provided extremely good value for money with high academic outputs.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 192)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.