Efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers: a meta-analysis

Transcription

1 DOI: /j x Systematic review Efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers: a meta-analysis S-K Myung, a,b,c W Ju, d H-S Jung, e C-H Park, f S-W Oh, g HG Seo, a HS Kim, h for the Korean Meta-Analysis (KORMA) Study Group a Smoking Cessation Clinic, Family Medicine Clinic, and Centre for Cancer Prevention and Detection, National Cancer Centre, Gyeonggi-do b Carcinogenesis Branch, Research Institute, National Cancer Centre, Gyeonggi-do c Department of Family Medicine, School of Medicine, Graduate School, Seoul National University, Seoul d Department of Obstetrics and Gynaecology, School of Medicine, Medical Research Institute, Ewha Womans University, Seoul e Total Health Care Centre, Gangbuk Samsung Hospital, Seoul f Department of Family Medicine, Eulji University Hospital, Daejon g Department of Family Medicine, Healthcare System Gangnam Centre, Seoul National University Hospital, Seoul h Department of Nursing, Shinheung College University, Gyeonggi-do, South Korea Correspondence: Dr S-K Myung, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do , South Korea. msk@ncc.re.kr Accepted 13 March Background The efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers has not yet been established. Objective To investigate the efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers. Search strategy A search was made of PubMed, Embase and CENTRAL in June Selection criteria Randomised controlled trials (RCTs), quasi- RCTs and retrospective or prospective controlled studies were included. Data collection and analysis The main analyses were designed to examine the efficacy of pharmacotherapy for smoking cessation among pregnant smokers based on the longest follow-up data available and from data obtained at the latest available time-point in pregnancy in each study. Main results Of 74 articles identified from the databases, seven studies (five RCTs, one quasi-rct and one prospective study) involving a total of 1386 pregnant smokers, 732 in the intervention groups and 654 in the control groups, were included in the final analyses. In a fixed-effects meta-analysis of all seven studies based on the longest follow-up data available, pharmacotherapy had a significant effect on smoking cessation (relative risk [RR] 1.80; 95% confidence interval [CI] ). Subgroup meta-analysis by type of study design also showed similar findings for RCTs (RR 1.48; 95% CI ) and other types of studies (RR 3.25; 95% CI ). The abstinence rate at late pregnancy in the intervention ranged from 7 to 22.6% (mean abstinence rate 13.0%; 95% CI %). A few minor adverse effects and serious adverse effects were reported in several studies. Author s conclusions This study indicates that there may be clinical evidence to support the use of pharmacotherapy for smoking cessation among pregnant smokers. Further RCTs are needed. Keywords Meta-analysis, pharmacotherapy, pregnant smokers, smoking cessation. Please cite this paper as: Myung S, Ju W, Jung H, Park C, Oh S, Seo H, Kim H, for the Korean Meta-Analysis (KORMA) Study Group. Efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers: a meta-analysis. BJOG 2012;119: Introduction Smoking during pregnancy is one of the most important potentially modifiable causes of adverse pregnancy outcomes. 1 3 It has been reported that about 45% of pregnant smokers spontaneously quit before pregnancy or stop before their first antenatal visit to a clinic. 4,5 However, two-thirds of women who stop smoking during pregnancy resume smoking 1 year after delivery. 6 Data obtained in the general population have demonstrated the effectiveness of numerous medications available for tobacco dependence, such as nicotine replacement therapy (NRT), bupropion SR and varenicline. 7 For example, in a meta-analysis of 83 studies, when compared with placebo, ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1029

2 Myung et al. estimated odds ratios of pharmacotherapy for smoking cessation at 6 months were for NRT, 2.0 for bupropion SR and 3.1 for varenicline, all of which were statistically significant. 7 Pregnancy causes various physiological changes and can lead to important variations in the pharmacokinetic processes of absorption, distribution and elimination of drugs. 8 The efficacy and safety of pharmacotherapy for smoking cessation has been established in the general population, but not in pregnant smokers. Although several studies 9 15 have been published on this subject, their findings have been inconsistent. In 2009, a meta-analysis 16 reported the effects of various interventions, such as counselling, hypnosis and pharmacotherapy, for smoking cessation during pregnancy and indicated that NRT was as effective as cognitive behavioural therapy. However, in that meta-analysis, detailed analyses were not performed to examine the efficacy of pharmacotherapy, its potential adverse side effects and its effects on birth outcomes. The purpose of this meta-analysis was to examine the efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers by conducting a meta-analysis of studies with subgroup meta-analyses by various factors such as type of study design, validation, type of pharmacotherapy, follow-up period, methodological quality and use of placebo. Methods PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2011 were searched using common keywords related to pharmacotherapy for smoking cessation among pregnant smokers. The bibliographies of relevant articles were also searched to identify additional studies. The keywords were as follows: pharmacological treatment or NRT or nicotine patch or nicotine gum or nicotine inhaler or nicotine spray or bupropion or varenicline; and pregnant smokers. We included randomised controlled trials (RCTs), quasi-rcts, and retrospective or prospective controlled studies that reported the efficacy and safety of pharmacotherapy for smoking cessation among pregnant smokers. The principal outcome measures included point-prevalence abstinence and continuous abstinence self-reported or validated with biochemical markers such as exhaled carbon monoxide, and salivary or urinary nicotine. We did not restrict the language of publication, and excluded unpublished articles. Two authors (MSK and JW) independently assessed the eligibility of all studies retrieved from the databases and bibliographies. Disagreements regarding study eligibility were resolved by discussion. From the studies included in the final analysis we extracted the following data: study name (along with the name of the first author and the year of publication), country, study design, recruitment period (in years), number of participants by condition, the details of the intervention and control conditions, outcome measures, abstinence rates, relative risk (RR) with 95% confidence interval (95% CI) calculated from the numbers of the four cells of the 2 2 tables in each of the studies, the number of women who stopped smoking compared with the number of participants, and the percentage lost to follow up in both the intervention and control groups. The methodological quality of the studies was assessed based on a validated scale for RCTs developed by Jadad et al. 17 This five-point quality scale uses points for randomisation (i.e. randomised, 1 point; table of random numbers or computer-generated randomisation, additional 1 point), double-blinding (i.e. double-blind, 1 point; using identical placebo, additional 1 point), and follow up (i.e. stating numbers and reasons for withdrawal in each group, 1 point). 16 We considered scores of 2 or less to indicate low quality and scores of 3 5 to indicate high quality studies. The main analyses were designed to examine the efficacy of pharmacotherapy for smoking cessation among pregnant smokers based on data available for the longest follow-up period and at the highest gestation, in each study. Another main aim of the study was to perform a meta-analysis by type of study design. We also performed subgroup metaanalyses by type of validation (self-report versus validation using carbon monoxide or cotinine), type of pharmacotherapy (nicotine patch versus nicotine gum versus bupropion), follow-up period (short [<12 weeks] versus intermediate [12 24 weeks] versus long [>24 weeks]), methodological quality (high quality [score 3] versus low quality [score <3]), and use of placebo (placebo RCTs versus non-placebo studies). Statistical analyses were conducted based on 2 2 tables consisting of the number of participants and number who gave up smoking in each intervention and control group in each study. If there was no event (i.e. if there were no women who gave up smoking) in one of the intervention or control groups (i.e. a zero cell in the 2 2 table), 9, was added to each cell of the table to avoid the estimated RR being zero or infinity; in this way the standard error could be calculated. For the test for heterogeneity across studies, we used Higgins I 2, which measures the percentage of total variation across studies. I 2 was calculated as follows: I 2 ¼ 100% ðq dfþ=q where Q is Cochran s heterogeneity statistic, and df is the degrees of freedom. Negative values of I 2 are set to zero so that I 2 lies between 0% (no observed heterogeneity) and 100% (maximal heterogeneity). We considered an I 2 value of >50% to represent substantial heterogeneity ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

3 Pharmacotherapy for smoking cessation in pregnant smokers The pooled RR with 95% CI was calculated on the basis of both the fixed-effects and random-effects models. When there was no substantial heterogeneity, the pooled RR with 95% CI on the basis of the fixed-effects model is reported because the summary estimates from the fixed-effects and random-effects models are similar. When there was substantial heterogeneity, the summary estimates from the random-effects model are presented because CIs tend to be larger in the random-effects model than in the fixed-effects model. The Mantel Haenszel method was used in the fixed-effects model, and the DerSimonian and Laird method was used in the random-effects model. We evaluated publication bias using a contour-enhanced funnel plot of each study s effect size and standard error. 18 Funnel plot asymmetry was assessed using Begg and Egger tests. 19,20 If the funnel plot was asymmetrical or the P-value was found to be <0.10 by Egger s test, then publication bias was considered to exist. Also, mean abstinence rates were calculated by computing a sample size-weighted summary. Stata SE version 10.0 software (StataCorp, College Station, TX, USA) was used for statistical analysis. Results Figure 1 shows a flow diagram for the identification of relevant studies. A total of 74 articles were identified after searching the three databases (PubMed, EMBASE and CENTRAL), and hand-searching relevant bibliographies. After excluding 23 duplicated articles and 41 articles that did not satisfy the selection criteria mentioned in the Methods section, the full texts of ten articles were reviewed Figure 1. Flow diagram for identification of relevant studies. by two of the authors. Of those, three articles were excluded for the following reasons: not a comparison study (n = 1); 21 a study not related to pharmacotherapy (n = 1); 22 a study sharing an identical population with the study included in this analysis (n = 1). 23 Seven studies 9 15 were included in the final analysis. The seven studies included a total of 1386 pregnant smokers, with 732 randomised to pharmacological intervention groups and 654 to placebo or control groups. In the studies that reported age and cigarettes smoked per day, the mean age of the intervention and control groups ranged from 25.5 to 33.4 years and from 24.7 to 31.4 years, respectively; the number of cigarettes smoked per day in the intervention and control groups ranged from 13.4 to 25.4 and from 14 to 24.5, respectively. One prospective controlled study and one quasi-rct showed that the use of either bupropion or a multimodal intervention regimen with counselling supplemented by NRT as a voluntary option had a significant effect on smoking cessation among pregnant smokers. 11,12 The remaining five RCTs reported that there was no significant effect of NRT, including nicotine patch, gum and lozenge. 9,10,13 15 Table 1 shows the general characteristics of the seven trials (five RCTs, one quasi-rct and one prospective controlled observational study) included in the final analysis. The included trials were published from 2000 to 2008, spanning 8 years. The countries in which the studies were carried out were as follows: USA (n = 2), Denmark (n = 2), Canada (n = 2) and Australia (n = 1). The follow-up period ranged from 12 weeks to about 26 weeks; the overall period of recruitment was from 1995 to The number of participants in each study ranged from 30 to 250. Of the seven studies, five used a nicotine patch or gum, one used nicotine gum, and one used bupropion. The doses of pharmacotherapy used were generally 15 mg nicotine patch/day (a choice of 7, 14 or 21 mg nicotine patch in Hotham et al. s study 12 ), 2 mg nicotine gum or lozenge for every cigarette usually smoked per day, and 150 mg bupropion ( mg/day). The treatment period ranged from 6 to 12 weeks. The abstinence rate at late pregnancy in the intervention and control groups ranged from 7 to 22.6% (mean abstinence rate 13.0%; 95% CI %; Cochrane s Q = 0.062; n =7; random-effects model) and from 0 to 19.8% (mean abstinence rate 8.2%; 95% CI %; Cochrane s Q = 0.011; n = 7; random-effects model), respectively. Overall effect in the seven studies In a fixed-effects meta-analysis of all seven studies, based on the longest follow-up data available in each study, pharmacotherapy had a significant effect on smoking cessation (RR 1.80; 95% CI ; I 2 = 41.5%) (Figure 2). Also, in subgroup meta-analyses by type of study design, a significant effect on smoking cessation was found in both RCTs ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1031

4 Myung et al. Table 1. Characteristics of studies included in the final analysis (n = 7) No. Study name (Ref. no.) Country Study design Recruitment period Industry funding Participants Intervention versus control Outcome measure RR (95% CI)* Intervention group Control group Abstinence rate (%)** No. of loss to follow-up (%) Abstinence rate (%)** No. of loss to follow-up (%) 1 Wisborg Denmark RCT Nicotine patch et al. 9 provided from Pharmacia & Upjohn 2 Kapur Canada RCT NA Nicotine and et al. 10 placebo patches donated by Pharmacia 3 Hegaard Denmark Quasi-RCT Supported by et al. 11 Pharmacia A/S 4 Chan Canada Prospective, et al. 12 controlled, observational study 250 pregnant women who smoked 10 or more cigarettes per day after the first trimester 30 pregnant women who smoked 15 or more cigarettes per day 647 pregnant smokers 2001 None 44 pregnant smokers 5 Hotham Australia RCT NA None 40 mid-trimester et al. 13 pregnant smokers 6 Pollak USA Open-label RCT NRT donated by et al. 14 GlaxoSmithKline 7 Oncken USA RCT Nicotine gum et al. 15 provided from Glaxo-Smith Kline 181 pregnant smokers 194 pregnant women who were currently smoking at least one cigarette per day 15 mg nicotine patch (16 hours/day) for 8 weeks and then 10 mg nicotine patch for 3 weeks (n = 124) versus placebo patch (n = 126) 15 mg nicotine patch (18 hours/day) for 8 weeks, 10 mg nicotine patch for the next 2 weeks, and 5 mg nicotine patch for the last 2 weeks versus placebo patch 2 mg nicotine chewing gum and/or 15 mg nicotine patch (16 hours/day) up to 11 weeks versus counselling only 150 mg bupropion ( mg/day) versus no medication 15 mg nicotine patch (16 hours/day) for 12weeks plus counselling versus counselling only A choice of 7, 14, or 21 mg nicotine patch (16 hours/day) and 2 mg nicotine gum or lozenge for 6 weeks plus CBT versus CBT only 2 mg nicotine gum for 6 weeks followed by a 6-week taper period versus placebo gum Continuous abstinence rate validated with a salivary cotinine level <26 ng/ml at 4 weeks before the expected delivery date Assumed that self-reported abstinence rate during the second-trimester were used Self-reported smoking cessation with a salivary cotinine of 30 ng/ml at the 37th week of pregnancy Assumed that self-reported smoking cessation during pregnancy was used Salivary cotinine levels (cut-off values not presented) at late pregnancy Seven-day point prevalent abstinence rate validated with a salivary cotinine at the 38th week of pregnancy Seven-day point prevalence abstinence rate validated with an exhaled carbon monoxide of less than 8 ppm at weeks of gestation 1.14 ( ) 7.00 ( ) 3.22 ( ) 3.33 ( ) 7.00 ( ) 2.66 ( ) 1.21 ( ) 28/124 (22.6) NA 25/126 (19.8) NA 4/17 (23.5) NA 0/13 (0) NA 23/327 (7.0) NA 7/320 (2.2) NA 10/22 (45.5) NA 3/22(13.6) NA 3/20 (15.0) 7 (35) 0/20 (0) 7 (35) 22/122 (18.0) 3 (2.5) 4/59 (6.8) 5 (8.5) 18/100 (18.0) 22 (22) 14/94 (14.9) 34 (36) NA, not available. *A relative risk with 95% confidence interval was calculated from the 2 2 table data consisting of No. of women who stopped smoking / No. of participants in each intervention and control group of an individual study. If a group had no quitter, then 0.5 was added to the value in each cell. **No. of quitters/ No. of participants in each group ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

5 Pharmacotherapy for smoking cessation in pregnant smokers Figure 2. Effect of pharmacotherapy for smoking cessation among pregnant smokers based on the longest follow-up data available in each study in a fixed-effects meta-analysis (n = 7). (RR 1.48; 95% CI ; I 2 = 20.9%; n = 5) and other studies (RR 3.25; 95% CI ; I 2 = 0.0%; n = 2). In the five selected studies, Begg s funnel plot was asymmetrical, and Egger s test showed that P for bias was (Figure 3) (two 10,13 of the seven studies were excluded because of zero cells in the 2 2 table). A contourenhanced funnel plot indicated that the missing studies were in areas of statistical significance (in darker shaded areas). This suggests that the observed asymmetry is more likely to be attributable to factors other than publication bias, such as variable study quality. 18 Methodological quality of studies Of the seven studies, five received a score of 3 or more, while two studies 11,12 received a score of zero (Table 2). Figure 3. Begg s funnel plots and Egger s test for identifying publication bias (P = 0.036) in a meta-analysis of trials (n = 5). Those two studies were a quasi-rct and a prospective controlled observational study. Other subgroup meta-analyses Table 3 shows the effects of pharmacotherapy for smoking cessation in pregnant smokers in subgroup meta-analyses by various factors. When compared with control groups, the summary RR for groups receiving pharmacotherapy at late pregnancy for smoking cessation was 1.65 (95% CI ; I 2 = 41.5%; n = 5). Subgroup meta-analyses of the studies reporting abstinence validated with salivary cotinine or exhaled carbon monoxide showed a significant effect of pharmacotherapy, while those studies with selfreported abstinence showed no significant effect. Regarding the type of pharmacotherapy, a meta-analysis of the four studies in which a nicotine patch was used showed a significant effect for smoking cessation (RR 1.60; 95% CI ; I 2 = 39.2%). One study using bupropion reported an RR of 1.21 (95% CI ) for smoking cessation. Subgroup meta-analyses for short-term (<12 weeks) and intermediate-term (12 24 weeks) follow up showed an increased abstinence rate in the pharmacotherapy groups, whereas the meta-analysis for long-term follow up (>24 weeks) did not show a difference between the pharmacotherapy and control groups. The significant effect of pharmacotherapy for smoking cessation was found regardless of methodological quality. In subgroup meta-analyses by use of placebo, no significant effect of pharmacotherapy was found in the three placebo RCTs, whereas a significant effect was found in the four non-placebo studies (RR 3.17; 95% CI ). ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1033

6 Myung et al. Table 2. Methodological quality of studies included in the final analysis based on the Jadad scale (n = 7) No. Study Randomisation Double-blind Follow-up reporting Description of randomisation methods Using identical placebo Total score 1 Wisborg et al Kapur et al Hegaard et al ) Chan et al Hotham et al Pollak et al Oncken et al Table 3. Effects of pharmacotherapy for smoking cessation in pregnant smokers in subgroup meta-analyses Variable No. of studies Summary RR (95% CI) Heterogeneity, I 2 (%) Model used Longest follow-up data in each trial ( ) 41.5 Fixed-effects Late pregnancy ( ) 46.7 Fixed-effects Type of study design RCTs ( ) 20.9 Fixed-effects Non-RCTs (quasi-randomised or ( ) 0.0 Fixed-effects prospective studies) Validation Self-reported abstinence ( ) 52.9 Random-effects Abstinence validated with salivary cotinine ( ) 37.1 Fixed-effects or exhaled carbon monoxide Type of pharmacotherapy Nicotine patch ( ) 39.2 Fixed-effects Nicotine gum ( ) NA NA Bupropion ( ) NA NA Follow-up period Short-term (<12 weeks) ( ) 21.7 Fixed-effects Midterm (12 24 weeks) ( ) 46.7 Fixed-effects Long-term (>24 weeks) ( ) 0.0 Fixed-effects Methodological quality High quality (score 3) ( ) 20.9 Fixed-effects Low quality (score <3) ( ) 0.0 Fixed-effects Use of placebo Placebo-RCTs ( ) 0.0 Non-placebo-studies ( ) 0.0 NA, not applicable. Adverse effects of pharmacotherapy and main birth outcomes Table 4 summarises adverse effects of pharmacotherapy and main birth outcomes. Adverse effects were reported in three 9,13,15 of the seven studies: skin irritation, headache, palpitation, nausea, an arm feeling dead, worsening of morning sickness symptoms and exacerbation of postnatal depression among the nicotine patch and placebo users; headache, dizziness, fatigue, heartburn, nausea and vomiting among the nicotine gum and placebo users. The remaining studies did not mention any adverse effects. Other adverse effects were reported in three studies. 10,14,15 Kapur et al. s study 10 reported the use of a placebo patch in one participant. After a night s sleep, the woman stopped smoking, and 3 hours later she experienced severe signs of withdrawal and at the same time the fetus exhibited rapid, forceful movements. The woman resumed smoking and the fetal movements subsided within 20 minutes. In Pollak et al. s study, 14 in which a nicotine patch, gum or lozenge was used, serious adverse effects were reported, such as preterm birth (<37 weeks), neonatal intensive care unit (NICU) admission (the newborn being 1034 ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

7 Pharmacotherapy for smoking cessation in pregnant smokers Table 4. Adverse effects of pharmacotherapy and main birth outcomes No. Study Type of pharmacotherapy Adverse effects Serious adverse effects Main birth outcomes Variables Intervention Control Comparison 1 Wisborg et al. 9 Nicotine patch Skin irritation, headache, palpitation, and nausea were reported in some subjects 2 Kapur et al. 10 Nicotine patch Not mentioned The fetus of one participant that received the placebo patch exhibited rapid and forceful movements 3 Hegaard et al. 11 Nicotine patch and/or gum None Mean birthweight 3457 g 3271 g MD = 186 g (95% CI = g) Low birthweight (<2500 g) Preterm delivery rate (<37 weeks) 3% 9% RR = 0.4 (95% CI = ) 8% 10% RR = 0.8 (95% CI = ) Not mentioned Not mentioned Not mentioned Mean birthweight 3401 g 3433 g P = 0.60 Low birthweight (<2500 g) 3.6% 3.0% P = Chan et al. 12 Bupropion Not mentioned Not mentioned Mean birthweight 3500 g 3400 g P = 0.18 All participants delivered healthy, full-term infants 5 Hotham et al. 13 Nicotine patch Rash, arm felt dead, increase in morning sickness symptoms, nausea, and exacerbation of postnatal depression in 5 out of 20 nicotine patch users 6 Pollak et al. 14 Nicotine patch, nicotine gum, or lozenge Not mentioned Preterm birth (<37 weeks), NICU admissions, small-for gestational age, placenta abruption,and fetal demise Not mentioned Not mentioned SAE rates (P = 0.07): a) CBT plus NRT group 34/113 (30%) b) CBT-only 10/58 (17%) *An imbalance between the arms was observed in the proportion of women with a previous preterm birth (12% in CBT-only versus 32% CBT plus NRT) Mean birthweight 3061 g 3132 g P = 0.51 Mean gestational age 37.9 weeks 38.6 weeks P = 0.14 ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1035

8 Myung et al. Table 4. (Continued) No. Study Type of pharmacotherapy Adverse effects Serious adverse effects 7 Oncken et al. 15 Nicotine gum Headache, dizziness, fatigue, heartburn, nausea, and vomiting were reported by at least 10% of participants. The incidence of nausea increased more from baseline to treatment in the nicotine gum group than in the placebo group (P = 0.019) Maternal hospitalisation, low birthweight (<2500 g), preterm delivery (<37 weeks), spontaneous abortion, intrauterine fetal demise, second-trimester pregnancy loss, newborn death, and NICU admission. SAE rates (P = 0.06) a) Nicotine gum group: 24/97 (24.7%) b) Placebo group: 33/87 (37.9%) *No significant differences in baseline characteristics including preterm delivery were reported between two groups SAE, serious adverse effects; CBT, cognitive behavioural therapy. Main birth outcomes Variables Intervention Control Comparison Mean birthweight 3287 g 2950 g P < Low birthweight (<2500 g) Preterm delivery rate (<37 weeks) 2% 18% P < % 18% P = ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

9 Pharmacotherapy for smoking cessation in pregnant smokers small for gestational age), placental abruption and fetal demise. Rates of serious adverse effects were 30% in the cognitive behavioural therapy plus NRT group and 17% in the cognitive behavioural therapy only group (P = 0.07). However, an imbalance between the arms was observed in the proportion of women with a previous preterm birth (12% in the cognitive behavioural therapy only group versus 32% in the cognitive behavioural therapy plus NRT group). In Oncken et al. s study, 14 in which nicotine gum was used, maternal hospitalisation, low birthweight (<2500 g), preterm delivery (<37 weeks), spontaneous abortion, intrauterine fetal demise, second-trimester pregnancy loss, newborn death and NICU admission were reported as serious adverse effects. There was no significant difference in the rate of serious adverse effects or in baseline characteristics between the nicotine gum and placebo groups (P = 0.06). Five studies 9,11,12,14,15 reported mean birthweight, low birthweight rate, preterm delivery rate and/or mean gestational age. Two studies 9,15 reported that the pharmacotherapy group had a higher mean birthweight than the control group, while three studies 11,12,14 reported that there was no significant difference in mean birthweight between the two comparison groups. No significant difference in low birthweight rate, mean gestational age or preterm delivery rate was observed between the two comparison groups in the three studies. 9,11,14 Only one study, 15 in which nicotine gum was used, showed that low birthweight and preterm delivery rates were lower in the pharmacotherapy group, who used nicotine gum, than in the control group. Discussion The current meta-analysis of seven studies, including five RCTs and two others, showed that pharmacotherapy for smoking cessation among pregnant smokers yielded a significantly greater abstinence rate, about 1.8 times higher, than in the control group. When data were pooled, the mean abstinence rate at late pregnancy in the intervention and control groups was 13.6% (95% CI %) and 8.1% (95% CI %), respectively. Also, although a few minor adverse effects and serious adverse effects were reported in several studies, there was no evidence directly linking those serious adverse effects to the pharmacotherapy used in individual studies, and overall pharmacotherapy did not affect birth outcomes and was generally safe. Our findings indicate that there may be clinical evidence to support the use of pharmacotherapy for smoking cessation among pregnant smokers in terms of its efficacy and safety. Pharmacotherapy for smoking cessation among pregnant smokers, to date, is not recommended because its efficacy and safety have not yet been established. For example, in the 2008 update to Treating Tobacco Use and Dependence, a Public Health Service-sponsored Clinical Practice Guideline of the US Department of Health and Human Services, the Panel did not make a recommendation regarding pharmacotherapy during pregnancy because at the time there was insufficient evidence to support its use. 7 In the general population, two meta-analyses 7,24 showed that the abstinence rate was times higher in the pharmacotherapy group than in the placebo groups at 6 months 7 and 1.8 times higher at 12 months. 24 Our study found that pharmacotherapy (mainly NRT) had a similar effect on smoking cessation in pregnant smokers, with an RR of 1.8. Also, the quit rate for pharmacotherapy (mainly nicotine patch) at late pregnancy (at 4 5 months of followup since the beginning of the study) in pregnant smokers (13.0%; 95% CI %) was lower than that of pharmacotherapy (nicotine patch) at 6 12 months in the general population (15.4%; 95% CI %) (calculated by computing a sample-sized summary based on the figure Analysis 1.1. of Stead et al. s meta-analysis 24 ). This finding may indicate that it is more difficult for pregnant smokers to stop smoking than for those in the general population, but further studies are required to confirm this, because the sample size of the current study was much lower than that of Stead et al. s meta-analysis. As described in the Results section, some studies reported minor adverse effects related to pharmacotherapy, such as skin irritation, headache, dizziness and nausea, which are also commonly observed in the general population. In addition, although several serious adverse effects were reported, such as preterm birth, NICU admissions, the infant being small for gestational age, placental abruption, fetal demise, spontaneous abortion and neonatal death, there was no evidence directly linking these serious adverse effects to the pharmacotherapy used in the individual studies. Overall, there was no significant difference in mean birthweight, low birthweight rate, mean gestational age, and preterm delivery rate between the pharmacotherapy and control groups. Of the seven studies, two reported a higher mean birthweight in the pharmacotherapy group than in the control group, and one study showed lower rates of low birthweight and preterm delivery in the pharmacotherapy group than in the control group. These findings may be attributable to a higher abstinence rate in the intervention group. Our study has several possible limitations. First, because of the paucity of studies on this subject published to date, we were able to include only seven studies, involving 1386 pregnant smokers, in the analysis. In particular, only three of the seven studies were RCTs using identical placebos. This paucity of studies is associated with difficulties in recruiting pregnant smokers and receiving approval from institutional review boards. Second, most of the included studies included had follow-up times of at best 26 weeks. Only one study 14 reported abstinence data at about ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1037

10 Myung et al. 34 weeks and up to 3 months postpartum. Hence, we were unable to investigate the long-term efficacy of pharmacotherapy for smoking cessation among pregnant smokers. Third, publication bias was observed in our study. The asymmetry of the funnel plot in the current study may imply that studies that showed no significant effect or a negative effect of pharmacotherapy have not been published or have had their publication delayed. Therefore, our findings should be interpreted cautiously. Fourth, we included the only trial in which bupropion was used. Further trials are required to investigate the effects of oral medications such as bupropion or varenicline in addition to NRT. Lastly, only three RCTs using placebo as a control were included in our study because of a paucity of published data. As shown in the subgroup meta-analyses by use of placebo, no significant effect of pharmacotherapy was found in the three placebo RCTs, whereas a significant effect was found in the four non-placebo studies. This finding may attenuate the main finding of a positive effect of pharmacotherapy in pregnant smokers in the current study. However, the meta-analysis of the three placebo RCTs showed a non-significant positive effect (RR = 1.25) and involved only 474 participants, much fewer than in the four non-placebo studies, which involved 1386 participants. Further larger, randomised, double-blind, placebocontrolled trials are required to confirm the findings of our study. In summary, we found that there may be clinical evidence to support the use of pharmacotherapy for smoking cessation among pregnant smokers. Further, larger RCTs are needed to confirm the efficacy and safety of pharmacotherapy for these populations. Also, an economic evaluation of pharmacotherapy for smoking cessation during pregnancy should be performed based on a cost benefit analysis of smoking cessation versus adverse effects. We believe that, although researchers have had difficulty in conducting such RCTs because of difficulties in recruiting pregnant smokers and receiving approval from ethics committees to date, our findings in the current study would form the basis for them to perform RCTs of pharmacotherapy for smoking cessation during pregnancy. Disclosure of interest None. Contribution to authorship SKM, as principal investigator, had full access to all of the data in the study and is the guarantor for this paper, taking responsibility for the integrity of the data and the accuracy of the data analysis. SKM was responsible for the initial plan, study design and statistical analysis and for conducting the study. SKM and WJ were responsible for data collection, data extraction, data interpretation, and drafting of the manuscript. HSJ, CHP, SWO, HGS and HSK were responsible for data interpretation and drafting of the manuscript. Details of ethics approval Not applicable. Funding No funding was received. j References 1 American College of Obstetricians and Gynecologists. ACOG Committee Opinion No.: 316: smoking cessation during pregnancy. Obstet Gynecol 2005;106: Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev 2007;83: Chapin J, Root W, American College of Obstetricians and Gynecologists. Improving obstetrician gynecologist implementation of smoking cessation guidelines for pregnant women: an interim report of the American College of Obstetricians and Gynecologists. Nicotine Tob Res 2004;6(suppl.):S Quinn VP, Mullen PD, Ershoff DH. Women who stop smoking spontaneously prior to prenatal care and predictors of relapse before delivery. Addict Behav 1991;16: Woodby LL, Windsor RA, Snyder SW, Kohler CL, Diclemente CC. Predictors of smoking cessation during pregnancy. Addiction 1999;94: Centers for Disease Control Prevention. Women and smoking a report of the Surgeon General (Executive Summary). Morb Mortal Wkly Rep 2002;51 (No. RR-12): Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service, Tsutsumi K, Kotegawa T, Matsuki S, Tanaka Y, Ishii Y, Kodama Y, et al. The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. Clin Pharmacol Ther 2001;70: Wisborg K, Henriksen TB, Jespersen LB, Secher NJ. Nicotine patches for pregnant smokers: a randomised controlled study. Obstet Gynecol 2000;96: Kapur B, Hackman R, Selby P, Klein J, Koren G. Randomised, double-blind, placebo-controlled trial of nicotine replacement therapy in pregnancy. Curr Ther Res Clin Exp 2001;62: Hegaard HK, Kjaergaard H, Moller LF, Wachmann H, Ottesen B. Multimodal intervention raises smoking cessation rate during pregnancy. Acta Obstet Gynecol Scand 2003;82: Chan B, Einarson A, Koren G. Effectiveness of bupropion for smoking cessation during pregnancy. J Addict Dis 2005;24: Hotham ED, Gilbert AL, Atkinson ER. A randomised-controlled pilot study using nicotine patches with pregnant women. Addict Behav 2006;31: Pollak KI, Oncken CA, Lipkus IM, Lyna P, Swami GK, Pletsch PK, et al. Nicotine replacement and behavioral therapy for smoking cessation in pregnancy. Am J Prev Med 2007;33: Oncken C, Dornelas E, Greene J, Sanky H, Glassmann A, Feinn R, et al. Nicotine gum for pregnant smokers: a randomised controlled trial. Obstet Gynecol 2008;112: Lumley J, Chamberlain C, Dowswell T, Oliver L, Watson L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2009;3:CD ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG

11 Pharmacotherapy for smoking cessation in pregnant smokers 17 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials 1996;17: Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contourenhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 2008;61: Myung SK, McDonnell DD, Kazinets G, Seo HG, Moskowitz JM. Effects of web- and computer-based smoking cessation programs: meta-analysis of randomized controlled trials. Arch Intern Med 2009;169: Myung SK, Ju W, McDonnell DD, Lee YJ, Kazinets G, Cheng CT, et al. Mobile phone use and risk of tumors: a meta-analysis. J Clin Oncol 2009;27: Schroeder DR, Ogburn PL Jr, Hurt RD, Croghan IT, Ramin KD, Offord KP, et al. Nicotine patch use in pregnant smokers: Smoking abstinence and delivery outcomes. J Matern Fetal Neonatal Med 2002;11: Rigotti NA, Park ER, Chang Y, Regan S. Smoking cessation medication use among pregnant and postpartum smokers. Obstet Gynecol 2008;111: Swamy GK, Roelands JJ, Peterson BL, Fish LK, Oncken CA, Pletsch PK, et al. Predictors of adverse events among pregnant smokers exposed in a nicotine replacement therapy trial. Am J Obstet Gynecol 2009;201: Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Syst Rev 2008:1 162, Issue 1. Art. No.: CD DOI: / CD pub3. ª 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2012 RCOG 1039