Is it safe to use smoking cessation therapeutics during pregnancy?

Review

Is it safe to use smoking cessation therapeutics during pregnancy? Nicole E De Long, Nicole G Barra, Daniel B Hardy & Alison C Holloway† †

McMaster University, Department of Obstetrics & Gynecology, Hamilton, Ontario, Canada

1.

Introduction

2.

Nicotine replacement therapy

3.

Noncombustible forms of

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Texas A & M University on 11/12/14 For personal use only.

nicotine delivery (e-cigarettes) 4.

Varenicline

5.

Bupropion

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Conclusion

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Expert opinion

Introduction: Worldwide, 10 to 35% of pregnant women smoke. It is clear that smoking cessation has positive impacts for both the mother and child, yet many women are still unable to quit due to the addictive properties of nicotine. There are limited data surrounding their safety and efficacy in pregnancy. Areas covered: This review highlights evidence from clinical studies and animal experiments regarding the effects of smoking cessation therapeutics on pregnancy, neonatal and long-term postnatal outcomes. Expert opinion: There are insufficient data at this time to recommend the use of varenicline and/or bupropion for smoking cessation during pregnancy. In addition, the efficacy and safety of nicotine replacement therapy use for smoking cessation in pregnant women has not been clearly demonstrated. Until further studies are completed, there will continue to be considerable uncertainty regarding the use of these drugs in pregnancy despite the well-documented benefits of smoking cessation. Keywords: bupropion, e-cigarettes, nicotine replacement therapy, varenicline Expert Opin. Drug Saf. [Early Online]

1.

Introduction

There is compelling evidence that cigarette smoking during pregnancy is associated with a number of adverse obstetrical and neonatal outcomes including an increased risk of miscarriage, placenta previa, placental abruption, preterm birth, stillbirth, low birth weight, intrauterine growth restriction and sudden infant death syndrome [1-3]. Although cigarette smoking during pregnancy has been identified as a significant modifiable risk factor for adverse pregnancy outcomes, recent data suggest that 10 -- 35% of women still smoke during their pregnancies [4-9], with prevalence rates as high as 59% reported in some regions [5]. While ~ 75% of pregnant smokers desire to quit smoking [10] and smoking cessation reduces the risk of harmful pregnancy outcomes [11], studies now suggest that 42.6 -- 54.3% of women successfully abstain from smoking during pregnancy [4,12]. Therefore, clinical practice guidelines now strongly advocate for effective interventions leading to smoking cessation during pregnancy [13-15]. Psychosocial strategies including counseling, cognitive and behavioural therapy have been shown to increase the proportion of women who quit smoking during pregnancy [16]; however, pharmacotherapy is still considered to be beneficial for pregnant women who are highly dependent and have been unable to quit smoking by other means [17-20]. Currently, there are three drugs which have been approved for use for smoking cessation in North America [21]: nicotine replacement therapy (NRT), varenicline tartrate and bupropion hydrochloride. Although NRT, varenicline and bupropion have been shown to be more effective than placebo for smoking cessation in non-pregnant adults [22], there are limited data on their efficacy in pregnancy [23,24]. Moreover, there is considerable uncertainty regarding the benefits and risk associated with the use of these smoking cessation pharmacotherapies during pregnancy. In this review, the latest research regarding the use, efficacy and 10.1517/14740338.2014.973846 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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N. E. De Long et al.

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Recent data show that 10 -- 35% of women still smoke during their pregnancies, although there are clear benefits of smoking cessation. Smoking cessation pharmacotherapies (nicotine replacement therapy [NRT], varenicline and bupropion) are effective in non-pregnant smokers; however, their efficacy in pregnancy is equivocal. The studies to examine the safety of NRT use in pregnancy have been limited by poor compliance and low recruitment rates. There are no RCTs which have addressed the safety of varenicline or bupropion use during pregnancy. Although electronic nicotine delivery systems (e-cigarettes) are receiving attention for their use in smoking cessation in non-pregnant adults, there remains considerable concern about their use in pregnancy. There are insufficient data available to recommend the use of smoking cessation pharmacotherapies during pregnancy.

This box summarizes key points contained in the article.

safety of approved pharmaceuticals for the cessation of smoking throughout pregnancy is discussed. 2.

Nicotine replacement therapy

NRT was introduced almost 30 years ago to help with smoking cessation. Cigarette smoke is estimated to contain as many as 4000 chemicals that may be toxic to the fetus including arsenic, lead, hydrogen cyanide, nicotine and tar [25,26], therefore, administration of nicotine alone in the form of NRT is commonly thought to be less harmful than smoking during pregnancy. Since nicotine plays a central role in tobacco dependence, NRT was designed to replace nicotine in order to reduce cravings and other withdrawal symptoms, such as irritability, restlessness, anxiety and increased appetite, in order to aid in smoking cessation [27,28]. NRT can be delivered in the form of a gum, lozenge, transdermal patch, nasal spray or oral inhaler. Nicotine gum and lozenges have been classified by the US FDA as pregnancy category C (i.e., animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Other nicotinedelivery formulations (transdermal patches, inhalers and spray nicotine products) are classified as pregnancy category D (i.e., there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Nicotine is able to cross the placenta and is found in higher concentrations in fetal serum, the placenta and amniotic fluid compared with the maternal serum [29]. During lactation nicotine is also detectable in breast milk, demonstrating that maternal NRT 2

use can result in fetal and neonatal nicotine exposure [30]. Although the rationale for NRT use in pregnancy is based on the premise that exposure to nicotine alone, as delivered by NRT, is safer than smoking, which exposes women to both nicotine and all other toxins in cigarette smoke, this is not universally accepted. Indeed, there is considerable concern regarding the long-term consequences of fetal and neonatal exposure to nicotine [31-33]. Therefore, despite the known benefits of smoking cessation, there still remain concerns and uncertainties about the use of NRT for smoking cessation in pregnant women [33]. Despite an overall beneficial effect on smoking abstinence in non-pregnant adults [34], the effectiveness of NRT in pregnant women is equivocal. Indeed, the most recent Cochrane review on pharmacological interventions for smoking cessation during pregnancy concluded that there was insufficient evidence to demonstrate that NRT improved smoking cessation in pregnant women [24]. Interestingly in a subgroup analysis of placebo-controlled randomized controlled trials (RCTs) (i.e., low risk of bias) versus studies with a higher risk of bias (i.e., non-placebo-RCTs), the efficacy estimates was shown to depend on study design with placebo-controlled RCTs showing no effect on smoking cessation rates (risk ratio [RR]: 1.17; 95% CI: 0.83 -- 1.65) [35] and non-placebo-RCTs comparing NRT plus behavioural therapies versus behavioural interventions of similar intensity demonstrating an improvement in smoking abstinence with NRT (RR: 7.81; 95% CI: 1.51 -- 40.35) [35]. Unfortunately, RCTs evaluating the use of NRT during pregnancy have been marred by a number of challenges including: poor recruitment, insufficient power, low compliance rates and suspension of enrollment by the data safety and monitoring board due to adverse pregnancy events [24,35-41]. Furthermore, since nicotine metabolism is accelerated in pregnant women, it has been suggested that typically recommended dosing may result in underdosing resulting in lower efficacy for smoking cessation in pregnancy [42]. However, when NRT doses were individually adjusted to match levels attained by smoking, NRT did not improve relapse and abstinence rates compared with placebo controls [37]. Interestingly, a recent observational study by Brose et al. demonstrated that compared with women who did not use any medication for smoking cessation, the use of more than one form of NRT (i.e., combination NRT) was associated with higher odds of smoking cessation, whereas the use of a single NRT was not [43]. This observational study raises interesting questions regarding the benefit of using both short- and long-acting NRT to improve cessation rates in pregnant women [43]. Despite this study, there are still significant concerns about recommending higher doses of nicotine for use during pregnancy as there is considerable support for the view that there is no known safe nicotine dosage for pregnant women [32,44]. It is noteworthy that notwithstanding the lack of conclusive data on the efficacy of NRT use during pregnancy for smoking cessation, guidelines from a number of countries

Expert Opin. Drug Saf. (2014) 13(12)

Is it safe to use smoking cessation therapeutics during pregnancy?

recommend that NRT can be used for smoking cessation in patients who have not been able to quit smoking by other means [15,44-48]. However, recommendations from the World Health Organization (WHO) are more cautious about its use given the limited information regarding the risk of adverse pregnancy and postnatal outcomes [13] and the lack of longterm follow-up. As nicotine has been shown to alter a number of biological processes, the effects of NRT exposure on postnatal health outcomes in the offspring have received considerable attention and are reviewed below. Pregnancy outcomes Cigarette smoking during pregnancy is associated with an increased risk of preterm birth, miscarriage, stillbirth and neonatal death [49-52]. A recent systematic review of six trials of NRT use during pregnancy found no increased risk of preterm birth, perinatal mortality, fetal death, neonatal intensive care unit visits, miscarriage or spontaneous abortion with NRT use [35]. Similarly, pregnant women who received behavioural cessation support and were randomized to receive either nicotine patches or placebo did not have an increased risk of any adverse pregnancy or birth outcomes, although compliance in both the NRT groups in this trial was low [40]. Interestingly, Lassen et al. reported that simultaneous use of more than one NRT product was associated with low birth weight [53]. It is biologically plausible that perinatal nicotine exposure leads to impaired fetal growth. Indeed, there have been numerous animal studies that have demonstrated reductions in birth weight with maternal nicotine administration [54-56]; however, human exposure to nicotine alone does not appear to increase the risk of fetal growth restriction [24].


2.1

Pediatric asthma The effects of maternal smoking on lung function and asthma risk in the offspring is well established [57,58]; however, the effects of nicotine alone in promoting asthma in children is largely unknown. Animal studies have shown that nicotine alone can compromise lung development, leading to structural and functional alterations that persist into adulthood. Petre et al. [59] found that rats prenatally exposed to nicotine had delayed alveolarization and decreased vascularization, suggesting early abnormal lung development, which may clinically predispose offspring to respiratory disease like asthma later in life [60]. Other rodent studies have reported that in utero nicotine exposure increased collagen deposition in airways and vessels in fetal, early postnatal and adult lungs [61-63]. Importantly, increased collagen deposition promotes airway remodeling and resembles alterations characteristic to asthma [63]. Furthermore, prenatal nicotine exposure may also indirectly affect fibroblast activity through the activation of immune cells found in the lung [64], which may in turn promote fibroblast proliferation and production of extracellular matrix proteins like collagen and fibronectin involved in airway remodeling [64,65]. In animal studies, prenatal nicotine exposure can also leads to altered pulmonary function similar 2.2

to that seen in asthmatic infants and children. Prenatal nicotine exposure increases bronchoreactivity, resulting in lung hyperresponsiveness in the absence of allergic stimulation, all of which lead to asthma development [63]. Primates exposed to nicotine in utero have decreased forced midexpiratory flow and increased airway resistance [66]. It has also been suggested that this increased airway resistance may be due to altered differentiation of lung fibroblasts to myofibroblasts [67] and increased interstitial pulmonary fibrosis [68] in developing lungs exposed to nicotine. Lastly, the longterm adverse effects on nicotine on lung function may be regulated via epigenetic mechanisms given that exposure to nicotine exposure during pregnancy can result in structural changes in the F2 progeny [69]. Data from animal experiments, therefore, suggest that NRT may impact lung development and result in an increased risk of long-term adverse respiratory outcomes. To date, there is only one study which has examined the effects of NRT use during pregnancy on respiratory outcomes in the offspring. Cooper et al. reported that at 2 years of age there was no difference in the frequency of respiratory problems between children who were exposed to NRT and placebo (odds ratio [OR]: 1.28; 95% CI: 0.95 -- 1.73) [70]. However, it remains to be determined whether or not NRT use will be associated with adverse respiratory outcomes in the longer term. Metabolism Cigarette smoking during pregnancy increases the risk of delivering a baby preterm and small for gestational age [71], both of which are associated with an increased incidence of adverse metabolic outcomes, including glucose intolerance, insulin resistance and obesity [72]. While a recent metaanalysis of 30 prospective studies suggest that babies born to smoking mothers have a 47% increase in the odds of becoming overweight [73], the association between the use of NRT during pregnancy and metabolic abnormalities in the offspring is not yet known. There are considerable data from animal studies that demonstrate that nicotine exposure during fetal and neonatal life results in a battery of metabolic disturbances such as increased adiposity, hyperglycemia, reduced b-cell mass [74], increased circulating and hepatic triglycerides [54] and vascular dysfunction [75,76]. Despite the compelling data from animal models to suggest that nicotine exposure alone results in postnatal metabolic deficits, it remains to be determined whether or not similar outcomes are observed in the children who were born to mothers who used NRT during pregnancy. 2.3

Child behavior In humans, maternal smoking during pregnancy results in adverse behavioural outcomes in the children including increased psychiatric and behavioural disorders, increased rates of conduct disorder and decreased IQ [77,78]. Furthermore, a recent study using data from the Danish National Birth Cohort reported that maternal smoking increases the risk of attention 2.4


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deficit hyperactivity disorder (ADHD) in the children (hazard ratio: 1.63; 95% CI: 1.36 -- 1.94) even after controlling for parental psychopathology [79-81]. Given that prenatal smoking results in lifelong brain alterations and behaviors in children, this raises concerns regarding the safety of NRT use during pregnancy [82-84]. Studies from rodent models have shown that maternal nicotine exposure during pregnancy increases anxiety-like behaviors into adulthood along with a decline in cognitive function [82,84]. Furthermore, similar to humans, there is now considerable evidence in rodents that prenatal nicotine exposure may result in behaviors consistent with those seen in ADHD and conduct disorder [83,85]. More importantly, Zhu et al. reported an increased risk of ADHD in children of mothers who used NRT during pregnancy raising significant concerns about the long-term behavioural consequences of nicotine exposure [79]. It is hypothesized that these behaviors may be a result of altered neuronal development in the hippocampus of these offspring. Nicotine serves as a major neurotransmitter that acts on the nicotinic acetylcholine receptors throughout brain development and has been demonstrated to alter dopaminergic signaling, a key regulator for proper fetal brain development [86]. Clearly, more measures of long-term behavioural outcomes in children exposed to NRT during fetal and/or neonatal life need to be considered in the safety assessment of NRT use by pregnant women. Addiction Children born to mothers who smoked during pregnancy are more likely to smoke themselves [87,88]. Indeed, a 40-year prospective study has demonstrated that maternal smoking increases the likelihood of nicotine dependence, particularly in daughters [89]. Emerging evidence in animal models suggests that nicotine exposure alone throughout pregnancy and lactation also increases addictive behaviors in the offspring. Based on the animal literature, it is plausible that these effects are mediated by nicotine alone. Interestingly, in utero nicotine exposure in a rat model reported that nicotine-exposed offspring had an increased response to the odor of nicotine early in postnatal life due to modifications in the olfactory bulb [90]. This increased preference of nicotine was also observed into adulthood as nicotine-exposed offspring preferred drinking water supplemented with nicotine over the control water [91]. This enhanced preference for nicotine may be due to the fact that prenatal nicotine exposure increases reward-driven behaviors as a consequence of altered dopaminergic signaling in the ventral tegmental area of the mesocorticolimbic system [92]. It is also noteworthy that prenatal nicotine exposure also increased sensitivity to methamphetamine and altered responses to cocaine [93,94]. However, there is no evidence to support or refute the hypothesis that NRT exposure during fetal life increases substance abuse in exposed children later in life. Collectively, there is considerable evidence from animal studies to demonstrate that prenatal nicotine exposure adversely affects pregnancy outcomes and results in compromised long2.5

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term mental, respiratory and metabolic health of the offspring. It is worth noting that these animal studies compare nicotine with placebo and not nicotine alone to all of the other components of cigarette smoke. Therefore, the consequences of exposure to NRT versus smoking may be less clear in human populations. Regardless, many of the adverse long-term developmental outcomes observed in animal studies have largely been unexplored in human populations. Until these outcomes have been considered in human trials, it will continue to be challenging to ascertain whether NRT is a safe and effective smoking cessation strategy for pregnant women.

Noncombustible forms of nicotine delivery (e-cigarettes)

3.

More recently, interest in the use of electronic cigarettes (e-cigarettes) for smoking cessation has grown dramatically in popularity, despite limited safety testing of these products [95]. E-cigarettes are battery powered units that vaporizes a liquid containing flavoring and in most products nicotine [96]. Although e-cigarettes are believed by some to be safer than smoking, a recent study found that the vapor produced during use contains potentially toxic and carcinogenic substances such as formaldehyde, acetaldehyde, acrolein, nitrosamines and some heavy metals albeit at lower levels than typically found in cigarette smoke [97,98]. There is currently limited evidence to suggest e-cigarettes aid in smoking cessation in non-pregnant adults [99] and no data are available for their efficacy during pregnancy. Moreover, although e-cigarettes minimize exposure to many of the toxins associated with cigarette smoking, the safety of the propellants found in e-cigarettes such as propylene glycol is unknown [23] and users may be exposed to similar levels of nicotine as found in conventional cigarettes [100-102]. Given the lack of clinical and animal studies, the safety of e-cigarettes during pregnancy cannot be determined. Indeed, a recent statement from WHO recommended that pregnant women should be cautioned about the use of electronic nicotine delivery systems [103]. However, since e-cigarettes represent a rapidly growing market, especially among women [104], and there is increased interest in their use for smoking cessation [105], an evaluation of their safety during pregnancy is urgently required. 4.

Varenicline

Originally developed by Pfizer, Inc. in 1997, varenicline tartrate (marketed as Champix or Chantix) was approved for smoking cessation in adults by the FDA in 2006 [28]. Varenicline is a partial agonist at the a4b2 nicotinic acetylcholine receptor (nAChR) subtype and a full a7 nAChR agonist [106]. Compared with placebo, varenicline is highly effective for smoking cessation [107], likely due to its ability to reduce cravings, negative withdrawal symptoms and smoking satisfaction [108,109]. Although varenicline is well tolerated in healthy adult smokers [108,109], and has been designated as




pregnancy category C drug by the FDA, the manufacturer does not recommend its use by pregnant women [110]. Similarly, guidance documents and clinical practice guidance for smoking cessation during pregnancy in most countries do not recommend the use of varenicline during pregnancy in large part due to the paucity of human pregnancy outcome data [13,111,112]. A 2012 a meta-analysis [113] and a Cochrane Systematic review [24] failed to identify any RCTs, quasi-RCTs, retrospective or prospective controlled studies of varenicline use in pregnant women. Aside from the lack of clinical data, no animal studies exist examining the effects of prenatal varenicline exposure on short- or long-term developmental outcomes in the offspring. Recently, one small prospective study from New Zealand reported on pregnancy outcomes in 23 women who were exposed to varenicline at some point during pregnancy [114]. Of these 23 women, there were 4 terminations, 2 spontaneous or missed abortions, 1 ectopic pregnancy and 16 live births [114]. Of the 16 women who had live births, the majority took varenicline between conception and 6 weeks of gestational age, with 9% delivering preterm [114]. Furthermore, none of babies born at term was growth restricted or exhibited any major congential malformations [114], despite the fact that administration of varenicline to pregnant rabbits resulted in reduced fetal weight in preclinical toxicity testing [115]. Similarly, a recent case report did not identify any adverse pregnancy or developmental outcomes following first trimester exposure to varenicline [116]. Although these studies do not definitively resolve all the questions regarding the safety of varenicline during pregnancy, they do highlight the fact that pregnant women are being still exposed to varenicline despite recommendations to the contrary. To address this further, there is currently an ongoing prospective population-based cohort study (Varenicline Pregnancy Cohort Study ClincalTrial.gov Identifier: NCT01290445; estimated study completion date December 2015) to examine whether varenicline use during pregnancy is associated with an increased risk of adverse pregnancy and neonatal outcomes. These include accounting for major congenital malformations, stillbirths, the incidence of intrauterine growth restriction, preterm delivery, premature rupture of membranes and sudden infant death syndrome. Until the results of this study are available, to date, there is still insufficient evidence to completely determine the safety of varenicline use for smoking cessation in pregnancy.

5.

Bupropion

Initially approved for use as an antidepressant in 1985, bupropion has been used as a smoking cessation agent under the trade name Zyban since 1997 [27,115,117]. Bupropion is classified as pregnancy category C drug by the FDA [117].

Bupropion acts as a norepinephrine and dopamine reuptake inhibitor and as a nAChR antagonist [118]. In addition, bupropion has been demonstrated to increase long-term cessation, decrease nicotine cravings and smoking withdrawal symptoms [109]. At this time, the use of bupropion for smoking cessation during pregnancy is not recommended in most countries [15,48]. Although very few women report the use of bupropion for smoking cessation [117,119,120], it is still commonly prescribed for perinatal depression [121,122]. Currently, there are no RCTs available regarding the safety or efficacy of bupropion use for smoking cessation during pregnancy [14,24]. There is one prospective controlled observational study of the effectiveness of bupropion for smoking cessation during pregnancy [123] and one prospective comparative study of pregnancy outcomes in women (n = 136) exposed to bupropion during the first trimester [124]. In addition, the Bupropion Pregnancy Registry established by GlaxoSmithKline prospectively followed pregnancies with bupropion exposure on short-term outcomes including birth defects and spontaneous pregnancy losses [125]. The observed proportion of birth defects in women exposed to bupropion during pregnancy was 3.1% (95% CI: 2.1 -- 4.5%) [117]. While this study concluded that there was no evidence of a major teratogenic effect of bupropion, it failed to include a proper comparison group (i.e., unexposed women). Regardless, studies that included appropriate comparison groups have made similar conclusions [123,126]. Moreover, in an observational study of 113 pregnancies with bupropion exposure, there were no reports of major malformations [126]. With respect to cardiovascular health, emerging evidence has suggested that bupropion use in early pregnancy may be associated with an increased risk of cardiac malformations in neonatal life [120,127]. In 1038 infants with left outflow tract defects, Alwan et al. [127] reported a positive association between bupropion exposure and the congential cardiac anomalies (adjusted OR [aOR]: 2.6; 95% CI: 1.2 -- 5.7). Conversely, Louik et al. [120] did not report an increased risk of left side cardiac defects with first trimester bupropion exposure (aOR: 0.4; 95% CI: 0.1 -- 1.6), but this was likely due to the limited number of exposed infants (n = 2). Louik et al. did find an increased risk of ventricular septal defects, an effect which was more profound in women taking bupropion alone [120]. To date, no animal studies have been conducted to investigate the molecular mechanisms underlying the bupropion-induced increased risk of congenital cardiac abnormalities. In addition to the adverse effects of bupropion exposure on cardiac function, a small (n = 136) prospective comparative study has demonstrated that it is also associated with an increased risk of spontaneous abortion [124]. Interestingly, animal studies indicate bupropion exposure in utero does not lead to fetal demise (i.e., reduced litter size) [117,128]. The same clinical study also indicated that bupropion did not increase the risk of stillbirth, low birth


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weight, preterm delivery or neonatal death [123]. However, a study from the Swedish Medical Birth Register suggest that serotonin-norepinephrine reuptake inhibitors (SNRIs) (including bupropion) in pregnancy do increase the risk of preterm birth, low birth weight and small for gestational age ( < 2 standard deviations form expected weight) babies [129]. While the relative contribution of bupropion to these outcomes is unknown, it is likely to be minimal given that bupropion use only accounted for 2.4% of SNRIs identified in this study [129]. In retrospect, it is currently unknown if the reported increase in cardiac abnormalities and spontaneous abortion in women with bupropion exposure is modified based on the underlying indication for use. Indeed, most studies have looked at bupropion use in the context of depression but untreated depression has repeatedly been shown to be independently associated with an increased risk of low birth weight and preterm delivery [122,124,126,127]. However, preclinical animal studies also reported impaired fetal growth with bupropion exposure [117], suggesting the possibility that the drug may have an affect on fetal growth, which is independent of any underlying maternal mental illness. Importantly, a recent study identified that chronic and acute use of bupropion in pregnancy was associated with reduced uterine blood flow identifying an important mechanism by which bupropion may elicit deficits in fetal growth and survival [130]. Moreover, the observed reduction in placental blood flow may also explain the increased risk of spontaneous abortion in bupropion-exposed women [123]. While further animal studies are warranted, to date, there is insufficient evidence to recommend the use of bupropion for smoking cessation in pregnancy [13,14,111,112]. However, since bupropion use is reported in ~ 0.7% of all pregnant women [121,122], further clinical studies are also urgently required.

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Conclusion

In summary, there is compelling evidence that maternal cigarette smoking is associated with multiple adverse outcomes that affect the health of both the mother and fetus and there are clear benefits associated with smoking cessation for both the mother and her child. Although the use of smoking cessation pharmacotherapies may benefit some women who cannot quit by other means, the current safety and effectiveness of these products short- and long-term have not been sufficiently assessed to ascertain whether they should be recommended for use by pregnant women. Therefore, it is not surprising that the WHO guidelines do not endorse the use of pharmacological interventions such as NRT, bupropion, and varenicline for tobacco-use cessation in pregnancy. Clearly, welldesigned, controlled clinical trials are urgently required to 6

address the uncertainties regarding the use of pharmacotherapies for smoking cessation during pregnancy. 7.

Expert opinion

Smoking during pregnancy still remains a significant problem globally and represents a significant modifiable risk factor for numerous adverse pregnancy and fetal outcomes. Although there is no question that smoking cessation is associated with benefits for both the mother and her child, for most pregnant women smoking cessation without pharmacological support remains a great challenge. Unfortunately, there is paucity of data from well-designed RCTs addressing the safety of the three smoking cessation therapeutics (i.e., NRT, bupropion and varenicline) in pregnancy. Moreover, despite the fact that RCTs of NRT use in pregnant women have been conducted, there is still insufficient evidence to determine if NRT leads to detrimental fetal outcomes, in part, because adherence was low [24]. Another major concern about NRT use in pregnancy arises from the fact that there is considerable evidence from animal studies that prenatal nicotine exposure can impact long-term health of the offspring, yet these outcomes have yet to be examined in clinical populations. Most guidelines for smoking cessation during pregnancy clearly indicate that well-designed RCTs of NRT should be conducted. However, it remains uncertain whether or not NRT use in any form during pregnancy will ever gain widespread acceptance; concerns about its safety even in nonpregnant adults have been reported in numerous studies. Moreover, it has also been reported that clinical care providers are reluctant to recommend or prescribe NRT for smoking cessation even outside of pregnancy. Therefore, it may be more beneficial for the field to focus on evaluating the safety of other smoking cessation drugs or on developing new pharmacological strategies to aid smoking cessation in pregnant women. To date, there are currently no RCTs which have examined the safety of varenicline or bupropion use during pregnancy. In addition, there is a paucity of animal studies examining pregnancy and/or developmental outcomes with maternal exposure to either of these drugs. Given that these studies have a number of serious concerns about the safety of varenicline and adverse cardiovascular and neuropsychiatric events, proposing RCTs of varenicline use in pregnancy does not seem prudent. Conversely, clinical studies addressing the safety of bupropion’s use in smoking cessation for pregnant women are urgently warranted. There are a few studies of the safety of bupropion use during pregnancy but the results have been highly variable, perhaps in part to the small sample sizes and/or the fact that many of these studies focused on bupropion use for antenatal depression, which is itself a risk factor for adverse pregnancy and neonatal complications. Given that bupropion is already widely accepted for use in the treatment of antenatal depression and that in




non-pregnant adults it is more effective than NRT for smoking cessation, it is critical to identify whether or not it is safe for smoking cessation during pregnancy. There is no argument that smoking cessation at any time is beneficial, but during pregnancy the benefits also extend to the unborn child. For women who cannot quit smoking without pharmacological support, she currently has to consider the balance between the risks of smoking and the risks of taking the smoking cessation drugs. Until we can more clearly provide recommendations based on well-designed RCTs about the safety of the existing smoking cessation therapeutics, there will continue to be uncertainties for both the patient and her care providers about the use of these drugs. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest NE De Long receives salary support from the CIHR Training Program in Reproduction, Early Development and the Impact on Health. DB Hardy and AC Holloway have received funding from the Canadian Institutes for Health Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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Affiliation Nicole E De Long1, Nicole G Barra1, Daniel B Hardy2 & Alison C Holloway†1 † Author for correspondence 1 McMaster University, Department of Obstetrics and Gynecology, RM HSC-3N52, 1280 Main Street West, Hamilton, Ontario, L8S 4K1, Canada Tel: +1 905 525 9140 ext. 22130; Fax: +1 905 524 2911; E-mail: [email protected] 2 University of Western Ontario, Department of Obstetrics and Gynecology, London, Ontario, Canada

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