Since 1981, official advisories have warned against the use of alcohol by pregnant women or women considering pregnancy. Yet the 2022 National Survey on Drug Use and Health noted that 11.0% of pregnant women 15 to 44 years of age reported past-month alcohol use; of those, 5.3% reported binge drinking. Not all of these people have alcohol use disorder or are drinking alcohol recklessly. Some may not be aware that they are pregnant or may not be knowledgeable of the adverse effects of alcohol on their pregnancy.

Alcohol is absorbed through the gastrointestinal tract, primarily within the small intestine, and is then metabolized by alcohol and acetaldehyde dehydrogenases. This process leads to the production of acetaldehyde and the reduction of nicotinamide adenine dinucleotide (NAD ⁺ ) to NADH. The intracellular accumulation of NADH relative to NAD ⁺ contributes to metabolic derangements, including the inhibition of fatty acid oxidation (which may result in fatty liver) and the inhibition of gluconeogenesis (which can lead to hypoglycemia or lactic acidosis).

Legally defined “intoxication” implies a blood alcohol ≥ 80 mg/dL, although behavioral, cognitive, and psychomotor changes can occur at levels of 20 to 30 mg/dL (after one to two drinks) ( Table 52.3 ).

Alcohol has complex effects on the central nervous system (CNS); it acts as both a depressant and a stimulant through a variety of neurotransmitter pathways. Consuming alcohol in conjunction with barbiturates or benzodiazepines compounds these effects. Endogenous opioids interact with alcohol to “reinforce” further alcohol use; this effect is blunted by opioid antagonists such as naltrexone, which can be used in the treatment of alcohol use disorder.

Alcohol and its metabolites (e.g., acetaldehyde) can be directly toxic to brain tissue. Chronic alcoholism is associated with brain atrophy that results in impairment of memory, abstract problem-solving, verbal learning, and visual-spatial processing. Additional adverse neurologic effects result from vitamin (e.g., thiamine, vitamin B ₁₂ ) deficiencies.

Heavy alcohol consumption can result in hepatic cirrhosis, which, in turn, can lead to encephalopathy, coagulopathy, and esophageal varices ( Table 52.4 ). Gastrointestinal mucosal injury, pancreatitis, and cardiomyopathy may also occur. In a retrospective cohort study of the Nationwide Inpatient Sample database in the United States, women with a diagnosis of alcohol use disorder undergoing cesarean delivery were twice as likely as women without alcohol use disorder to develop a hospital-acquired infection, including urinary tract infection or sepsis. The underlying pathophysiology was not reported but could be attributable to an immunocompromised state.

Symptoms of acute alcohol withdrawal (e.g., nausea, vomiting, tachycardia, hypertension, arrhythmias, tremors, hallucinations, agitation, seizures) usually occur within 6 to 48 hours after cessation of chronic consumption ( Table 52.5 ). Pharmacologic therapy to minimize the signs and symptoms of alcohol withdrawal includes the use of benzodiazepines and alpha ₂ -adrenergic receptor agonists (e.g., clonidine). Dexmedetomidine, a potent alpha ₂ -adrenergic receptor agonist, has also been investigated as an adjunct therapy. The most severe condition associated with alcohol withdrawal, delirium tremens, manifests as agitation, disorientation, hallucinations, and fever combined with autonomic instability. Delirium tremens, though rare in pregnant women, can lead to maternal and fetal death if untreated.

Intrauterine alcohol exposure is the leading cause of preventable birth defects in the United States. No safe level of alcohol consumption by pregnant women has been identified, as studies investigating minimal to moderate prenatal alcohol exposure during pregnancy have been limited by confounding variables. Fetal alcohol spectrum disorder describes the range of effects that can occur in an individual whose mother drank alcohol during pregnancy. These effects include physical, mental, behavioral, and/or learning disabilities with possible lifelong implications. Fetal alcohol syndrome (FAS) is a clinical diagnosis based on the presence of particular neonatal facial features (e.g., small palpebral fissures; flat mid-face with a short, upturned nose; thin upper lip) and significant impairment in neurodevelopment and physical growth. A range of complications that occur with a high prevalence in children affected by FAS include disorders of conduct and language, chronic serous otitis media, and peripheral nerve abnormalities. Education and screening for prenatal alcohol exposure can facilitate treatment and improve pregnancy outcomes by encouraging cessation of alcohol consumption as soon as pregnancy is recognized.

Alcohol-intoxicated parturients are at increased risk for behavioral problems, electrolyte abnormalities, greater gastric acid secretion, and cointoxication with other substances. Determining whether the patient can protect her airway is of paramount importance because acute intoxication increases the risk for pulmonary aspiration of gastric contents. In addition, these patients may have intravascular volume depletion secondary to vomiting, inadequate oral intake, diuresis, and hypoalbuminemia. Significant alcohol ingestion in the setting of poor oral intake may also manifest as severe hypoglycemia.

Neuraxial analgesia or anesthesia can be safely administered for labor or cesarean delivery in patients with alcohol use disorder provided that (1) the patient is cooperative, (2) there is no evidence of coagulopathy (as a result of liver disease), (3) the patient is volume replete, and (4) baseline neurologic deficits (e.g., peripheral neuropathy, cognitive deficits) are assessed and documented.

If emergency delivery is required and the patient is either uncooperative or too sedated to protect their airway, general anesthesia will be necessary. The patient should receive pharmacologic aspiration prophylaxis (e.g., nonparticulate antacid, histamine-2 [H ₂ ]-receptor antagonist, metoclopramide) and should undergo a rapid-sequence induction of general anesthesia with tracheal intubation (see Chapter 26 ).

Evidence from published reports is inconclusive about predictable differences in anesthetic requirements in patients with acute and chronic alcohol use. Acute alcohol intoxication is believed to decrease anesthetic requirements, in part because of the additive effect of alcohol and other CNS depressants. Findings from two small studies suggest that the propofol dose required to induce anesthesia in chronic alcoholic patients is higher than in patients who drink alcohol socially. However, no large population studies have assessed dose requirements for volatile anesthetic agents or hypnotic agents in patients who chronically drink alcohol.

Short-term consumption of alcohol inhibits the metabolism of drugs by the liver through competition for cytochrome P450, which results in higher plasma concentrations of hepatically metabolized drugs. Long-term consumption of alcohol increases the activity of cytochrome P450, resulting in decreased levels of medications such as diazepam and labetalol and increased levels of toxic metabolites from hepatic degradation of illicit drugs such as cocaine (see Chapter 16 ). Both pregnancy and liver disease can lead to decreased plasma concentrations of pseudocholinesterase; however, this does not seem to have a clinically significant effect on the degradation of succinylcholine or ester local anesthetic agents.

Pregnant women who regularly consume large amounts of alcohol and undergo general anesthesia for cesarean delivery may be at high risk for awareness under anesthesia. The high doses of volatile anesthetic agents often recommended in nonpregnant, chronic alcohol-using patients can lead to significant uterine atony and potential increased blood loss. Therefore, a balanced anesthetic technique with a generous dose of hypnotic agent and optimal neuromuscular blockade (e.g., with succinylcholine) for induction, followed by maintenance with a volatile anesthetic agent (limited to 0.5 MAC [minimum alveolar concentration] after delivery to prevent uterine atony), nitrous oxide, and an opioid and benzodiazepine (for analgesia and amnesia) should be considered. For postoperative pain management, a transversus abdominis plane (TAP) block or alternative regional anesthetic technique (e.g., erector spinae plane block, quadratus lumborum block) may be performed, in conjunction with the administration of systemic nonopioid analgesic medications, to reduce or eliminate the use of opioids (see Chapter 27 ). Withholding additional muscle relaxation after induction and adding a brain function monitor if the circumstance permits may help identify patients who could benefit from additional anesthesia.

On a daily basis, 80% to 98% of women drink caffeine-containing beverages. Dietary caffeine consumption during pregnancy is common in the United States, although the quantity appears to decrease after pregnancy recognition.

Caffeine (1,3,7-trimethylxanthine) is a naturally occurring alkaloid found in coffee, tea, cocoa, caffeinated soft drinks and energy drinks, and medicines. The primary sources of caffeine in the adult diet are coffee (56 to 100 mg/100 mL if brewed) and tea (20 to 73 mg/100 mL). Caffeine is readily absorbed through the gastrointestinal tract and reaches maximum blood concentrations 1 to 1.5 hours after ingestion. Caffeine undergoes hepatic metabolism and is excreted in the urine. In pregnancy, the half-life increases from 4 hours in the first trimester to 11.5 to 18 hours by the third trimester. Caffeine crosses the placenta and can also be found in breast milk. The half-life in the neonate is prolonged compared with that in children and in nonpregnant women. Habitual use of caffeine at levels greater than 500 to 600 mg/day is defined in some studies as abuse.

Caffeine acts as an antagonist to the adenosine receptor. In the absence of the inhibitory effects of adenosine, the neurotransmitters norepinephrine, dopamine, and serotonin are released in increased concentrations. Systemic effects of caffeine include CNS stimulation, changes in blood pressure and metabolic rate, and diuresis (see Table 52.3 ). The side effects attributed to caffeine vary among individuals, in part related to the dose ingested and the chronicity of use. Studies of the effects of caffeine on alertness, vigilance, mood, and memory have produced inconsistent results.

Moderate caffeine intake for nonpregnant women is defined as less than 400 mg/day (3 to 5 cups/day), whereas moderate consumption during pregnancy is defined as less than 200 mg/day (1 to 2 cups/day). In general, moderate consumption does not seem to negatively affect cardiovascular health in most people. Although some people who ingest caffeine report tachycardia and palpitations, doses < 450 mg/day do not appear to increase significant cardiac arrhythmias in healthy people or those with ischemia or ventricular ectopy. Caffeine doses as low as 250 mg have been reported to have a hypertensive effect after acute ingestion (an increase in systolic blood pressure of 5 to 15 mm Hg and an increase in diastolic blood pressure of 5 to 10 mm Hg), particularly in caffeine-naïve individuals; however, epidemiologic studies have produced inconsistent results. Caffeine appears to affect bladder function; moderate caffeine intake may exacerbate preexisting bladder symptoms, and excessive intake (>400 mg/day) may increase the risk for bladder dysfunction.

Evidence suggests that caffeine is not a human carcinogen. The lethal dose of caffeine in humans is estimated to be 10 g; however, only a few such cases have been reported.

Caffeine withdrawal is associated with headache, anxiety, depressed mood, and fatigue (see Table 52.5 ). Typically, symptoms begin 12 to 24 hours after cessation of use, peak at 20 to 48 hours, and last up to 7 days. The severity and likelihood of symptoms are not predictable.

Caffeine readily crosses the placenta and in lower doses (i.e., 8 mg/kg) does not appear to cause a decrease in uterine blood flow or fetal oxygenation. Whereas animal studies have shown a teratogenic effect with very high doses, moderate doses of less than 200 mg/day in pregnancy do not appear to result in teratogenesis in humans. A 2021 study and a 2023 systematic review and metaanalysis reported an association between maternal caffeine consumption, even in amounts less than 200 mg/day, and intrauterine growth restriction and decreased birth weight. Moderate caffeine intake (<200 mg/day) during pregnancy does not appear to be a major contributing factor in spontaneous abortion or preterm birth. Weng et al. found an increased risk of miscarriage with increasing caffeine consumption, with an adjusted hazard ratio of 2.23 (95% confidence interval [CI], 1.34 to 3.69) for consumption greater than 200 mg/day, but other studies have reached contradictory conclusions.

Moderate first-trimester caffeine intake was found to have either no significant effect or to have a protective effect on the development of maternal gestational diabetes mellitus, depending on the population studied. Moderate intake of caffeine in lactating women does not appear to adversely affect postnatal development.

Perhaps of greatest significance to the anesthesia provider is the potential for caffeine withdrawal headache from abrupt caffeine cessation during the peripartum period. Caffeine withdrawal should be considered in a postpartum patient with a nonspecific, nonpositional headache without associated lateralizing neurologic findings (see Chapter 30 ). There is no compelling evidence that caffeine is effective in the treatment of post–dural puncture headache (see Chapter 30 ).

As public awareness has grown regarding the hazards of smoking during pregnancy, the prevalence of cigarette smoking during pregnancy has declined. An estimated 13.6% of pregnant women reported past-month smoking in 2015, compared to 5.5% in 2022. However, the use of electronic cigarettes (e-cigarettes), which have been marketed as a safe alternative to cigarette smoking, has been steadily increasing. Studies estimate the prevalence of “vaping” during pregnancy between 0.6% and 15%. As the dose of nicotine consumed by patients who use e-cigarettes is thought to be comparable to that consumed by cigarette smokers, the US Food and Drug Administration ruled in 2016 that electronic nicotine delivery systems should be subject to the same regulations as cigarettes.

More than 4000 chemicals are found in tobacco, including nicotine, carbon monoxide, and cyanides. Tobacco is most often smoked, but it can also be chewed or sniffed. Nicotine, the principal component of tobacco, can be extracted from tobacco and administered electronically via e-cigarettes, vaporizers, vape pens, hookah pens, mod or pod systems, and e-pipes. Nicotine acts at peripheral and central nicotinic (acetylcholine) receptors throughout the body to affect the release of catecholamines. Its effects begin immediately upon exposure, and the half-life is typically a few hours; it is metabolized in the liver and the lungs and excreted by the kidneys. Nicotine’s acute effects are of a shorter duration in heavy smokers than in light smokers.

Carbon monoxide, which is formed by the incomplete combustion of tobacco and charcoal in cigarettes and water pipes (i.e., hookahs), interferes with oxygen delivery to the cells by competitively binding to hemoglobin, decreasing the latter’s oxygen-binding capacity and shifting the oxyhemoglobin dissociation curve to the left. Depending on the extent of smoke inhalation, carbon monoxide may occupy 3% to 15% (or more) of the oxygen-carrying capacity of the blood.

Electronic nicotine delivery systems contain solvent carriers (e.g., propylene glycol, glycerol) to produce aerosols that resemble cigarette smoke, and may contain flavoring. The health consequences of these substances on the mother and fetus are largely unknown.

Peripherally, nicotine increases sympathetic tone, thereby increasing maternal heart rate, blood pressure, and cardiac work (see Table 52.3 ). Nicotine affects neurotransmitter release in different areas of the brain, producing feelings of alertness, euphoria, and, ultimately, dependence.

Increased production of carboxyhemoglobin is thought to be a major factor in the impaired wound healing observed in smokers. Smoking also promotes atherosclerosis. The pulmonary effects of tobacco smoking include increased volume of mucus, impaired mucociliary clearance, and an increased incidence of bronchitis and chronic obstructive pulmonary disease (see Table 52.4 ).

Tobacco is addictive, and cessation of its use produces withdrawal symptoms of cravings, irritability, headache, cough, and insomnia (see Table 52.5 ). Smoking cessation interventions include counseling and therapy, hypnosis, acupuncture, and pharmacologic therapy. There is insufficient evidence to recommend nicotine replacement therapy (e.g., nicotine patch) in pregnancy; the American College of Obstetricians and Gynecologists (ACOG) recommends that it be used only after a detailed discussion with the patient of the possible risks of pharmacotherapeutic smoking cessation agents, the known risks of continued smoking, and the need for close supervision.

Significant perinatal risks are associated with cigarette smoking and alternative nicotine delivery products during pregnancy. Nicotine has a low molecular weight and readily crosses the placenta, eventually yielding higher fetal than maternal nicotine concentrations. Nicotine intake in any form during pregnancy has known adverse effects on fetal lung and brain tissue. Smoking cigarettes may result in decreased fetal oxygenation because of increased concentrations of carboxyhemoglobin and reduced uteroplacental perfusion. This compromised state can lead to decreased uptake of nourishing amino acids by the placenta. Smoking also adversely affects fetal growth. Smoking cessation in early pregnancy has been associated with a greater reduction in risk for intrauterine growth restriction compared with cessation later in pregnancy.

Cigarette smoking during pregnancy is also associated with orofacial clefts, low birth weight, spontaneous fetal loss, preterm premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, and increased perinatal mortality. Children born to mothers who smoke during pregnancy have a higher incidence of asthma and respiratory infections. Paradoxically, smoking has been associated with a reduced risk for preeclampsia, although this may be related to the higher rates of early pregnancy loss among pregnant smokers (see Chapter 35 ).

Although the negative impact of fetal tobacco exposure on growth appears to resolve by 2 years of age, there may be other long-term effects. A growing number of studies indicate that prenatal tobacco exposure may be associated with an increased risk for attention deficit/hyperactivity disorder, although it is not clear whether the relationship is causal. Holz et al. examined offspring exposed to prenatal cigarette smoking using functional magnetic resonance imaging in a prospective 25-year study. After controlling for confounders, including adversity and sex, prenatal smoking exposure appeared to have long-term effects on neural activity and development. A study by Quinn et al. suggested this association may be caused by confounding effects of other lifestyle and genetic issues; when cousins and siblings discordant on prenatal smoking and severe mental illness were compared, increased risk for severe mental illness in the smoking-exposed newborns was not observed.

Limited studies have reported that infants born to women who use smokeless tobacco during pregnancy have comparable rates of low birth weight, stillbirth, shortened gestational age, and neonatal apnea to those infants born to women who smoked cigarettes during pregnancy. Data derived from animal studies suggest that the nicotine exposure from e-cigarette use during pregnancy appears to have similar harmful effects on lung development and offspring lung health as conventional cigarettes. More research is needed to quantify the perinatal effects of alternative nicotine and tobacco delivery products.

Cigarette smoking is a risk factor for several perioperative complications, including respiratory sequelae and impaired wound healing. Smoking results in increased airway secretions, decreased ciliary motility, and impaired gas exchange. Smoking is also associated with an increase in nonspecific airway reactivity; tracheal intubation may provoke bronchospasm. Smokers may be more likely to cough following emergence from general anesthesia, but the data are mixed and may be related to the specific volatile anesthetic agent used.

The physiologic benefits of smoking cessation are progressive. Even brief smoke-free intervals can result in a reduction in the carboxyhemoglobin concentration, some improved ciliary function, and decreased small airway obstruction. However, 6 months of abstinence may be required before the function of alveolar macrophages and pulmonary cytokines during and after general anesthesia in former smokers is similar to that of nonsmokers. Neuraxial anesthesia avoids airway manipulation and is typically preferred in parturients who smoke.

Emerging evidence suggests that the inhaled agents and byproducts from e-cigarettes with and without nicotine may increase the risk of perioperative complications. Like combustible tobacco products, e-cigarette use results in increased airway reactivity and, with chronic use, reversible obstructive lung disease. General surgical patients are advised to abstain from e-cigarette use for 6 weeks prior to elective procedures and may benefit from administration of a short-acting beta-adrenergic agonist, such as albuterol. E-cigarette users may also present with elevated blood pressure and tachycardia, which are known effects of nicotine. New-onset hypertension in pregnancy resulting from recent nicotine intake must be distinguished from preeclampsia. Inhalation of vaping aerosols from e-cigarettes with or without nicotine may increase platelet aggregation, resulting in an increased risk of thrombosis. Nicotine from e-cigarettes impairs wound healing because of decreased blood flow to the surgical site and impaired inflammatory response.

Women of reproductive age may use methamphetamines for a variety of reasons, including appetite suppression, weight loss, and a means of coping with stress. According to the 2021 National Survey on Drug Use and Health, 0.9% of pregnant women reported past-month methamphetamine use compared with 0.6% of nonpregnant women aged 15 to 44 years. In endemic areas, however, the estimated prevalence ranges from 0.7% to 5%. Survey data from 2021 reported 0.2% past-month MDMA use among pregnant women compared with 0.4% among nonpregnant women 15 to 44 years of age. Polydrug use in women who use methamphetamine and MDMA appears to be common.

Amphetamines (and related compounds) are amines that exist as either salts of various acids or free bases. Used illicitly, they can be ingested orally, inhaled, or, less commonly, injected, resulting in significant CNS penetration. The plasma half-life ranges from 5 to 30 hours. Metabolism is variable; up to 30% of the parent compound can be found in the urine. Detection of these compounds and their metabolites in the urine is possible up to several days after ingestion.

Methamphetamine (“speed,” “meth,” “ice,” or “crystal”) is a congener of amphetamine that contains a methyl radical. This white, odorless, bitter-tasting powder can be smoked, snorted, ingested orally, or administered rectally. Its availability is facilitated by production in low-cost home laboratories. Methamphetamine is more potent than amphetamine and has a longer half-life; 50% of the drug is cleared in 12 hours. When it is smoked or injected intravenously, the “flash” from this drug is intense and of short duration. Snorting produces euphoria within 5 minutes, while oral ingestion takes approximately 20 minutes.

The use of MDMA during pregnancy is increasingly common in the United States. MDMA has a methylenedioxy group attached to the aromatic ring of the amphetamine molecule that confers some of its hallucinogenic effects (see later discussion). The effects of MDMA typically begin approximately 20 minutes after ingestion and last approximately 6 hours; large doses have effects for up to 2 days. MDMA is metabolized by the liver and excreted by the kidneys.

The “club” drug, gamma-hydroxybutyric acid (GHB), also known as liquid ecstasy or liquid X, is derived from gamma-aminobutyric acid (GABA), which readily enters the brain when ingested, producing hallucinogenic, anxiolytic, euphoric, and sedative effects. Severe cardiorespiratory depression, coma, and seizures can occur at high doses. Overdose is common, owing in part to the variable individual responses to the drug. Chronic use may be associated with a downregulation of GABA receptors, and withdrawal manifests as insomnia, tachycardia, hypertension, and nausea/vomiting.

Another designer drug of the phenethylamine class is 3,4-methylenedioxypyrovalerone, also known as “bath salts.” Typically sold in crystal or powder form that can be snorted, smoked, or injected, this substance acts as a norepinephrine and dopamine reuptake inhibitor. It is not detected by common drug screening tests. Adverse effects resemble those of amphetamines (e.g., agitation, hypertension, tachycardia), and dependence and withdrawal can occur. In rare instances, it can cause severe hyperthermia or hyponatremia. The DEA banned the active ingredients in bath salts after several deaths were reported.

Acute amphetamine ingestion leads to indirect sympathetic activation through the release of norepinephrine, dopamine, and serotonin from adrenergic nerve terminals (see Table 52.3 ). The physiologic effects of amphetamines are similar to those of cocaine and other stimulants, with two important differences: (1) amphetamines and their derivatives lack local anesthetic properties and (2) amphetamine can inhibit monoamine oxidase activity, leading to decreased degradation of catecholamines.

Long-term, unrestricted use of high doses of amphetamines can have a number of adverse maternal effects, including damage to the cardiovascular and neurologic systems as well as behavioral changes such as hostility, violence, hallucinations, and paranoid psychosis (see Table 52.4 ). Methamphetamine is slow to metabolize and has a much longer duration of action than cocaine.

The cardiovascular effects of amphetamines and their derivatives are similar to those of cocaine : vasoconstriction, tachycardia, and labile blood pressure. Patients are typically hypertensive, although catecholamine depletion can result in hypotension. Arrhythmias, myocardial ischemia, endothelial damage, dilated cardiomyopathy, and acceleration of atherosclerosis can also occur. Indeed, cardiovascular disease-related mortality is the leading cause of death among chronic methamphetamine users. Recommendations for the management of cardiovascular complications include resuscitation using intravenous fluids or judicious use of phenylephrine for hypotension. If pharmacotherapy is needed to treat hypertension, then labetalol, an alpha- and beta-adrenergic receptor antagonist, may be preferred over a pure beta-adrenergic receptor antagonist. Direct vasodilators (e.g., nitrates or hydralazine) can be used but may exacerbate tachycardia. Acute amphetamine intoxication may result in severe headache, hypertension, and seizures, and can mimic the signs and symptoms of severe preeclampsia or eclampsia.

The pleasurable effects of methamphetamine and the deleterious neurologic sequelae are believed to be the result of high levels of dopamine in the brain. In addition to positive feelings, patients who have taken methamphetamine may experience anxiety, mood disturbances, paranoia, and hallucinations. Severe intracranial hypertension and hemorrhagic stroke have been reported in the setting of acute use. Chronic use has been associated with impairment of motor function and verbal learning, as well as with significant changes in the areas of the brain associated with memory and emotion (see Table 52.4 ). Volkow et al. observed that prolonged abstinence (12 to 17 months) resulted in significant recovery of brain dopamine transporters, although performance on neuropsychologic tests did not improve to the same extent. In addition, psychotic features of long-time amphetamine use may be precipitated by stress in former users after months or even years of abstinence.

MDMA use has been associated with numerous adverse effects, including hyperthermia, hyponatremia, and seizures. Healthy volunteers given MDMA in experimental settings have demonstrated CNS effects that include enhanced mood and heightened awareness, as well as a dose-dependent moderate increase in blood pressure. Recreational MDMA use has also been associated with neurohormonal changes, including increased cortisol and oxytocin.

Psychostimulant withdrawal causes fatigue, depression, hunger, and intense cravings (see Table 52.5 ). Pharmacologic therapy for stimulant withdrawal (e.g., tricyclic antidepressants, dopaminergic agents [e.g., bromocriptine], amino acid replacement therapy) has not been particularly successful. Seizures, severe hypertension, and hyperthermia from methamphetamine overdose can be fatal. Treatment goals include provision of a calm environment (with or without a benzodiazepine) and airway protection. Active cooling, antihypertensive agents, and anticonvulsants should be used as needed.

Further research is needed to evaluate the long-term effects of prenatal exposure to supratherapeutic doses of amphetamines. Amphetamine ingestion results in high levels of circulating catecholamines, which may lead to vasoconstriction and decreased uteroplacental blood flow. Animal studies have suggested that intrauterine exposure to methamphetamine is associated with an increased incidence of retinal defects, cleft palate, and rib malformations as well as a decreased overall rate of growth and motor development. Results from a retrospective cohort study indicate that methamphetamine use in pregnant women was associated with an increased risk for gestational hypertension, preeclampsia, fetal death, abruption, preterm birth, neonatal death, and infant death. A 2018 metaanalysis of retrospective, case-controlled studies found that methamphetamine use during pregnancy resulted in lower neonatal birth weight, head circumference, and body length compared to control pregnancies, but found no difference in the incidence of maternal hypertension or preeclampsia. Studies of the potential long-term effects on neonatal neurodevelopment and cardiovascular outcomes are limited by a small sample size and confounding factors. Findings from the Infant Development, Environment and Lifestyle study and the National Institute on Drug Abuse suggest that children prenatally exposed to methamphetamine appear to be at a higher risk for impaired executive function, attention deficit/hyperactivity disorder, and increased aggressive behavior, although early adversity (e.g., abuse or neglect) is a likely confounding variable. Effects on language and cognition and gross motor development appear to be transient or negligible, respectively.

Amphetamines cause indirect sympathetic activation. Intoxicated patients are at risk for dangerous cardiovascular events, including hemodynamic instability and cardiac arrest.

Recommendations for anesthetic management of patients with amphetamine and cocaine toxicity are similar. A cooperative patient may be a candidate for neuraxial analgesia or anesthesia, although refractory hypotension has been reported in a long-time amphetamine user who received neuraxial anesthesia with intravenous propofol sedation. The authors attributed the response to downregulation of beta-adrenergic receptors and catecholamine depletion. As with cocaine, phenylephrine may be a better choice for the treatment of hypotension than ephedrine; as an indirect-acting agent, ephedrine may cause an exaggerated hemodynamic response if circulating catecholamines are high or, alternatively, be ineffective if catecholamines are depleted.

Parturients who use amphetamines may be at increased risk for urgent cesarean delivery requiring general anesthesia. Evidence from animal studies suggests that acute ingestion of amphetamines increases the MAC for volatile halogenated anesthetic agents, whereas chronic ingestion of amphetamines decreases the MAC of volatile agents. There is a well-recognized association between methamphetamine use and severe tooth decay (i.e., “meth mouth”), which can present a significant hazard during laryngoscopy. The airway assessment should include attention to fragile or loose teeth that might be dislodged during laryngoscopy as well as to the possibility of burns throughout the airway. High doses of MDMA can cause rhabdomyolysis.

The prevalence of cocaine use during pregnancy is difficult to estimate as 60% to 90% of pregnant cocaine users engage in polysubstance use, including tobacco. Survey data in 2021 reported the prevalence of past-month cocaine use in pregnant women 15 to 44 years of age as 0.2%.

Cocaine is an ester of benzoic acid and the base ecgonine, which is the parent compound of atropine and scopolamine. When dissolved in hydrochloric acid to form a water-soluble powder (cocaine hydrochloride), cocaine can be chewed, administered intravenously (“mainlined”), or taken intranasally (“snorted”). Intrarectal and intravaginal use has also been reported. When cocaine is processed with either sodium bicarbonate (“crack”) or ammonia and ether (“free base”), the resulting cocaine alkaloid can be smoked. The amount and duration of exposure are more important determinants of cocaine’s effects than the chemical formulation. Smoked cocaine (“crack” or free base) is rapidly absorbed through the lungs and reaches the brain in 6 to 8 seconds; intravenous cocaine reaches the brain in 12 to 16 seconds; and snorted cocaine reaches the brain in 3 to 5 minutes. The typical half-life of cocaine is 30 to 90 minutes, although its effects can last as long as 6 hours.

Cocaine is metabolized to ecgonine esters and benzoylecgonine (biologically inactive) by plasma and hepatic cholinesterases and to norcocaine (biologically active) by nonenzymatic hydrolysis. Only small amounts of cocaine are excreted unchanged in the urine. In the presence of alcohol, cocaine is transesterified to cocaethylene, which has a longer half-life and greater physiologic effects than cocaine.

Cocaine has complex actions on the central and peripheral nervous systems and on nerve conduction. The powerful sympathomimetic effects of cocaine are caused by the drug’s inhibition of the reuptake of norepinephrine, dopamine, and serotonin, which allows these neurotransmitters to accumulate at the synaptic clefts and produce sustained stimulation. This process can result in as much as a fivefold increase in circulating concentrations of catecholamines, which, in turn, may lead to feelings of euphoria, increased energy, and decreased fear. Repetitive use of cocaine eventually leads to depletion of neurotransmitter stores, upregulation of receptors, and a higher dose requirement to achieve the desired euphoric effects.

The peripheral nervous system effects of cocaine and its derivatives result from binding to tissue receptors involved in monoamine reuptake, which results in hypertension and/or labile blood pressure and tachycardia. Cocaine produces widespread small- and large-vessel occlusion through vasospasm, thrombosis, and endothelial injury, which may result in significant end-organ damage.

Cocaine has profound effects on the cardiovascular system, and pregnancy appears to enhance them. Acute administration of cocaine increases peripheral vascular resistance, cardiac contractility, and myocardial oxygen demand (see Table 52.3 ). Coronary vasoconstriction also occurs; a greater effect occurs in diseased vessel segments than in nondiseased segments. Studies in vitro indicate that cocaine can have a procoagulant effect in small and large vessels. This may lead to thrombus formation and coronary plaque rupture in the setting of cocaine-induced hypertension.

Cocaine-induced chest pain is a common complaint among young people presenting to the emergency department. Mittleman et al. found that cocaine use was associated with a significant, abrupt, and transient increase in the risk for acute myocardial infarction in patients who were otherwise at low risk. The occurrence of cocaine-induced electrocardiographic changes is fairly common and is not necessarily associated with true ischemia. If ischemia is suspected, treatment with supplemental oxygen, aspirin, and vasodilators, with or without reperfusion therapy, as well as measurement of troponin levels, is indicated. Although cocaine users who suffer a myocardial infarction have fewer postinfarction sequelae than the general population, the incidence of major cardiovascular complications is not trivial; 5% to 7% have congestive heart failure, 4% to 17% have ventricular arrhythmias, and up to 2% die. Prompt recognition of acute cocaine-induced cardiovascular toxicity facilitates management.

Not all cocaine-induced hypertension in pregnant women requires immediate intervention, but if pharmacotherapy is used, it is important to understand the potential undesired consequences. Beta-adrenergic receptor blockade may result in unopposed alpha-adrenergic receptor–mediated vasoconstriction that can lead to coronary artery vasoconstriction and myocardial failure. Labetalol, an alpha- and beta-adrenergic receptor antagonist, may be preferred, although it does not fully ameliorate cocaine-induced coronary artery vasoconstriction. Direct vasodilators (e.g., nitrates, hydralazine) can be used but may cause further tachycardia and, in the case of hydralazine, may not restore uterine blood flow. Calcium entry-blocking agents, such as nifedipine and nimodipine, have been found to potentiate the toxic effects of cocaine in animal models, although the mechanism has not been determined. Based on a 2016 systematic review, benzodiazepines and other GABA-active agents are among the pharmacologic treatments that may at least partially mitigate tachycardia, hypertension, dysrhythmia, and coronary vasospasm associated with acute cocaine toxicity. High-quality randomized prospective studies are needed to further elucidate the optimal treatment.

Other acute cardiovascular effects of cocaine include QT prolongation, bradycardia, and arrhythmias, including supraventricular or ventricular tachycardia and ventricular fibrillation. Severe bradycardia can be treated with atropine or electrical pacing. Stable supraventricular tachycardia (SVT) can be treated with vagal maneuvers or with adenosine. In the unstable patient with SVT, direct current (DC) cardioversion may be required.

In a retrospective multicenter study, Shih et al. found that the therapeutic use of lidocaine in nonpregnant patients with cocaine-induced myocardial infarction did not potentiate the cardiovascular or CNS effects of cocaine. Although amiodarone therapy for maternal and fetal arrhythmias has been described as having only minor adverse effects in some patients, there are reports of associated fetal hypothyroidism and fetal growth restriction (see Chapter 41 ). Thus, amiodarone in pregnant women is reserved for malignant arrhythmias that are refractory to other therapies.

Long-time cocaine use can cause left ventricular hypertrophy or dilated cardiomyopathy with accompanying systolic dysfunction (see Table 52.4 ). Aortic dissection has also been reported. Intravenous use of cocaine and other injectable drugs increases the risk for development of infective endocarditis. Noncardiogenic pulmonary edema, pulmonary hypertension, and right-sided heart failure can also occur in the setting of cocaine use.

The neurologic complications of cocaine may be transient or permanent. Morbidity and mortality may result from subarachnoid hemorrhage, intracerebral hemorrhage, cerebral vasculitis, transient ischemic attacks, and/or cerebral infarcts, particularly in the setting of additional risk factors, such as hypertension, alcohol, or smoking. Cocaine-induced seizures, if self-limited, are typically treated with supportive care and benzodiazepines.

Respiratory complications occur in 25% of cocaine users. Smoking cocaine can have profound respiratory effects, which include bronchospasm, chronic cough, and diffusion capacity abnormalities. Pregnant women who use cocaine are at increased risk for peripartum wheezing. Inhaled cocaine vapor can produce thermal airway burns. “Snorting” cocaine can lead to epistaxis, oral ulcers, and nasal septal injury. The intense pulmonary and bronchial arterial vasoconstriction produced by cocaine can cause interstitial and alveolar hemorrhage. Pneumothorax, pneumomediastinum, and pneumopericardium have also been reported.

Cocaine ingestion can result in serious gastrointestinal complications, such as ischemia, ulceration, and perforation. Cocaine’s anticholinergic effects include delayed gastric emptying and an increased risk for aspiration. Although some cocaine users have abnormal liver enzyme levels, cocaine is not clearly hepatotoxic.

Hematologic consequences of cocaine exposure during pregnancy may, in rare instances, include thrombocytopenia. Whereas Kain et al. found the rate of thrombocytopenia to be higher in the cocaine group than in the drug-free group (6.7% versus 1.5%, respectively), Gershon et al. found that in pregnant women who tested positive for cocaine, only 2.5% had a platelet count < 140,000/μL, compared with 4.7% in the cocaine-negative group.

Renal failure can result from cocaine use secondary to rhabdomyolysis, renal infarction, or impaired immunologic function. Cocaine-using patients have a higher prevalence of syphilis, human immunodeficiency virus (HIV) infection, and other infectious diseases compared with noncocaine-using patients, even after controlling for intravenous drug use. Studies of the endocrine system in gravid ewes have shown that cocaine exposure results in increases in maternal adrenocorticotropic hormone and cortisol, as well as maternal and fetal plasma glucose and lactate. Cocaine also impairs cutaneous vasodilation and sweating. The lethal effects of cocaine are related, in part, to the drug’s tendency to produce hyperthermia , particularly in hot weather. Cocaine use has been associated with sudden death from several of the factors discussed earlier, including cardiac arrhythmias, respiratory arrest, status epilepticus, and impaired thermoregulation.

Cocaine withdrawal can be difficult to recognize because of its nonspecific signs and symptoms: extreme fatigue followed by hunger, anxiety, weakness, headache, tremors, and seizures (see Table 52.5 ). Recommended therapy involves supportive care and a slow taper over days to weeks.

Pregnant women metabolize cocaine to norcocaine to a greater extent than their nonpregnant counterparts, exposing both mother and fetus to this more potent metabolite. With its low molecular weight and high lipophilicity, it is mostly un-ionized at physiologic pH and readily crosses the placenta. Generalized vasoconstriction from cocaine and its metabolites may result in utero placental insufficiency, acidosis, and fetal hypoxia.

In a 2011 metaanalysis, Gouin et al. found that cocaine use during pregnancy was associated with significantly higher risk for preterm birth, low birthweight, and small-for-gestational-age infants. Obstetric complications associated with maternal cocaine use include a higher incidence of placental abruption and preterm labor; the latter occurs in 17% to 29% of pregnant women who use cocaine. Several small studies and case reports also suggest an increased risk of spontaneous abortion, stillbirth (likely related to placental abruption), and uterine rupture. Acute cocaine toxicity can mimic preeclampsia or eclampsia when pregnant women present with severe hypertension, hyperreflexia, headache, blurred vision, and/or seizures, but it can be differentiated through a positive urine test result for cocaine, the presence of normal laboratory measurements, and rapid resolution of symptoms without delivery. There is also an association between cocaine use and an increased risk for sexually transmitted diseases and failure to obtain prenatal care.

The impact of maternal use of cocaine (particularly “crack”) on the fetus has been the subject of intense legal, political, and scientific debate since the 1980s. Initial animal data and retrospective human studies suggested an increased risk for major congenital anomalies (e.g., genitourinary and abdominal wall defects) in fetuses exposed to cocaine. However, these reports are confounded by concurrent use of other drugs and low statistical power. Subsequent studies found no significant difference in type or number of congenital anomalies between infants with exposure to cocaine in utero and infants without exposure, after accounting for confounding variables.

Frank et al. reviewed studies published between 1984 and 2000 to assess the possible relationships between maternal cocaine use during pregnancy and childhood outcomes. After controlling for possible confounding factors, they found no consistent negative association with physical growth, developmental test scores, or expressive or receptive language skills. They observed less optimal motor performance up to 7 months of age, after which the differences between cocaine-exposed and nonexposed infants disappeared.

Studies investigating trajectories of motor, mental, or behavioral development in infants with prenatal cocaine exposure have had conflicting results, in part related to confounding risk factors such as exposure to adverse postnatal environments. In a 15-year follow-up study of adolescents prenatally exposed to cocaine, Richardson at al. noted that exposure to violence partially mediated the impact on (self-reported) delinquent behaviors by the adolescents. In addition, the first-trimester-exposed adolescents had poorer performance on tests related to problem solving and abstract thinking. Definitive assessment of long-term outcomes of children exposure to cocaine in utero remain elusive.

In terms of other health consequences, Bauer et al. found that infectious complications, such as hepatitis, syphilis, and, to a lesser extent, HIV infection, were more common in infants of women who ingest cocaine.

Pregnant women who use cocaine are at risk for acute and chronic multiorgan system dysfunction and the need for urgent cesarean delivery. During labor, early administration of neuraxial anesthesia should be encouraged if the patient is cooperative and has a platelet count above the threshold recommended by professional society guidelines. Neuraxial anesthesia can reduce circulating levels of catecholamines and mitigate some of the systemic effects of cocaine. Also, an epidural catheter placed for labor analgesia can usually be used to provide anesthesia for an intrapartum cesarean delivery, if needed. Treatment of hypotension should include volume resuscitation, and, if needed, careful titration of a direct-acting vasopressor, such as phenylephrine.

When an ester local anesthetic agent (or succinylcholine) is administered to a patient who has ingested cocaine, these medications may compete with cocaine for available plasma cholinesterase ; however, the clinical significance of these effects, if any, is unknown. Despite the theoretical risk for altered metabolism of succinylcholine, a standard intubating dose should be administered. Changes in mu- and kappa-opioid receptors and altered baseline endorphin levels may result in an increased perception of pain in cocaine-using patients despite the presence of an apparently satisfactory level of neuraxial anesthesia. Ross et al. observed a reduced duration of intrathecal sufentanil analgesia during labor in parturients who used cocaine, although the quality of analgesia was not diminished.

Patients who ingest cocaine and receive general anesthesia are at greater risk for hypertension and tachycardia during and after laryngoscopy and tracheal intubation. If general anesthesia is required, premedication with a benzodiazepine may help attenuate the acute physiologic effects of cocaine. As the anticholinergic effects of cocaine can delay gastric emptying and may also increase the risk for pulmonary aspiration, pharmacologic prophylaxis and a rapid-sequence induction of general anesthesia are indicated. Propofol may be well tolerated, whereas ketamine may potentiate the CNS vasoconstrictive effects of cocaine, potentially increasing the risk for cerebrovascular morbidity. Both etomidate and cocaine can result in disinhibition of CNS control of extrapyramidal activity, and their effects may be additive. Dexmedetomidine, an alpha ₂ -adrenergic receptor agonist, has been shown in animal studies to delay the onset of cocaine-induced seizures and may be useful in selected patients. Early studies in dogs demonstrated that acute cocaine ingestion can cause hyperthermia in both laboratory animals and humans ; therefore, the core temperature should be monitored in patients with acute cocaine intoxication. However, given the propensity for nasal septal defects in these patients, temperature probes (and other tubes and monitors) should not be inserted intranasally. Active warming should be used only if the patient is hypothermic.