Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Cite the prevalence of nicotine use among reproductive-age and pregnant women and identify populations at higher risk for nicotine use.
2. Explain basic nicotine pharmacokinetics and pharmacodynamics.
3. Describe how pregnancy can affect nicotine pharmacokinetics and pharmacodynamics.
This article is the first of 2 parts.
Nicotine use during pregnancy, particularly cigarette smoking, continues to be a leading preventable cause of poor maternal and birth outcomes.1 Cigarette smoking is more prevalent and recalcitrant in certain populations, including women in rural areas and women with substance use disorders. In addition to cigarettes, there are more nicotine products available than ever before, including tobacco products and nontobacco products (Figure 1). Tobacco products include the tobacco plant as part of the product. Combustible tobacco products are burned and inhaled, like cigarettes, cigars, cigarillos (little cigars), and hookah. Noncombustible products like chewing tobacco, snuff, and snus are administered through oral or buccal routes. Other nicotine products do not include the tobacco plant, though their nicotine may be derived by processing the plant itself. These products can be inhaled, like electronic cigarettes (e-cigs) and vapes, or administered orally or buccally, like nicotine-containing mints and candies. In this review, the term "nicotine products" or "nicotine use" will be used when discussing all tobacco- and nontobacco products in general, and specific language will be used to refer to specific products. This review covers terminology regarding nicotine use and impacts on pregnancy, the epidemiology of nicotine use among reproductive-age and pregnant women in various subpopulations, and nicotine pharmacokinetics and pharmacodynamics.
This review has at least 3 applications to practice. First, practitioners who are aware of the prevalence of nicotine use will be more likely to address nicotine use as part of standard care. Second, practitioners who understand the pharmacology and neurobiology of nicotine will be able to provide more effective and compassionate care to patients before, during, and after quit attempts. Third, practitioners who are knowledgeable about nicotine products, nicotine pharmacology, and the behavioral components of tobacco use disorder will be able to engage with their patients who may use nicotine products more confidently and compassionately.
Important Definitions and Consistent Language
Nicotine or tobacco use refers to the use of products, whereas tobacco use disorder is the diagnostic term used when official criteria are met as defined by the Diagnostic and Statistical Manual of Mental Disorders.2 As with any other substance use disorder, tobacco use disorder criteria include inability to control nicotine or tobacco use, use despite negative impacts on work or social functioning, and use despite knowledge that continuing to use is imminently dangerous or is exacerbating a physical or psychological harm associated with use. Generally, people who use tobacco or nicotine products daily meet criteria for tobacco use disorder, whereas those who use infrequently, such as on weekends or in social circumstances, do not.
Tobacco or nicotine tolerance refers to the reduction in effect derived from consistent use of the same dose and the need to increase intake to achieve the desired effect. Tobacco or nicotine withdrawal refers to unpleasant effects that occur when bioavailable nicotine levels fall. Tobacco or nicotine withdrawal includes psychological symptoms like anxiety, depressed mood, and irritability, motor symptoms like restlessness, insomnia, and cognitive symptoms like difficulty concentrating. Increased appetite also occurs in tobacco or nicotine withdrawal.
Smoking and Nicotine Effects on Reproduction and Pregnancy
The damaging effects of cigarette smoking on cardiovascular, pulmonary, and endocrine systems are well established.3 Smoking before, during, and after pregnancy is also associated with a variety of adverse effects.4 The effects of smoking on reproduction and pregnancy begin before conception. Fertility is reduced among women who smoke due to smoking-induced damage to germinal cells in both males and females.5 In addition to causing cell damage that interferes with successful reproduction, women who smoke may experience fewer years of reproductive capacity, experiencing menopause 2 years earlier than women who do not smoke.5
During pregnancy, tobacco smoke and nicotine each have been associated with maternal complications. Maternal smoking was found in meta-analyses to significantly increase the odds of experiencing placenta previa, placental abruption, and preterm premature rupture of membranes by 58% to 77%.6 Paradoxically, numerous studies have demonstrated that preeclampsia is significantly less common among pregnant women who smoke compared with nonsmokers.6,7 There are no definitive conclusions on underlying mechanisms or statistical biases underlying this effect; however, the numerous negative impacts of nicotine use on pregnancy and neonatal outcomes outweigh the reduction in preeclampsia.
For the fetus and neonate, exposure to tobacco smoke and nicotine are associated with gestational and birth complications including intrauterine growth restriction, low birth weight, preterm delivery, and stillbirth.8 Tobacco and nicotine exposure are also causally linked with congenital malformations including cleft lip, cleft palate, and club foot.3 Beyond the neonatal period, infants exposed to tobacco are at risk for sudden unexpected infant death,9 and children who continue to be exposed to tobacco smoke from maternal or familial smoking are at increased risk for chronic bronchitis and asthma.10
Epidemiology
As of 2017, 19.3% of the US adult population reported current use of any tobacco product, 14% reported cigarette smoking, and 2.7% reported use of other combustible tobacco products (eg, cigars, cigarillos, and pipes).11 These population estimates represent a new low in tobacco product use, which has declined by approximately 67% since the 1960s. This decline has been influenced by recognition of the negative health consequences of smoking, public health efforts to help current smokers quit and prevent young people from initiating smoking, increased cigarette taxes, and local laws that limit where smoking can occur (eg, prohibiting smoking in restaurants, bars, and other public areas). However, the prevalence of nicotine use and changes over time vary across subpopulations. There are some subpopulations where smoking continues to occur at significantly higher rates relative to the general population. Furthermore, smoking in these populations has declined more slowly, or not at all, compared with the general population. For the scope of this review, we focus on differences in nicotine use between the sexes, urban and rural environments, and other substance use.
Nicotine use has always been less prevalent among women compared with men. In 2018, 16.6% of women and 26.6% of men 12 years and older reported past-month use of any nicotine products.12 In addition to consistent differences in prevalence between sexes, there are differences in the rise and fall of tobacco product use between sexes over the last century. The rise and fall in smoking among women lagged 25 to 30 years behind men. Nicotine use among pregnant women has been extremely slow to decline, showing no consistent significant reductions in the past several years.13
Nicotine use among women is most common during the reproductive years, between 15 and 44 years of age. Approximately 20% of women of reproductive age smoke cigarettes; 7% use hookah; 6% use electronic nicotine delivery systems; 5% use any cigar product; and less than 1% use pipes, smokeless, or dissolvable tobacco products.14 During pregnancy, approximately 14% smoke cigarettes, 5% use electronic nicotine delivery systems, 3% use hookah, and 2% smoke cigars.15 Women who smoke cigarettes often change their smoking behavior during pregnancy. Between learning of pregnancy and attending the first prenatal visit, approximately 20% of women who smoke cease smoking, and 80% reduce the number of cigarettes smoked each day by the end of pregnancy.16 Reducing smoking during pregnancy may be a beneficial and achievable goal, as there is some evidence that nicotine and smoking effects on neonatal outcomes are dose-dependent. In one study, women who smoked fewer than 10 cigarettes per day had children with significantly higher birth weights than those who smoked 11+ cigarettes per day.17 Approximately 50% of women who quit during pregnancy return to smoking postpartum.18
There are also differences in the prevalence and trends in cigarette smoking between people living in urban and rural locations. Since at least 2007, cigarette smoking has been more common among people living in rural versus urban areas, with about 25% of women and 30% of men smoking in rural areas compared with 20% of both women and men in urban areas.19 Between 2007 and 2014, the prevalence of smoking declined among urban men and women and rural men, but remained constant among rural women.19 Among reproductive-age and pregnant women, those living in rural areas are significantly more likely to smoke cigarettes than those living in urban areas.20 Rural pregnant women are more likely to continue smoking through pregnancy than urban pregnant women.20
Cigarette smoking is also more common among socioeconomically disadvantaged women, meaning women with lower income, education, employment, and perception of their own social status. For example, smoking is more common among pregnant women on public insurance with approximately 26% of pregnant people on Medicaid/Medicare smoking in 2017 compared with 7% of those with private insurance.13
Finally, there is a strong association between cigarette smoking during pregnancy and substance use disorders. For example, smoking is nearly ubiquitous among pregnant women in treatment for opioid use disorder with prevalence exceeding 88%.21 The negative outcomes associated with maternal cigarette smoking during pregnancy (eg, intrauterine growth restriction, low birth weight, and cleft lip/palate) tend to be different and more severe relative to negative outcomes associated with use of most other substances. Thus, facilitating reduction or cessation in cigarette smoking should be a priority for practitioners working with pregnant and parenting women who have substance use disorders.
Nicotine Pharmacokinetics
Nicotine is the most psychoactive component of nicotine products. The amount of nicotine in products and the speed nicotine reaches the brain is widely variable depending on the route of administration and physiological factors. A typical cigarette contains between 10 and 14 mg of nicotine.22 Electronic nicotine delivery systems can contain anywhere from 0 to 40 mg or more per mL of fluid. These products are inhaled, and the large surface area of the lungs conveys nicotine into the bloodstream and brain within a few seconds. The total amount of nicotine absorbed from these inhaled products is dependent on how a person uses the product, like the length of individual inhales from the product or the time between inhales. For example, a person who smokes a cigarette absorbs about 10% of the cigarette's total nicotine content, or between 1 and 1.5 mg. This dose will be higher if the person takes longer inhalations (puffs) from the product or has a shorter time between puffs.
Smokeless tobacco products, like chewing tobacco, are kept in the mouth rather than inhaled. For these products, nicotine is absorbed through the buccal membrane. Ingestion is highly inefficient due to the acidic stomach environment and first-pass metabolism of nicotine, which significantly reduce the amount of nicotine that reaches the brain. Nonetheless, poisonings from oral consumption have occurred. With a substantially smaller surface area for absorption, smokeless oral tobacco products produce a more gradual increase in nicotine, with blood concentration peaking around 30 minutes after the start of use.
Nicotine can also be absorbed through the skin. Although this aided development of the transdermal nicotine patch used in smoking cessation, it also contributes to the global burden of tobacco use. People harvesting tobacco have incurred toxicities due to physical contact with wet tobacco leaves. For the close contacts of people who smoke tobacco, like infants and children, the physical residues from smoking that coat surfaces in the smoking environment, called third-hand smoke, also contain nicotine and related carcinogens that can be absorbed through skin contact.23
Absorbed nicotine deposits in organ tissues, particularly the liver, kidneys, spleen, and lungs, with far less affinity for adipose tissue. The deposited nicotine releases over time, giving rise to a longer half-life of nicotine than may be inferred from the frequency of self-administration. The plasma half-life of nicotine from inhaled products is about 2 hours. Those who use nicotine products use them every few hours or more frequently, resulting in an accumulation of nicotine across the waking hours. A person who uses nicotine products throughout their waking hours has accumulated enough nicotine to avoid withdrawal during sleep. Most people who use nicotine products do not wake up from sleep due to withdrawal, but by 6 to 8 hours of sleep, the majority of the nicotine has been metabolized and withdrawal signs peak.
Nicotine is metabolized into over 10 primary metabolites and more secondary metabolites. Up to 80% of nicotine is metabolized to cotinine, but note that there are many other metabolites, some with carcinogenic potential.22 Nicotine's metabolism into cotinine is a 2-step process involving cytochrome P450 enzymes and aldehyde oxygenase. Cytochrome P450 enzymes are strongly associated with interindividual differences in nicotine metabolism. CYP2A6 is responsible for most of the metabolism of nicotine to cotinine with lesser roles for CYP2B6, CYP2D6, and others. Nicotine metabolism is affected by genetics, sex, pregnancy, concomitant medications, diet, age, and other factors.24
About 10% to 15% of cotinine is excreted in urine, with the remainder metabolized into multiple other molecules. Cotinine metabolism is slower than nicotine metabolism, making cotinine detectable in urine for several days after nicotine use. Nicotine use can be biochemically verified by testing urine for cotinine, and several point-of-care tests are commercially available. Another method for biochemically assessing nicotine use is the total nicotine equivalent measure, which involves analyzing both nicotine and its metabolites as detected in urine.
Understanding how nicotine metabolism affects tobacco use disorder is important when considering smoking among reproductive-age or pregnant women. Faster conversion of nicotine to cotinine is associated with more severe tobacco use disorder, possibly because a faster metabolizer needs to use more often to maintain a steady-state level of nicotine. Nicotine metabolism is faster among females than males after accounting for differences in body weight and some genetic variants.24,25 Sex hormones may drive this difference. Reproductive-age women who use estrogen-containing contraceptives exhibit increased nicotine metabolism, and women taking progestin-only contraceptives or who are postmenopausal exhibit slower nicotine metabolism.25
Changes in nicotine metabolism occur during pregnancy that can deepen tobacco use disorder. Pregnancy increases nicotine metabolism by 50% to 150% through induction of CYP2A6 and other factors.26 As a result, a pregnant woman may experience more rapid onset of withdrawal. It is possible that women who continue to smoke throughout pregnancy may need to smoke more cigarettes or change how they smoke the cigarette (eg, taking longer inhalations from the cigarette or shorter times between inhalations from the cigarette) to achieve higher nicotine concentrations to prevent withdrawal. Furthermore, pregnant women with opioid use disorder experience greater increases in nicotine metabolism and/or clearance, which may partially explain why cigarette smoking is recalcitrant in this population.27,28
Nicotine Pharmacodynamics
Nicotine's pharmacological actions occur when it binds to a subset of acetylcholine receptors named for their sensitivity to nicotine. Nicotinic acetylcholine receptors (nAChRs) are located in muscle cells, sympathetic and parasympathetic neurons, and within the brain. All nAChRs are ion channels that open to allow sodium ions to enter and depolarize the cell. Some nAChR ion channels also allow calcium ions to enter the cell, which stimulates neurotransmitter release and calcium-dependent second messenger activity. The nAChRs in the brain and autonomic nervous system are the most sensitive to nicotine and account for the majority of nicotine's physiological, cognitive, behavioral, and reinforcing effects.
Like many drugs, nicotine causes the release of dopamine in various parts of the brain, including in the ventral tegmental area of the midbrain, considered to be the critical area for drug-based reinforcement and is central to the development of tobacco use disorder. Some of the dopamine release is directly elicited by nicotine, and a larger proportion comes from nicotine facilitating glutamate release and inhibiting [gamma]-amino butyric acid release. Said differently, nicotine makes it easier for other neurons to release dopamine. Dopamine is involved in the experience of pleasurable stimuli and learning new behaviors, and the presence of nicotine facilitating dopamine release seems to increase learning of nicotine-related stimuli and behaviors.
Nicotine produces general physiological arousal, increasing heart and respiratory rates and blood pressure by stimulating neurons in the sympathetic nervous system and causing release of adrenaline and noradrenaline. These effects are dose-dependent, discriminable among nicotine-naive and chronic nicotine users, and generally resistant to development of tolerance. In addition, neuronal activity in the visual system, thalamus, and prefrontal cortex increases after nicotine administration. This increased activity can enhance performance in tasks of reaction time, response rate, and working memory, but is also associated with reductions in accuracy and attention.29 Chronic nicotine use is associated with tolerance to these effects, requiring users of nicotine to increase their consumption to achieve similar enhancements.30
The behaviors associated with using nicotine are also part of tobacco use disorder. In addition to nicotine being a primary reinforcer of nicotine use behavior via its effects on dopamine and alleviation of withdrawal symptoms, nicotine use affects other behaviors and stimuli associated with nicotine use. Through classical conditioning processes, stimuli associated with using a nicotine product become paired with nicotine's reinforcing effects, causing those nonnicotine stimuli to reinforce nicotine use behaviors, even when the nicotine is removed from those products.31 These nonnicotine stimuli include proprioceptive feedback from the body movements associated with using the product, tastes of the product (including flavorings), and sensations provided by the product like heat or cooling from added menthol.
Other environmental stimuli that are experienced around nicotine use, including social reinforcement, may also be enhanced through these processes. These multiple associations between nicotine product use and stimuli can help to sustain use. In several laboratory studies where cigarette smokers could emit responses (pulls on a plunger-like apparatus) to earn puffs from cigarettes, participants made just as many responses for cigarettes that contained no nicotine as they did when the cigarettes contained nicotine when only 1 of the 2 types of cigarettes was available.32 When both types of cigarettes were available, participants regularly made more responses and preferred the cigarettes containing nicotine.33
Overall, it is important to remember that nicotine reinforces multiple behaviors by its pleasurable effects and its resolution of withdrawal symptoms. Stopping use of nicotine products means changing all of these related behaviors, which may be part of why stopping nicotine use is difficult for most people.
Conclusion
Nicotine use has declined for the past several decades. Nicotine use has been slower to decline among rural populations, especially rural women, and is particularly prevalent and recalcitrant among women with substance use disorders. These conditions, and pregnancy, may contribute to tobacco use disorder by changing pharmacokinetics and pharmacodynamics and smoking behaviors in ways that further entrench smoking. By understanding these factors, obstetrician/gynecologists are better able to identify and compassionately support individuals who use nicotine or meet criteria for tobacco use disorder.
REFERENCES