Nicotine gum (single and multiple dose studies)
Studies have examined maternal nicotine concentrations after a single dose of 2, 4, or 8 mg nicotine gum. Collectively, these studies show that chewing 2 mg nicotine gum increases plasma nicotine by 2.9 ng/ml, 4 mg increases nicotine concentrations by 4.4–9.2 ng/ml, and 8 mg gum increases nicotine concentrations by 14.9 ng/ml (i.e., chewing 2 pieces of 4 mg gum simultaneously; Gennser, Marsal, & Brantmark, 1975
; Lindblad & Marsal, 1987
; Manning & Feyerabend, 1976
). The increase in nicotine levels observed with the 8 mg dose is similar to concentrations observed with smoking one or two cigarettes (Gennser et al., 1975
; Oncken et al., 1996
). Together, these data suggest that smoking a single cigarette produces higher nicotine concentrations than those observed after chewing a piece of 2 mg gum. The nicotine concentrations typically observed with cigarette smoking are better approximated by chewing 4 or 8 mg gum.
In a multiple dose study of pregnant smokers (who smoked at least 10 cigarettes/day), women randomized to smoking cessation with 2 mg nicotine gum significantly decreased their nicotine and cotinine concentrations after 5 days of gum use compared with baseline smoking levels (Oncken et al., 1996
). Moreover, alterations in fetal and maternal hemodynamics were also generally less with gum use compared with smoking.
Nicotine patch (single and multiple dose studies)
Pharmacokinetic studies of the patch have recruited pregnant women who smoke at least 15 cigarettes/day (Ogburn et al., 1999
; Oncken et al., 1997
). In a single dose study, 8 hr use of 21 mg nicotine patch produced nicotine concentrations similar to smoking approximately 1 cigarette/hour (Oncken et al., 1997
). An inpatient study monitored pregnant women (N
= 21) after smoking cessation using the 22 mg patch/24 hr for 4 days. Nicotine concentrations with the patch were similar to those obtained with ad lib smoking (Ogburn et al.
). Safety measures (fetal heart rate and reactivity monitoring, measures of umbilical artery vascular resistance, and biophysical profiles) showed no evidence of fetal compromise during patch use (Ogburn et al.
). Women who participated in this study were offered transdermal nicotine for an additional 8 weeks. At the end of pregnancy, 38% of women were abstinent from smoking. The authors reported that although there were three pregnancies with serious adverse outcomes, none of these were attributable to patch use (Schroeder et al., 2002
We found no published pharmacokinetic studies of the use during pregnancy of other nicotine replacement products (nicotine nasal spray, inhaler), bupropion SR, or varenicline.
Effectiveness and efficacy studies
We categorized studies as effectiveness (randomized, but not placebo controlled) or efficacy (randomized double-blind placebo controlled) studies. We chose to differentiate between these two types of studies because placebo-controlled studies are the gold standard to assess safety and efficacy of medications and are the most scientifically rigorous (Silverman, 2009
). Randomized studies that are not placebo controlled may be confounded by (a) patient bias, (b) treatment team bias, and (c) evaluation bias (Pocock, 1991
We reviewed the following outcomes: (a) quit rates, because smoking is known to be harmful during pregnancy, and quitting smoking has been shown to improve infant outcomes; (b) measures of tobacco and nicotine exposure, because many of the adverse reproductive outcomes are dose related to maternal smoking (USDHHS, 2001
) and because tobacco reduction has also been correlated with increased birth weight (Li, Windsor, Perkins, Goldenberg, & Lowe, 1993
); (c) pregnancy outcomes (SA rates, stillbirth, preterm delivery, and placental abruption rates) and birth outcomes (birth defects, gestational age, birth weight, neonatal and infant deaths) given that one goal of pharmacotherapy should be to improve infant and child health (Dempsey & Benowitz, 2001
). Most of the studies were not of sufficient length to assess neonatal and childhood (cognitive and behavioral) outcomes. The outcomes reported also varied across studies. Consequently, we review the most commonly reported outcomes (quit rates, birth weight) and, where applicable, note effects on tobacco exposure measures or adverse pregnancy outcomes.
Three randomized controlled trials () evaluated the effectiveness
of NRT for smoking cessation (Hegaard, Kjaergaard, Moller, Wachmann, & Ottesen, 2003
; Hotham, Gilbert, & Atkinson, 2006
; Pollak et al., 2007
). In both studies with a sufficient sample size, the NRT group had statistically higher quit rates compared with the control group (Hegaard et al.; Pollak et al.
). In one study (Hegaard et al.), NRT was part of a multimodel intervention (intensive counseling and NRT administered only to heavier smokers), which was compared with a control group that received only behavioral counseling by a midwife. The intervention group had a higher biochemically verified quit rate compared with the control group, 7% versus 2% (p
< .003). Since NRT was part of a multicomponent intervention, dismantling studies are needed to determine the effectiveness of NRT per se. In the study by Pollak et al.
, pregnant women who smoked at least five cigarettes/day were randomized to a cognitive behavioral treatment (CBT) group versus an NRT/CBT group. All women received six counseling sessions and women in the NRT/CBT group were given a choice of NRT (gum, patch, or lozenge). NRT dosage was reduced for light smokers. The quit rate in the NRT group was approximately double that in the control group. However, this study was stopped due to a safety concern: The NRT/CBT group had twice the serious adverse event (SAE) rate of the control group. The most frequent SAE in this study was preterm delivery (i.e., delivery at <37 weeks gestation). It is noteworthy that 32% of NRT subjects versus 12% of control subjects had a history of preterm delivery (p
< .05) and after adjusting for this covariate, the difference in SAE rate between groups was no longer statistically significant.
Randomized controlled studies of NRT in pregnancy
Three NRT efficacy
studies have been conducted in pregnancy (Kapur, Hackman, Selby, Klein, & Koren, 2001
; Oncken et al., 2008
; Wisborg, Henriksen, Jespersen, & Secher, 2000
). In one study, all women were given counseling by nurse midwife and nicotine patch (15 mg/16 hr) for 6 weeks or a matching placebo (Wisborg et al.). At the end of pregnancy, both quit rates (28% vs. 25%, respectively) and the mean number of cigarettes smoked per day (7.2 cigarettes vs. 7 cigarettes, respectively) were similar for the two groups. The mean birth weight was 186 g (95% CI
= 35, 336) higher in the nicotine versus placebo group. There was a nonsignificant trend for the nicotine group to have a lower incidence of low birth weight babies than the placebo group. The authors hypothesized that a potential mechanism by which nicotine could increase birth weight was inhibition of thromboxane production (which causes vasoconstriction and platelet aggregation in the placental blood supply).
In another randomized placebo-controlled trial, pregnant smokers were randomized to behavioral treatment and 2 mg nicotine gum or a matching placebo (Oncken et al., 2008
). Medication treatment was 6 weeks, with a 6-week taper. Gum dosage was based on number of cigarettes smoked per day. Quit rates at the end of pregnancy were nonsignificantly higher in the nicotine versus placebo group (18% vs. 14.9%). There was also a modestly greater reduction in cigarettes smoked per day and in cotinine concentrations in the nicotine group compared with the placebo group. Treatment retention was also greater in the nicotine versus the placebo group. Mean (SD
) birth weight and gestational age were significantly higher in the nicotine gum versus placebo gum groups (3,287 g vs. 2,950 g; p
< .001; 38.9 wk [1.7] vs. 38.0 wk [3.3]; p
= .014). The incidences of low birth weight and preterm infants were lower in the nicotine versus the placebo group (2% vs. 18%, p
< .001, and 7% vs. 18%, p
< .02, respectively).
In summary, randomized controlled intervention (effectiveness) studies have shown that NRT increases quit rates in pregnant smokers, but one trial raised concerns about safety (which was partially explained by confounding factors). In contrast, randomized placebo-controlled studies have not shown NRT to be efficacious in enhancing quit rates but have shown that NRT compared with placebo increases birth weight and may improve birth outcomes (i.e., decreasing the incidence of low birth weight and preterm delivery). An increase in birth weight in two placebo-controlled studies is clinically significant and requires additional research regarding potential mechanisms. In terms of strength of the evidence, placebo-controlled trials should be given more weight in determining safety and efficacy; however, ultimately it is the effectiveness of a pharmacotherapy in a clinical setting that determines whether it will be a useful adjunctive treatment for smoking cessation.
Demonstrations of the effectiveness but not the efficacy of medications for smoking cessation during pregnancy may be due to (a) the small number of clinical trials in pregnancy, (b) poor treatment compliance in efficacy studies with either the dose (Oncken et al., 2008
) or the duration of treatment (Wisborg et al., 2000
), (c) the wide range of inclusion/exclusion criteria and behavioral treatments between trials, (d) recruitment of participants from clinic settings compared with advertising, which may lend itself better to demonstrations of effectiveness rather than efficacy. The possibility also exists that pharmacotherapy is not effective for smoking cessation during pregnancy; although this would seem unlikely given the strength of data on efficacy of each pharmacotherapy in nonpregnant smokers.