TY - JOUR
AU - Havard, Alys
AB - Abstract Introduction In the general population, varenicline is consistently shown to be more efficacious for smoking cessation than nicotine replacement therapy (NRT). Current clinical guidelines for the management of smoking during pregnancy recommend against the use of varenicline, whilst supporting the use of NRT. However, little is known about the comparative effectiveness of these smoking cessation therapies among pregnant women. Aims and Methods Routinely-collected records of all births in two Australian States during 2011 and 2012 were used to create a population-based cohort of women who smoked during the first half of pregnancy. Pharmaceutical dispensing data were used to identify varenicline and nicotine patch dispensings in the first half of pregnancy. Propensity score matching was used to account for the potentially different distribution of confounding factors between the treatment groups. The outcome was defined as smoking abstinence during the second half of pregnancy. Results After propensity score-matching, our cohort comprised 60 women who used varenicline and 60 who used nicotine patches during the first half of pregnancy. More varenicline users (33.3%, 95% CI: 21.7%–46.7%) quit smoking than nicotine patch users (13.3%, 95% CI: 5.9%–24.6%). The adjusted rate difference was 24.2% (95% CI: 10.2%–38.2%) and the adjusted relative risk was 2.8 (95% CI: 1.4–5.7). Conclusions Varenicline was almost three times more effective than nicotine patches in assisting pregnant women to quit smoking. Further studies are needed to corroborate our results. Together with data on the safety of varenicline during pregnancy, evidence regarding the relative benefit of varenicline and NRT during pregnancy important for informing clinical decisions for pregnant smokers. Implications This study is the first to measure the comparative effectiveness of varenicline and nicotine patches during pregnancy – women using varenicline were almost three times as likely to quit smoking than those using nicotine patches. This study addressed a clinically important question using an observational study, noting that there is an absence of evidence from randomized controlled trials because of the ethical issues associated with including pregnant women in clinical trials of medicines of unknown safety. Introduction Maternal smoking during pregnancy is a significant, yet preventable, risk factor for pregnancy complications and poor birth outcomes.1 In high-income countries, although smoking during pregnancy has been declining, between 6% and 18% of pregnant women still smoke.2–5 In Australia, 10% of women smoke during pregnancy.6 Eight in 10 smokers continue to smoke throughout their pregnancy despite the fact that three-quarters have at least one quit attempt.6–8 These figures illustrate the necessity for effective smoking cessation strategies for pregnant women, noting that behavioral interventions have modest effectiveness during pregnancy.9 Smoking cessation pharmacotherapies, which include varenicline, nicotine replacement therapy (NRT), and bupropion10 are the most effective smoking cessation interventions in the non-pregnant population. Varenicline is a partial agonist of the nicotine receptor, stimulating dopamine release to reduce withdrawal symptoms and at the same time blocking nicotine from binding to the receptor.11 NRT reduces withdrawal symptoms by providing pure nicotine that would otherwise be obtained from toxic cigarette smoke.12 NRT is available as transdermal patches, lozenges, gum, sprays and inhalers, and treatment may involve use of a single formulation of NRT or use of multiple formulations simultaneously.13 Bupropion is a weak inhibitor of dopamine and norepinephrine reuptake, thus reducing nicotine withdrawal.14 Since there has been limited use of bupropion as a smoking cessation aid in the past decade,15,16 we have restricted the focus on the current study to varenicline and NRT. Current Australian and international clinical guidelines for smoking cessation in pregnancy support the use of NRT when the expected benefits outweigh the potential risks.10,17–19 This support for NRT is based on the assumption that NRT is a relatively safe option for mothers and infants when compared to cigarette smoking. However, the evidence for NRT efficacy and effectiveness during pregnancy is limited and inconclusive, with the latest Cochrane review concluding that NRT may increase quitting during pregnancy, but the evidence is of low certainty.20 Varenicline has been found to be more efficacious than NRT in the general population in multiple studies,21–24 including a Bayesian network meta-analysis that synthesized evidence regarding the efficacy of varenicline and single forms of NRT from 12 double-blind RCTs.13 Varenicline is not recommended for pregnant women, however, due to a historical lack of evidence about its efficacy and safety when used in pregnancy. The evidence base regarding the safety of varenicline has grown recently, with two population-based cohort studies finding that varenicline is not associated with an increased risk of adverse birth outcomes such as preterm birth and small for gestational age.25,26 However, robust data on other important adverse birth outcomes, including stillbirth and congenital anomalies, are still lacking. There has also been no examination of the risk of known side effects among pregnant women, where varenicline use in non-pregnant individuals is associated with psychiatric symptoms, insomnia, suicidal ideation/attempted or completed suicide, agitation, abnormal dreams, hallucination, anger, or seizures.27 Meanwhile, there has been absolutely no investigation of the efficacy or effectiveness of varenicline during pregnancy. In order to inform evidence-based recommendations for the management of smoking during pregnancy, we established the Smoking MUMS (Maternal Use of Medications and Safety) Study, a retrospective population-based cohort study based on comprehensive linked person-level data. We have previously used this resource to demonstrate that varenicline, nicotine patches, and bupropion use during pregnancy was not associated with an increased risk of adverse birth outcomes.25A robust examination of other important safety endpoints, as outlined above, was note possible with this data source. In the current study, we use the Smoking MUMS data to evaluate whether varenicline was more effective than nicotine patch in assisting women to quit smoking in pregnancy. Methods Study Cohort and Data Sources This retrospective population-based cohort study included women who gave birth between January 1, 2011 and December 31, 2012 in two Australian states, New South Wales (NSW) and Western Australia (WA). Women were included in the cohort if they smoked and initiated varenicline or nicotine patch treatment in the first half of pregnancy. Women who used both pharmacotherapies in the first half of pregnancy were excluded. Plural pregnancies were excluded because the physical health of mothers who carry multiple fetuses could be different from those who carry a singleton, which might impact on the likelihood of quitting smoking.28,29 For women who used a pharmacotherapy in two or more pregnancies, only the first treated pregnancy was selected for analysis (Figure 1). Figure 1. Open in new tabDownload slide Flowchart for study cohort and treatment groups. * There was 1 pregnancy in which both varenicline and nicotine patches were dispensed during the corresponding initiation periods. ** Our propensity score matched model used the nearest neighbour 1-to-1 matching algorithm with a caliper of 0.2 standard deviations of the logit of the propensity score to match the varenicline and nicotine patches treatment groups. Figure 1. Open in new tabDownload slide Flowchart for study cohort and treatment groups. * There was 1 pregnancy in which both varenicline and nicotine patches were dispensed during the corresponding initiation periods. ** Our propensity score matched model used the nearest neighbour 1-to-1 matching algorithm with a caliper of 0.2 standard deviations of the logit of the propensity score to match the varenicline and nicotine patches treatment groups. The study used linked data from the Smoking MUMS (Maternal Use of Medications and Safety) Study.30 Briefly, routinely-collected records of all births (livebirths and stillbirths of at least 20 weeks gestation or at least 400 g) in NSW and WA were extracted from the NSW Perinatal Data Collection and the WA Midwives Notification Scheme (collectively referred to as perinatal data). These are statutory data collections that rely on the attending midwife or doctor to complete a notification form when a birth occurs. The perinatal data contained information on maternal socio-demographics, maternal smoking status during pregnancy, medical and obstetric factors, and information on labor, delivery and outcomes for the neonate. Perinatal records were linked to Pharmaceutical Benefits Scheme data (pharmaceutical claims), and the NSW Admitted Patients Data Collection and the WA Hospital Morbidity Data Collection (hospital data). The pharmaceutical claims data contain records of all dispensings of prescribed medicines subsidized by the Australian government. Each dispensing record contains an anatomical therapeutic chemical (ATC) code,31 date of prescribing, date of dispensing, and quantity and strength dispensed. The hospital data contain records of all hospital separations from both public and private hospitals in NSW and WA. Each hospital record contains socio-demographics, dates of admission and discharge, primary and secondary diagnoses and procedures, coded according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM)32 and Australian Classification of Health Interventions, Eighth Edition (ACHI).33 Measures Ascertainment of Women Who Smoked in the First Half of Pregnancy In the NSW perinatal data, smoking-related items comprised whether the mother smoked during the first half of pregnancy, whether she smoked in the second half of pregnancy, and the number of cigarettes smoked per day in each half of pregnancy. In the WA perinatal data, smoking-related items included whether the mother smoked anytime during pregnancy, and number of cigarettes smoked per day in the first 20 weeks of pregnancy and after 20 weeks. We identified women in NSW as smoking in the first half of pregnancy if it was recorded that she smoked during the first half of pregnancy, or consumed at least one cigarette/day during the first half of pregnancy. We identified women in WA as smoking in the first half of pregnancy if she was recorded as smoking anytime during pregnancy, or consuming at least one cigarette/day during the first 20 weeks of pregnancy. Ascertainment of Smoking Abstinence Effectiveness was measured in terms of smoking abstinence in the second half of pregnancy. For women in both states, abstinence was defined as the consumption of zero cigarettes/day in the second half of pregnancy. See Table S1, Appendix for detailed methods for identifying women who smoked in the first half of pregnancy and smoking abstinence. Ascertainment of Varenicline and Nicotine Patch Treatment Anatomical Therapeutic Chemical (ATC) codes were used to identify varenicline (ATC code N07BA03) and nicotine patch (N07BA01) treatments. Varenicline was available in two preparations that is a commencement pack (11 × 500 µg tablets and 42 × 1 mg tablets), and a continuation pack (56 × 1 mg tablets). At the time of the study, only the patch formulation of NRT (7 mg/day, 14 mg/day, 21 mg/day, and 25 mg/day) was subsidized in Australia. While patches and other formulations (eg, lozenges, gums) were available over the counter at greater out-of-pocket costs,34,35 we were not able to measure NRT purchased over the counter in this study. To ensure that the treatment preceded the outcome (ie, smoking abstinence in the second half of pregnancy), we required that the treatment was initiated in the first half of pregnancy. Taking into account clinical recommendations that NRT and varenicline should be initiated two weeks and one week, respectively, prior to the pre-determined quit date,36 we defined the varenicline-treated group as women who commenced varenicline in the period from one week prior to conception date to 19 weeks post-conception (referred to as treatment period). For the NRT-treated group, this treatment period was from two weeks prior to conception date to 18 weeks post-conception. To identify treatment groups, we first identified women who had varenicline and nicotine patch dispensing records with a date of dispensing in the respective treatment periods. To ensure that the treatment was initiated in the treatment period, we excluded women who had a dispensing of nicotine patch in the prior 8 weeks prior to the treatment period, or a dispensing of varenicline in the 12 weeks prior. These eight and 12 week lookback periods represent the recommended duration of a course of nicotine patch and varenicline, respectively.36 Women who were dispensed both varenicline and nicotine patch in the treatment period or in the prior 8 or 12 weeks were excluded. Covariates Maternal socio-demographic characteristics included mother's age at conception, State of delivery, living with a partner (yes or no), country of birth (Australia-born or overseas-born), living in a socio-economic disadvantaged area, and living in major cities. Aboriginal and/or Torres Strait Islander status (yes/no) was also included as a covariate because Aboriginal and/or Torres Strait Islander smokers are less likely to use smoking cessation pharmacotherapies than other Australian smokers.37 Socio-economic status for the mother's residential area was based on the 2006 Census Index of Relative Socio-economic Disadvantage (IRSD) quintiles38 and categorized as socio-economically disadvantaged area if quintiles 1 and 2. Remoteness of residential areas was derived from the extended version of the Accessibility/Remoteness Index of Australia39 and dichotomized as major cities or other remoteness areas. Parity, which was treated as a continuous variable, was obtained from perinatal data. The number of cigarettes consumed per day during the first half of pregnancy was categorized into “light” smoking (ie, 1 to 10 cigarettes/day) and “moderate-to-heavy smoking” (ie, more than 10 cigarettes/day).40 Timing of treatment commencement was calculated as the number of weeks between date of conception and date of first dispensing of the varenicline or nicotine patches. Pre-existing maternal morbidities were identified from hospital admission41,42 and dispensing data25,43 in the year prior to the date of conception as well as perinatal data. Based on the framework of maternal morbidities,44 we selected conditions known to be worsened by smoking (potentially influencing motivation to quit), and conditions in which the use of varenicline or NRT is contraindicated or cautioned against. The ICD-10-AM codes and ATC codes used to identify maternal morbidities are published elsewhere.25 Statistical Analysis We used propensity score matching (PS-matching) to control for differences in baseline characteristics between varenicline and nicotine patch-treated groups. Propensity score matching has been widely used to account for potential confounders and treatment-selection bias due to the non-random assignment of treatment options in observational studies.45 To estimate the propensity score, we fitted a multivariable logit model,45 including all of the aforementioned covariates based on evidence that they were associated with the outcome (prognostically important covariates) or were associated with both treatment and outcome (confounding covariates).45 To match the varenicline-treated group to the nicotine patch-treated group (1:1 ratio), we used the nearest neighbor 1-to-1 matching algorithm with a caliper of 0.2 standard deviations of the logit of the propensity score.46 To assess the balance in maternal characteristics between the two treatment groups, we calculated absolute standardized difference for the cohort before and after propensity matching (see Table 2).47 An absolute standardized difference of less than or close to 0.1 is considered negligible.47 Cumulative distributions of the propensity scores for the two treatment groups were calculated in the samples before and after propensity score matching (Figure S1).47 In our final model of the treatment effect of varenicline relative to nicotine patches, we included the covariates that were not balanced between the two treatment groups as independent variables, to adjust for potential confounding from these variables and produce doubly robust estimates for the treatment effect of varenicline used during pregnancy when compared to that of nicotine patches.47 Table 2. Crude and Adjusted Quit Rate Differences and Relative Risks with 95% confidence intervals (CI) for Varenicline Treatment Group verus Nicotine patch Treatment Group, Before and After Propensity Score Matching . Before Propensity Score Matching . . . . After Propensity Score Matchinga . . . . . No. of Pregnant Smokers . Crude Quit Rate (95% CI) . Crude Rate Difference (95% CI) . Crude Relative Risk (95% CI) . No. of Pregnant Smokers . Adjusted Quit Rate (95% CI) . Adjusted Rate Differenceb (95% CI) . Adjusted Relative Riskb (95% CI) . Varenicline treatment group 106 29.2% (20.8%–38.9%) 18.1% (8.0%–28.3%) 2.6 (1.5–4.6) 60 33.3% (21.7%–46.7%) 24.2% (10.2%–38.2%) 2.8 (1.4–5.7) Nicotine patch treatment group (reference) 135 11.1% (6.4%–17.7%) – 1.0 60 13.3% (5.9%–24.6%) – 1.0 . Before Propensity Score Matching . . . . After Propensity Score Matchinga . . . . . No. of Pregnant Smokers . Crude Quit Rate (95% CI) . Crude Rate Difference (95% CI) . Crude Relative Risk (95% CI) . No. of Pregnant Smokers . Adjusted Quit Rate (95% CI) . Adjusted Rate Differenceb (95% CI) . Adjusted Relative Riskb (95% CI) . Varenicline treatment group 106 29.2% (20.8%–38.9%) 18.1% (8.0%–28.3%) 2.6 (1.5–4.6) 60 33.3% (21.7%–46.7%) 24.2% (10.2%–38.2%) 2.8 (1.4–5.7) Nicotine patch treatment group (reference) 135 11.1% (6.4%–17.7%) – 1.0 60 13.3% (5.9%–24.6%) – 1.0 a Propensity score matching method was used to estimate relative risk and relative difference. b Further adjusted for maternal age, Australia-born, and having pre-existing mood/bipolar disorder, anxiety or psychotic disorder because there was still some imbalance between the two treatment groups in these covariates. Open in new tab Table 2. Crude and Adjusted Quit Rate Differences and Relative Risks with 95% confidence intervals (CI) for Varenicline Treatment Group verus Nicotine patch Treatment Group, Before and After Propensity Score Matching . Before Propensity Score Matching . . . . After Propensity Score Matchinga . . . . . No. of Pregnant Smokers . Crude Quit Rate (95% CI) . Crude Rate Difference (95% CI) . Crude Relative Risk (95% CI) . No. of Pregnant Smokers . Adjusted Quit Rate (95% CI) . Adjusted Rate Differenceb (95% CI) . Adjusted Relative Riskb (95% CI) . Varenicline treatment group 106 29.2% (20.8%–38.9%) 18.1% (8.0%–28.3%) 2.6 (1.5–4.6) 60 33.3% (21.7%–46.7%) 24.2% (10.2%–38.2%) 2.8 (1.4–5.7) Nicotine patch treatment group (reference) 135 11.1% (6.4%–17.7%) – 1.0 60 13.3% (5.9%–24.6%) – 1.0 . Before Propensity Score Matching . . . . After Propensity Score Matchinga . . . . . No. of Pregnant Smokers . Crude Quit Rate (95% CI) . Crude Rate Difference (95% CI) . Crude Relative Risk (95% CI) . No. of Pregnant Smokers . Adjusted Quit Rate (95% CI) . Adjusted Rate Differenceb (95% CI) . Adjusted Relative Riskb (95% CI) . Varenicline treatment group 106 29.2% (20.8%–38.9%) 18.1% (8.0%–28.3%) 2.6 (1.5–4.6) 60 33.3% (21.7%–46.7%) 24.2% (10.2%–38.2%) 2.8 (1.4–5.7) Nicotine patch treatment group (reference) 135 11.1% (6.4%–17.7%) – 1.0 60 13.3% (5.9%–24.6%) – 1.0 a Propensity score matching method was used to estimate relative risk and relative difference. b Further adjusted for maternal age, Australia-born, and having pre-existing mood/bipolar disorder, anxiety or psychotic disorder because there was still some imbalance between the two treatment groups in these covariates. Open in new tab Crude and adjusted rate differences (RD) and relative risks (RR) with 95% CIs were calculated. All tests were two-sided with a p < .05 significance. All analyses were performed with STATA MP 14.1 (College Station, TX). Sensitivity Analysis Due to the exclusion of a substantial proportion of treated women through propensity score matching (106 varenicline users and 135 nicotine patch users were reduced to 60 women treated with each), we conducted a sensitivity analysis to assess the robustness of our findings. We estimated the RR using Poisson regression for all women (ie, 106 varenicline and 135 nicotine patch), adjusting for all of the aforementioned covariates (see Table S2). This study was approved by the NSW Population and Health Services Research Ethics Committee (2012.06.397), Aboriginal Health & Medical Research Council of NSW Ethics Committee (871/12), the Australian Institute of Health and Welfare Ethics Committee (EC2012.2.22), the Department of Health WA Human Research Ethics Committee (2013/38), and the Western Australian Aboriginal Health Ethics Committee (460). Results We identified 106 and 135 women who had varenicline and nicotine patch treatment respectively (Figure 1). The PS-matching (1:1 ratio) yielded matched groups of 60 varenicline users and 60 nicotine patch users. In the matched sample, all women had only one dispensing of varenicline or nicotine patches during the treatment initiation period. Noting that each varenicline and nicotine patch dispensing provides a maximum of 56 days of treatment and a maximum of 28 days of treatment respectively (if used once daily as recommended), this suggests that treatment duration and/or daily dose used was suboptimal in all participants. For varenicline, more than 95% of women were dispensed the commencement pack [11 × 500 µg tablets and 42 × 1 mg tablets]. The most commonly dispensed strengths of nicotine patches were 21 mg/day (51.3%) and 25 mg/day (46.7%), with each dispensing containing up to 28 patches. Maternal Characteristics Table 1 presents the characteristics of the treatment groups before and after propensity score matching. Prior to matching, only four covariates (state of delivery, maternal age, and pre-existing gastro-esophageal reflux, or thyroid disease) were balanced between the varenicline and nicotine patch treatment groups. After matching, imbalance remained for five covariates: maternal age, Australia-born, having a pre-existing anxiety disorder, mood or bipolar disorder, or psychotic disorder. We noted that the corresponding distributions of propensity scores between the two treatment groups were closely similar in the matched sample (Figure S1, Appendix). For the variables with absolute values of standardized difference greater than 0.1, we further adjusted for these variables to produce doubly robust estimates when estimating the treatment effect. Table 1. Characteristics of Varenicline and Nicotine Patch Treatment Groups, and Absolute Standardized Differences before and after Propensity Score Matching . Before Propensity Score Matching . . . . . After Propensity Score Matchinga . . . . . . Varenicline-treated (N = 106) . . Nicotine patch-treated (N = 135) . . Absolute Standardised Differenceb . Varenicline-treated (N = 60) . . Nicotine patch-treated (N = 60) . . Absolute Standardised Differenceb . . N . % . n . % . . N . % . n . % . . Maternal characteristics State of delivery  New South Wales 83 78.3% 107 79.3% 0.045 45 15 75.0% 25% 46 14 76.7% 23.3% 0.039  Western Australia 23 21.7% 28 20.7% Maternal age at conception (years), mean [SD] 28.4 [5.7] 28.9 [6.1] 0.089 28.1 [5.6] 28.8 [5.7] 0.11 Parity, mean [SD]e 1.40 [1.1] 1.53 [1.16] 0.13 1.4 [1.1] 1.4 [1.2] 0.073 Socioeconomically disadvantaged 55 51.9% 63 45.7% 0.11 33 55.0% 31 51.7% 0.066 Living in major city 55 51.9% 55 39.9% 0.20 23 38.3% 25 41.7% 0.068 Living with partner 67 63.2% 63 45.7% 0.37 34 56.7% 31 51.7% 0.099 Aboriginal or Torres Strait Islander origin 9 8.5% 23 16.7% 0.23 8 13.3% 7 11.7% 0.05 Australia-born 88 83.0% 130 96.3% 0.44 59 98.3% 57 95.0% 0.18 Moderate-to-heavy cigarette consumptiond 30 28.3% 48 35.6% 0.13 19 31.7% 19 31.7% 0 Timing of treatment commencement from conception date (in weeks)c 3.8 [4.8] 7.3 [5.6] 0.65 4.6 [4.4] 5.05 [5.4] 0.099 Maternal pre-existing conditions  Anxiety 5 4.7% 13 9.6% 0.23 * * * * 0.15  Mood or bipolar disorder 24 22.6% 49 36.3% 0.28 16 26.7% 20 33.3% 0.14  Chronic airway 8 7.6% 26 19.3% 0.37 7 11.7% 7 11.7% 0  Epilepsy * * 8 5.9% 0.20 * * * * 0  Gastro-oesophageal reflux 5 4.7% 7 5.2% 0.012 * * * * 0.070  Thyroid disease * * * * 0.045 * * * * 0  Psychotic disorder * * 12 8.9% 0.37 * * * * 0.18  Steroid responsive diseases * * 8 5.9% 0.20 * * * * 0.080 . Before Propensity Score Matching . . . . . After Propensity Score Matchinga . . . . . . Varenicline-treated (N = 106) . . Nicotine patch-treated (N = 135) . . Absolute Standardised Differenceb . Varenicline-treated (N = 60) . . Nicotine patch-treated (N = 60) . . Absolute Standardised Differenceb . . N . % . n . % . . N . % . n . % . . Maternal characteristics State of delivery  New South Wales 83 78.3% 107 79.3% 0.045 45 15 75.0% 25% 46 14 76.7% 23.3% 0.039  Western Australia 23 21.7% 28 20.7% Maternal age at conception (years), mean [SD] 28.4 [5.7] 28.9 [6.1] 0.089 28.1 [5.6] 28.8 [5.7] 0.11 Parity, mean [SD]e 1.40 [1.1] 1.53 [1.16] 0.13 1.4 [1.1] 1.4 [1.2] 0.073 Socioeconomically disadvantaged 55 51.9% 63 45.7% 0.11 33 55.0% 31 51.7% 0.066 Living in major city 55 51.9% 55 39.9% 0.20 23 38.3% 25 41.7% 0.068 Living with partner 67 63.2% 63 45.7% 0.37 34 56.7% 31 51.7% 0.099 Aboriginal or Torres Strait Islander origin 9 8.5% 23 16.7% 0.23 8 13.3% 7 11.7% 0.05 Australia-born 88 83.0% 130 96.3% 0.44 59 98.3% 57 95.0% 0.18 Moderate-to-heavy cigarette consumptiond 30 28.3% 48 35.6% 0.13 19 31.7% 19 31.7% 0 Timing of treatment commencement from conception date (in weeks)c 3.8 [4.8] 7.3 [5.6] 0.65 4.6 [4.4] 5.05 [5.4] 0.099 Maternal pre-existing conditions  Anxiety 5 4.7% 13 9.6% 0.23 * * * * 0.15  Mood or bipolar disorder 24 22.6% 49 36.3% 0.28 16 26.7% 20 33.3% 0.14  Chronic airway 8 7.6% 26 19.3% 0.37 7 11.7% 7 11.7% 0  Epilepsy * * 8 5.9% 0.20 * * * * 0  Gastro-oesophageal reflux 5 4.7% 7 5.2% 0.012 * * * * 0.070  Thyroid disease * * * * 0.045 * * * * 0  Psychotic disorder * * 12 8.9% 0.37 * * * * 0.18  Steroid responsive diseases * * 8 5.9% 0.20 * * * * 0.080 The bold/italic values with absolute standardized difference >0.1, indicating imbalance of the corresponding covariates. * Suppressed due to cell size < 5. a Propensity score matching used the nearest neighbour 1-to-1 matching algorithm with a caliper of 0.2 standard deviations of the logit of the propensity score. b An absolute standardized difference of less than or close to 0.1 is considered negligible. c Timing of treatment commencement was calculated as number of completed weeks between date of conception and date of the first dispensing of varenicline or nicotine patches. d Cigarette consumption is more than 10 cigarettes/day. e Parity as numerical value (0, 1, 2, 3, etc.). Open in new tab Table 1. Characteristics of Varenicline and Nicotine Patch Treatment Groups, and Absolute Standardized Differences before and after Propensity Score Matching . Before Propensity Score Matching . . . . . After Propensity Score Matchinga . . . . . . Varenicline-treated (N = 106) . . Nicotine patch-treated (N = 135) . . Absolute Standardised Differenceb . Varenicline-treated (N = 60) . . Nicotine patch-treated (N = 60) . . Absolute Standardised Differenceb . . N . % . n . % . . N . % . n . % . . Maternal characteristics State of delivery  New South Wales 83 78.3% 107 79.3% 0.045 45 15 75.0% 25% 46 14 76.7% 23.3% 0.039  Western Australia 23 21.7% 28 20.7% Maternal age at conception (years), mean [SD] 28.4 [5.7] 28.9 [6.1] 0.089 28.1 [5.6] 28.8 [5.7] 0.11 Parity, mean [SD]e 1.40 [1.1] 1.53 [1.16] 0.13 1.4 [1.1] 1.4 [1.2] 0.073 Socioeconomically disadvantaged 55 51.9% 63 45.7% 0.11 33 55.0% 31 51.7% 0.066 Living in major city 55 51.9% 55 39.9% 0.20 23 38.3% 25 41.7% 0.068 Living with partner 67 63.2% 63 45.7% 0.37 34 56.7% 31 51.7% 0.099 Aboriginal or Torres Strait Islander origin 9 8.5% 23 16.7% 0.23 8 13.3% 7 11.7% 0.05 Australia-born 88 83.0% 130 96.3% 0.44 59 98.3% 57 95.0% 0.18 Moderate-to-heavy cigarette consumptiond 30 28.3% 48 35.6% 0.13 19 31.7% 19 31.7% 0 Timing of treatment commencement from conception date (in weeks)c 3.8 [4.8] 7.3 [5.6] 0.65 4.6 [4.4] 5.05 [5.4] 0.099 Maternal pre-existing conditions  Anxiety 5 4.7% 13 9.6% 0.23 * * * * 0.15  Mood or bipolar disorder 24 22.6% 49 36.3% 0.28 16 26.7% 20 33.3% 0.14  Chronic airway 8 7.6% 26 19.3% 0.37 7 11.7% 7 11.7% 0  Epilepsy * * 8 5.9% 0.20 * * * * 0  Gastro-oesophageal reflux 5 4.7% 7 5.2% 0.012 * * * * 0.070  Thyroid disease * * * * 0.045 * * * * 0  Psychotic disorder * * 12 8.9% 0.37 * * * * 0.18  Steroid responsive diseases * * 8 5.9% 0.20 * * * * 0.080 . Before Propensity Score Matching . . . . . After Propensity Score Matchinga . . . . . . Varenicline-treated (N = 106) . . Nicotine patch-treated (N = 135) . . Absolute Standardised Differenceb . Varenicline-treated (N = 60) . . Nicotine patch-treated (N = 60) . . Absolute Standardised Differenceb . . N . % . n . % . . N . % . n . % . . Maternal characteristics State of delivery  New South Wales 83 78.3% 107 79.3% 0.045 45 15 75.0% 25% 46 14 76.7% 23.3% 0.039  Western Australia 23 21.7% 28 20.7% Maternal age at conception (years), mean [SD] 28.4 [5.7] 28.9 [6.1] 0.089 28.1 [5.6] 28.8 [5.7] 0.11 Parity, mean [SD]e 1.40 [1.1] 1.53 [1.16] 0.13 1.4 [1.1] 1.4 [1.2] 0.073 Socioeconomically disadvantaged 55 51.9% 63 45.7% 0.11 33 55.0% 31 51.7% 0.066 Living in major city 55 51.9% 55 39.9% 0.20 23 38.3% 25 41.7% 0.068 Living with partner 67 63.2% 63 45.7% 0.37 34 56.7% 31 51.7% 0.099 Aboriginal or Torres Strait Islander origin 9 8.5% 23 16.7% 0.23 8 13.3% 7 11.7% 0.05 Australia-born 88 83.0% 130 96.3% 0.44 59 98.3% 57 95.0% 0.18 Moderate-to-heavy cigarette consumptiond 30 28.3% 48 35.6% 0.13 19 31.7% 19 31.7% 0 Timing of treatment commencement from conception date (in weeks)c 3.8 [4.8] 7.3 [5.6] 0.65 4.6 [4.4] 5.05 [5.4] 0.099 Maternal pre-existing conditions  Anxiety 5 4.7% 13 9.6% 0.23 * * * * 0.15  Mood or bipolar disorder 24 22.6% 49 36.3% 0.28 16 26.7% 20 33.3% 0.14  Chronic airway 8 7.6% 26 19.3% 0.37 7 11.7% 7 11.7% 0  Epilepsy * * 8 5.9% 0.20 * * * * 0  Gastro-oesophageal reflux 5 4.7% 7 5.2% 0.012 * * * * 0.070  Thyroid disease * * * * 0.045 * * * * 0  Psychotic disorder * * 12 8.9% 0.37 * * * * 0.18  Steroid responsive diseases * * 8 5.9% 0.20 * * * * 0.080 The bold/italic values with absolute standardized difference >0.1, indicating imbalance of the corresponding covariates. * Suppressed due to cell size < 5. a Propensity score matching used the nearest neighbour 1-to-1 matching algorithm with a caliper of 0.2 standard deviations of the logit of the propensity score. b An absolute standardized difference of less than or close to 0.1 is considered negligible. c Timing of treatment commencement was calculated as number of completed weeks between date of conception and date of the first dispensing of varenicline or nicotine patches. d Cigarette consumption is more than 10 cigarettes/day. e Parity as numerical value (0, 1, 2, 3, etc.). Open in new tab Comparative Effectiveness of Varenicline and Nicotine Patches Table 2 presents the crude and adjusted RD and RR of smoking abstinence for the varenicline treatment group relative to the nicotine patch treatment group. Using the full cohort, the proportion of women who quit smoking was higher in the varenicline-treated group than nicotine patch-treated group (29.2% [95% CI: 20.8%–38.9%] vs. 11.1% [95% CI: 6.4%–17.7%]; crude RD:18.1% [95% CI: 8.0%–28.3%]; crude RR: 2.6 [95% CI: 1.5–4.6]). After PS-matching, the proportion of women who quit was 24.2% higher (95% CI: 10.2%–38.2%) in the varenicline-treated group compared to the nicotine patch-treated group (33.3% vs. 13.3%) and the RR was 2.8 (95% CI: 1.4–5.7). Sensitivity Analysis Our sensitivity analysis indicated that our results were robust. The multivariable Poisson regression model yielded an adjusted RR of 3.4 [95% CI: 1.8–6.4] (Table S2, Appendix). Discussion To our knowledge, this the first study to evaluate the comparative effectiveness of varenicline and nicotine patches in pregnancy. We addressed this clinically important question using an observational study, noting that there is an absence of evidence from RCTs because of the ethical issues associated with including pregnant women in clinical trials of medicines of unknown safety. This study found that varenicline was nearly three times more effective than nicotine patches in helping women to quit smoking during pregnancy. Our finding that varenicline was more effective than nicotine patches when used during pregnancy is consistent with studies conducted in the non-pregnant population.13,22–24,48 The majority of prior RCTs and observational cohort studies found that smokers who used varenicline were more likely to quit smoking when compared to those who used any single form of NRT.13,22–24,48 A notable strength of our study was that we adopted state-of-the-art methods to deal with potential confounding in observational studies. The PS-matching approach has several practical advantages when compared to the traditional multivariable regression model. First, the PS-matching method can mitigate potential treatment allocation bias in the observational data by mimicking the randomisation feature of RCTs. By comparing distributions of measured baseline covariates between the treatment groups using balance diagnostics, the PS-matching method can provide a way to empirically determine whether the treatment selection is associated with the baseline covariates. This is more difficult to achieve in with traditional regression modelling.47 Second, the PS-matching method can also provide more robust, more precise, and less biased treatment effect compared to that of the traditional multivariable method, especially when the outcome is rare and there are fewer than seven events per covariate.49 This is particularly important for this research question because the use of varenicline and nicotine patches during pregnancy is not common. Our results should be interpreted in the context of several limitations. First, although we had data for all births delivered in two states of Australia (about 43% of the obstetric population in Australia),50 the number of pregnant smokers who used either varenicline or nicotine patches was still small. This clinically important question warrants further investigation through future studies with greater statistical power to obtain more precise risk estimates. Second, dispensing data do not provide information about the actual use of medications, and it could not be determined whether women in our study actually used the pharmacotherapy and the actual duration and quantity of use. Adherence did appear to be suboptimal, with all women in our study receiving only one dispensing of the pharmacotherapy. Given that varenicline use during pregnancy is not recommended, there may have been greater non-use of treatment among the varenicline-treated group leading to an underestimation of the effectiveness of varenicline. On the other hand, adherence to NRT outside of research trials is known to be poor.51 Third, our dispensing data captured all prescription NRT subsidized by the Australia government (only patches at the time of the study), but not NRT purchased over-the-counter. This could have led to some misclassification, with varenicline users potentially using over-the-counter NRT simultaneously or previously, and subsidized NRT users potentially supplementing the subsidized patches with over-the-counter NRT products. While we are not aware of any evidence regarding the extent to which this occurred, it is likely to be minimal given the out-of-pocket cost of over-the-counter NRT in Australia is at least three times that of subsidized NRT.34,35 Fourth, using administrative databases limited our ability to examine environmental and psychosocial factors that could potentially influence maternal smoking cessation, and potentially confound the relationship between treatment type and smoking abstinence. Such factors potentially include women's mental health and well-being, their resilience levels and their coping styles in the process of smoking cessation, and smoking behavior of their partners or family members and their level of support towards smoking cessation.52 Receipt of other smoking cessation support besides medications should theoretically not differ between treatment groups because it is a requirement of subsidized access to both of these pharmacotherapies that the patient been undergoing concurrent counselling for smoking cessation; however, the extent to which this occurs has not been measured. Given these limitations and challenges, further studies are needed to corroborate our findings regarding the relative benefit of varenicline over nicotine patches during pregnancy. Such evidence would assist health care providers to make informed decisions about which pharmacotherapy (varenicline or nicotine patches) to recommend for women smoking during pregnancy.30,53 Current Australian and international clinical guidelines for smoking cessation support the use of NRT during pregnancy and recommend against the use of varenicline.10,17–19 These recommendations have arisen due to a historical lack of evidence regarding the efficacy and safety of varenicline during pregnancy, and the assumption that NRT is unlikely to be more harmful than tobacco smoke. These guidelines may be challenged should the findings of the current study be confirmed in future research. This would also be contingent on robust evidence regarding varenicline's safety during pregnancy. While recent research has found no increased risk of adverse birth outcomes with varenicline use during pregnancy,25,26 this research has lacked the statistical power to precisely measure the risk of rare but serious outcomes such as stillbirth and specific congenital anomalies. Conclusion In the first study to measure the comparative effectiveness of varenicline and nicotine patches during pregnancy, women using varenicline were almost three times as likely to quit smoking than those using nicotine patches. Further studies are needed to corroborate these results, with evidence regarding the relative benefit of varenicline and NRT during pregnancy important for informing clinical decisions for women smoking during pregnancy. Supplementary Material A Contributorship Form detailing each author’s specific involvement with this content, as well as any supplementary data, are available online at https://academic.oup.com/ntr. Acknowledgements This study was funded by the Australian National Health and Medical Research Council (NHMRC #1028543). Author AH was supported by a New South Wales (NSW) Health Early-Mid Career Fellowship. The authors would like to thank the NSW Ministry of Health, the WA Department of Health, the Australian Government Department of Health and Ageing, the Department of Human Services, and data custodians of the NSW Perinatal Data Collection, WA Midwife Notification System, NSW Admitted Patient Data Collection, WA Hospital Morbidity Data Collection, and the PBS data for allowing access to the data. We thank the NSW Centre for Health Record Linkage, the Australian Institute for Health and Welfare, the Western Australia Data Linkage Branch for conducting the linkage of records. The authors would also like to thank the Centre for Big Data Research in Health Aboriginal and Torres Strait Islander Maternal and Child Reference Group for their input. Declaration of Interests None. Funding This study was supported by the Australian National Health and Medical Research Council (NHMRC #1028543). Author AH was supported by a NSW Health Early-Mid Career Fellowship. The funding source had no influence on the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. References 1. Gould GS , Havard A, Lim LL, The PSIPEG, Kumar R. Exposure to tobacco, environmental tobacco smoke and nicotine in pregnancy: a pragmatic overview of reviews of maternal and child outcomes, effectiveness of interventions and barriers and facilitators to quitting . Int J Environ Res Public Health. 2020 ; 17 ( 6 ): 2034 . Google Scholar Crossref Search ADS WorldCat 2. Al-Sahab B , Saqib M, Hauser G, Tamim H. Prevalence of smoking during pregnancy and associated risk factors among Canadian women: a national survey . 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TI - The Comparative Effectiveness of Varenicline and Nicotine Patches for Smoking Abstinence During Pregnancy: Evidence From a Population-based Cohort Study
JF - Nicotine and Tobacco Research
DO - 10.1093/ntr/ntab063
DA - 2021-08-16
UR - https://www.deepdyve.com/lp/oxford-university-press/the-comparative-effectiveness-of-varenicline-and-nicotine-patches-for-bM9nlrm6ny
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -