TOPICS

INTRODUCTION

The prevalence of substance abuse in women of reproductive age has increased markedly over the past 20 years. Thus, it is likely that an anesthesiologist will encounter a pregnant woman who abuses illicit drugs.¹ A combination of drug abuse and related social ills can lead to poor fetal outcomes and serious maternal morbidity or even mortality.² Anesthesiologists are likely to first meet drug-abusing parturients in an acute setting, either when labor analgesia is requested or in an emergency situation such as fetal distress, placental abruption, uterine rupture, or sudden onset of maternal dysrhythmias. These women often have not had the benefit of prenatal care. Risk factors associated with drug abuse include lack of prenatal care, history of premature labor, and cigarette smoking.³ The possibility of drug abuse should also be considered if there is an unanticipated untoward reaction to an otherwise routine anesthetic.

Polysubstance abuse is common among drug abusers. It has been estimated that 50% of unregistered patients admitted to labor and delivery test positive for cocaine and that 25% of these patients also test positive for other drugs.⁴ Complication rates are significantly higher when drugs are used in concert than when one drug is used alone.⁵ When interviewed by anesthesiologists or obstetricians, drug-abusing parturients will most likely not be forthcoming about their addiction. However, the most common cause of failure to diagnose drug abuse is a failure to ask. The American College of Obstetricians and Gynecologists (ACOG) recommends that a drug history be obtained from all patients. In addition, ACOG advocates that support, aid, and counseling be made available to all women who acknowledge substance abuse. The role of caregivers should be to focus on prevention and treatment rather than punitive measures against the mother. Routine drug testing in patients with a history of drug abuse should be considered as a method to encourage abstinence.¹

COCAINE

Cocaine abuse continues to be a major problem affecting society. Although it is difficult to estimate the prevalence of cocaine use in parturients, its use appears to be on the rise. In 2008, 772,000 adolescents and adults reported first-time cocaine use.

Diagnosing the cocaine-abusing parturient poses unique challenges because the hallmarks associated with cocaine use—tachycardia, hypertension, and dysrhythmias—may also be confused with cardiac responses to normal labor. In addition to the cardiovascular symptoms, other signs of cocaine use are seizures, hyperreflexia, fever, dilated pupils, emotional instability, proteinuria, and edema. Cocaine-induced hypertension, seizures, and proteinuria can be mistakenly diagnosed as preeclampsia-eclampsia. The differential diagnosis is usually aided by toxicology screening. Most commonly, cocaine metabolites are tested for in maternal urine and can be detected for up to 60 hours after use. A rapid latex agglutination test can detect urine cocaine metabolites within a few minutes, and this test can be performed easily at the bedside in labor and delivery or in an emergent situation. Otherwise, maternal urine can be sent for analysis by the hospital laboratory. Cocaine can be detected in neonatal urine, meconium, and maternal hair over longer time periods.¹

Maternal Effects

Cocaine is highly lipid soluble and has a low molecular weight, which allows for easy diffusion through lipid membranes. It produces prolonged adrenergic stimulation by blocking the presynaptic uptake of sympathomimetic neurotransmitters, including norepinephrine, serotonin, and dopamine. The euphoric effects arise from prolongation of dopaminergic activity in the cerebral cortex and limbic system. Additionally, adrenergic stimulation is prolonged by blockade of catecholamine-binding mechanisms, allowing free catecholamines to continue to stimulate the sympathoadrenal axis.⁴

Complications of cocaine use in parturients include hypertension, tachycardia, malignant cardiac dysrhythmias, cardiac ischemia, premature rupture of membranes, placental abruption, uterine rupture, hepatic rupture, cerebral ischemia and hemorrhage, and death. By increasing the three major determinants of myocardial oxygen demand—heart rate, arterial blood pressure, and left ventricular contractility—cocaine increases the risk of myocardial ischemia and infarction. Parturients are at particular risk for myocardial ischemia because of the underlying increase in oxygen demand from the normal physiology of pregnancy.¹ Some data suggest that pregnancy may be associated with an increased sensitivity of the cardiovascular system to cocaine. This is believed to be secondary to an increased sensitivity of α-adrenergic receptors or an increased metabolism to the biologically active metabolite nor-cocaine, mediated by increased levels of progesterone.⁶

Fetal Effects

The unique pharmacologic properties of cocaine may cause deleterious effects in the fetus. A low molecular weight and high lipophilicity, coupled with the fact that it exists primarily in the unionized form, allows cocaine to readily cross the placenta, leading to rapid accumulation in fetal tissue and blood. Fetal anomalies associated with cocaine use in early pregnancy include urogenital tract abnormalities, gastroschisis, microcephaly, growth restriction, central nervous system (CNS) defects, and musculoskeletal derangements. Chronic maternal cocaine use has been associated with postnatal learning deficiencies and low IQ scores. Preterm delivery is four times more likely with cocaine-exposed fetuses as compared to non–cocaine-exposed ones. With acute cocaine use, there is a significantly increased risk of fetal distress and intrauterine fetal demise.⁶ The fetus is at particular risk for uteroplacental insufficiency, hypoxia, and acidosis from the concomitant decrease in uteroplacental blood flow, as a result of maternal hypertension associated with the vasoconstrictive effects of cocaine.

Anesthetic Management

The use of neuraxial anesthesia may be beneficial to cocaine-abusing parturients, by reducing the level of circulating catecholamines and diminishing the systemic effects of cocaine, particularly during labor. However, an individualized anesthetic plan should be established based on the clinical presentation. Concerns regarding the use of regional anesthesia may include hypotension, altered pain perception, combative behavior, and cocaine-induced thrombocytopenia. A well-documented phenomenon is that cocaine and opioid users frequently complain of pain, even with a demonstrable adequate level of neuraxial anesthesia. This seems to be particularly true during regional anesthesia for a cesarean section. It has been suggested that abnormalities in endorphin levels and chronic changes in both μ and κ opioid receptor densities likely to play a role.^4,7

When general anesthesia is indicated, it is important to remember that surges in catecholamines during periods of light anesthesia, such as laryngoscopy, can produce dysrhythmias in the presence of cocaine. Hypertension and myocardial ischemia have also been reported. Ketamine should be used with caution, if at all, because its CNS-stimulating properties and increasing catecholamine levels may potentiate the cardiac effects of cocaine.

Care must be taken to minimize the severe hypertension and tachycardia that can accompany stimulation from laryngoscopy in cocaine-intoxicated patients. It is recommended that pharmacologic control be exerted before induction. Several approaches have been suggested to lower the risk of severe hypertension, but the optimal sequence remains to be determined. Nonselective β-blockers such as propranolol are relatively contraindicated because of the potential for unopposed α-adrenergic stimulation that can occur in the face of cocaine intoxication. In addition, nonselective β-blockers have also been implicated in enhancing cocaine-induced coronary vasoconstriction. It is clear that administration of a pure β-blocker can worsen cardiac perfusion and/or produce paradoxical hypertension. If a nonselective β-blocker must be used, esmolol may provide effective short-term on-and-off control of tachycardia and hypertension because of its short elimination half-life. Labetalol, with its 7:1 ratio of β- and α-blocker action, has also been used with success even though predominantly, it is a β-blocker. A combination of labetalol with nitroglycerin has been recommended as an effective treatment of cocaine-induced severe hypertension. Incremental small doses of nitroglycerin are safe and effective for lowering blood pressure acutely and can also be given to relieve coronary artery spasm pain caused by acute cocaine ingestion. Hydralazine is a direct vasodilator that also has been used in the treatment of cocaine-induced hypertension, even though it may produce a reflex tachycardia that can be problematic in an already tachycardic patient.¹

Pregnant cocaine abusers may also present to the labor and delivery unit with hypertension and chest discomfort related to acute cocaine ingestion. Most patients with cocaine-induced myocardial ischemia develop chest pain within 1 hour of ingestion of cocaine, when the blood level is highest. The pathogenesis of the myocardial ischemia involves an increase in myocardial oxygen demand with a concomitant low oxygen supply resulting from coronary artery vasoconstriction and enhanced platelet aggregation and thrombus formation. The electrocardiogram may be abnormal in about 50% of these patients.⁸ Guidelines from the American Heart Association recommend the administration of benzodiazepines and nitroglycerin as first-line agents.

AMPHETAMINES

Amphetamines, like cocaine, are a group of noncatecholamine indirect-acting sympathomimetics that increase the release of norepinephrine, serotonin, and dopamine from presynaptic neurons and inhibit their breakdown. They are powerful stimulants of the CNS with an ability to produce profound euphoria, wakefulness, alertness, and decreased appetite. Methamphetamine (N-methyl-1-phenyl-propan-2-amine) is methylated amphetamine, and it is the most commonly abused form of amphetamine. More powerful than amphetamine, methamphetamine is the only illicit drug that can be produced from legally obtained ingredients such as decongestants and cold medications. Because methamphetamine is easy to produce, has a low cost, and is highly addictive, it has become a major drug of abuse. Historically, in the United States, the most prevalent regions for methamphetamine abuse have been in the West and Southwest; however, its use has been spreading steadily to include the rest of the country. It has been estimated that where methamphetamine abuse is most prevalent in the United States, 5.2% of women have used methamphetamine at some point during their pregnancy.

Clinically, amphetamine intoxication is indistinguishable from that of cocaine. Hypertension, tachycardia, dilated pupils, cardiac dysrhythmias, and cardiac ischemia are all presenting signs of acute methamphetamine use. Coexistence of seizures, hyperreflexia, and proteinuria with acute cocaine or amphetamine use has been mistaken for eclampsia. Chronic use of amphetamines depletes body stores of catecholamines and may manifest clinically with anxiety, somnolence, or psychosis.²

Anesthetic management of amphetamine-intoxicated parturients is similar to that of cocaine-affected parturients. Emergent cesarean section may be likely secondary to fetal jeopardy, placental abruption, or other obstetrical emergencies. Reports of cardiac decompensation and even death during cesarean section using either regional or general anesthesia have been described. There is no apparent contraindication to regional anesthesia, but clinicians should be prepared to treat hypotension related to sympathectomy, and these women may have unpredictable responses to vasopressors. Indeed, due to depleted body stores of catecholamines, indirect-acting pressors (ie, ephedrine) may not be effective in treating hypotension and direct-acting pressors such as phenylephrine should be considered. Acute intake of amphetamines can increase the minimum alveolar concentration (MAC) of potent inhaled anesthetics, whereas chronic ingestion may decrease the dose requirements of general anesthetics. Inhaled volatile anesthetics may sensitize the myocardium to endogenous catecholamines, and it is recommended that halothane be avoided.¹

ETHANOL

Alcohol consumption by pregnant women remains a major problem in society. More than 15 million people in the United States are addicted to alcohol, and women account for 25% of these individuals.⁹ The 2006 national survey on drug use and health found that 11.8% of pregnant women reported current alcohol use and 2.9% reported binge drinking (five drinks or more on one occasion).¹⁰ Because alcoholism is more subtle and more difficult to diagnose than other drug addictions, it is frequently overlooked.

Stigma, shame, fear of legal repercussions, and fear of mandatory placement into detoxification programs may lead pregnant alcohol users to underreport alcohol use and avoid consistent prenatal care. Simple, sensitive, and effective evidence-based screening tools have been developed to help physicians detect problem drinking in patients. There is good evidence overall for the effectiveness of screening and behavioral interventions in reducing the amount of drinking in pregnant patients. Various four to five question surveys have been widely validated. The TWEAK questionnaire is preferred because it takes into tolerance (Tolerance: how many drinks does it take to make you high?, Worried, Eye-opener, Amnesia [blackouts], Cut[K] down) into account. The tolerance question assumes that the patient is drinking and avoids patient denial.¹¹

Maternal Effects

Alcohol has numerous effects on the CNS and acts as both a depressant and a stimulant. With acute intoxication, patients may be unable to adequately protect their airway and risk pulmonary aspiration. With chronic use, ethanol can lead to liver disease, malnutrition, altered drug metabolism, coagulopathy, pancreatitis, esophageal varices, neuropathies, and cardiomyopathy. Hypoglycemia and electrolyte imbalances may also be present when heavy alcohol consumption is coupled with poor nutritional intake.

Alcohol withdrawal symptoms can be encountered in patients 6 to 18 hours after cessation of consumption, although delays of up to 10 days have been reported. Symptoms of withdrawal include nausea/vomiting, tachycardia, dysrhythmias, hypertension, delirium, hallucinations, seizures, and cardiac failure. Delirium tremens is a rare, although life-threatening medical emergency. Symptoms of withdrawal can be treated with benzodiazepines, α-adrenergic agonists (eg, clonidine), or ethanol.¹²

Fetal Effects

Alcohol and its metabolites (eg, acetaldehyde) freely cross the placenta and can cause structural and behavioral teratogenicity. No safe level of consumption has been established during pregnancy. Therefore, abstinence appears to be the safest choice for pregnant women.²

Spontaneous abortion, prenatal and postnatal growth restriction, low birth weight, birth defects, and neurodevelopmental deficits are all increased in pregnant women who abuse alcohol. Fetal alcohol syndrome is the best known disorder, and it is associated with characteristic facial features; growth retardation; physical anomalies; and developmental abnormalities, including mental retardation.¹³

Anesthetic Management

Depending on the degree of dependence and the timing of most recent intake, patients can present to labor and delivery with a variety of clinical manifestations. Acutely intoxicated patients may present to labor and delivery with the fetus in “nonreassuring” status and/or be at a higher risk for pulmonary aspiration.

Regional anesthesia can be safely administered to cooperative patients. Contraindications to neuraxial anesthesia are usually encountered in chronic abusers with end-stage liver failure and coagulopathy. Patients may have neuropathy, usually as a result of vitamin deficiency, but this should not pose a contraindication to a regional technique. However, the extent of the neuropathy should be determined and documented prior to proceeding with regional anesthesia. In addition, intravascular fluid status should be assessed and corrected to avoid excessive hypotension as a consequence of the sympathetic blockade.

In case of emergency delivery or if patients are too sedated or uncooperative to protect their airway, general anesthesia is warranted. Acute alcohol consumption can decrease the MAC for anesthetics due to the additive effects of CNS depressants. The notion that chronic alcohol abusers have a higher MAC for inhaled or hypnotic anesthetics has not been substantiated.¹² Anesthesia providers should avoid arbitrarily administering high doses of inhaled anesthetics to pregnant patients with a history of chronic alcohol abuse, because these women, in addition to requiring lower MAC as a result of their pregnancy, can also be at risk for intravascular volume depletion, cardiomyopathy, and hypoalbuminemia. A bispectral index monitor may be useful in guiding anesthetic depth. High concentrations of inhaled volatile anesthetics can also depress uterine tone and may increase blood loss at cesarean delivery.

OPIOIDS

Opioids include the opiates, which are natural or semisynthetic morphine-like substances, as well as the fully synthetic opioid compounds. The opiates include morphine, codeine, hydromorphone, and heroin. Synthetic opioids include meperidine, fentanyl, and methadone. Opioids can be abused orally, subcutaneously, or intravenously. Most of the information on the effects of opioids on the mother and fetus derives from studies involving heroin or methadone. More recently, there has been an increase in the use of prescription opioids such as hydromorphone and codeine.

Maternal Effects

Pregnant women who use heroin can expect a sixfold increase in obstetric complications such as intrauterine growth restriction (IUGR), third-trimester vaginal bleeding, malpresentation, preterm delivery, and nonreassuring fetal status.¹⁴ In addition to the chemical effects of heroin, the drug can pose additional risks because it is injected intravenously. Patients who use intravenous drugs are at increased risk for developing cellulitis, skin abscesses, sepsis, thrombophlebitis, hepatitis, human immunodeficiency virus (HIV), endocarditis, and malnutrition. Patients should be counseled regarding the benefits of a methadone maintenance program. Methadone maintenance treatment provides a steady concentration of opiates in pregnant women’s circulation and therefore prevents acute withdrawal, which can be detrimental to both mothers and their fetuses. Women who use methadone have decreased use of other illicit drugs, better compliance with prenatal care, better obstetric outcomes, and improved infant birth weights. Maternal methadone, however, is also associated with neonatal abstinence syndrome.¹⁵

Fetal Effects

All opioids freely cross the placenta. There are no specific congenital abnormalities associated with chronic opioid abuse, but there is a higher risk of stillbirth, meconium staining, decreased head circumference, and depressed Apgar scores in fetuses of opioid-abusing parturients. Neonatal abstinence syndrome can be observed in 50% to 95% of infants exposed to heroin and is manifested by signs and symptoms withdrawal from an addictive substance. Neonatal withdrawal symptoms are similar to those encountered in adults, with the addition of irritability, poorly coordinated sucking, and in the most severe cases, seizures and death. Infants born to mothers who abuse hydromorphone or oxycodone have also been shown to develop neonatal withdrawal syndrome.^1,15 The use of opioid antagonist may precipitate withdrawal.

Anesthetic Management

Opioid-addicted parturients present several challenges to the anesthesiologist. In addition to concerns regarding acute opioid overdose or withdrawal, difficulties with placement of vascular access, and management of labor analgesia and postoperative pain may also occur.

Opioid-abusing parturients may present with symptoms of overdose or acute opioid withdrawal. Opioid overdose can be characterized by a slow respiratory rate, increased tidal volumes, and miotic pupils. Acute withdrawal is manifested by increased sympathetic nervous system activity (ie, restlessness, lacrimation, sweating, diarrhea, insomnia, mydriasis, tachycardia, tachypnea, and hypertension). CNS manifestations of acute withdrawal can range from dysphoria to unconsciousness. Withdrawal symptoms can occur 4 to 6 hours following the last dose of opioids and peak at 48 to 72 hours. Symptoms of opioid withdrawal can be treated with nonopioid medications such as clonidine, doxepin, or diphenhydramine. Clonidine attenuates withdrawal symptoms by replacing opioid-mediated inhibition with α₂-agonist–mediated inhibition of the CNS. Administration of opioid antagonists or agonist-antagonists must be avoided in these patients because they can precipitate acute withdrawal syndrome. Opioid withdrawal syndrome may develop within minutes of naloxone administration.

Methadone maintenance has been an acceptable form of therapy for opiate-addicted pregnant women since the late 1960s. More recently, buprenorphine has also been used; it has less placental transfer to the fetus than methadone, reducing the incidence of neonatal abstinence syndrome. Patients who have previously been on methadone maintenance therapy should continue with their regular dosing during labor and throughout the postpartum period. It is recommended that patients recovering from opioid addiction have a clear plan in place for pain management before labor. A multidisciplinary approach involving the obstetrician, anesthesiologist, and drug addiction treatment service is best.¹⁶

Regional anesthesia may be safely administered to opioid-addicted parturients. However, increased tendency for hypotension following spinal or epidural anesthesia should be anticipated. Extra-analgesic requirements during regional anesthesia for cesarean section have been reported, which is consistent with the theory of opioid-induced abnormal pain sensitivity.¹⁷ An increased incidence of spinal, epidural, and disk space infections has also been reported in these patients, regardless of the type of anesthesia used; any symptoms and signs of neuraxial infection should be evaluated immediately. Acute opioid ingestion reduces anesthetic requirements and may also cause respiratory depression and loss of airway reflexes. Chronic opioid-abusing parturients may have decreased production of endogenous peptides, which may be responsible for the degree of exaggerated pain they can experience postoperatively.

MARIJUANA

Marijuana is used by 3% to 16% of parturients. Although the most important and potent chemical from the cannabis plant is delta 9-tetrahydrocannabinol (THC), more than 400 chemical impurities can be found mixed into a marijuana cigarette. Marijuana is highly lipophilic and rapidly accumulates in adipose tissue. Complete elimination of a single dose may take up to 30 days. The presenting signs of patients intoxicated with marijuana can include euphoria, tachycardia, conjunctival congestion, and anxiety.

Even though THC readily crosses the placenta, there is no known increase in risk of serious congenital abnormalities in the fetus. The evidence regarding fetal effects of marijuana is inconclusive, but it is suggested that chronic use of marijuana results in decreased uteroplacental perfusion and IUGR.¹⁸

Anesthetic concerns related to marijuana use are mainly due to potential depression of the myocardium. During general anesthesia, the additive effects marijuana and potent inhaled anesthetics can result in pronounced myocardial depression. Marijuana can also have additive effects with other CNS depressants. Acute marijuana use may also produce tachycardia, and sympathomimetic drugs such as ketamine, pancuronium, atropine, and epinephrine should be avoided. Emphysema, bronchitis, and squamous metaplasia can result from chronic cannabis use, as they do in tobacco smoking. It has been reported that airway obstruction from uvular edema and oropharyngitis may result from recent preoperative marijuana smoking.¹³

HUMAN IMMUNODEFICIENCY VIRUS

Women, often of reproductive age, are the fastest growing population infected with human immunodeficiency virus (HIV) in the United States. In 2000, almost 30% of new HIV infections were in women. The prevalence of seropositivity in pregnant women in the United States has been estimated to be as high as 1.7 per 1000.¹⁹

HIV is an RNA virus that belongs to the lentivirus family, a subtype of human retroviruses. The virus is characterized by its cytopathic action on CD4+ lymphocytes. It is transmitted (1) via contact with sexual fluids or blood and blood products or (2) by vertical transmission from an infected mother to her fetus. Te greatest risk factor for HIV transmission in women is heterosexual at-risk activity with high-risk partners. Other risk factors include substance abuse (intravenous drug abuse and crack/cocaine use), sexually transmitted disease, and tattoo of body surfaces. Screening women with risk factors detects only about 50% of the patients who are seropositive, but if screening is applied to all pregnant women, the detection rate increases to approximately 87%.

Given that chemoprophylaxis can dramatically improve perinatal outcome, ACOG recommends that voluntary HIV screening be included in the comprehensive antenatal laboratory testing. Most women test positive within 1 month of primary infection. However, in rare circumstances, seroconversion may not occur for 6 months. Therefore, a second screening test is recommended once again at the beginning of the third trimester. If high-risk parturients present with undocumented HIV status on labor and delivery, a rapid test can be performed. Viral load levels (cells/mL) usually correlate with the CD4+ T-lymphocyte count. The goal of successful anti-HIV therapy should be viral load suppression to an undetectable level.

Among newborns with perinatally acquired HIV, 60% to 70% are infected with HIV during the intrapartum period, with the remainder infected before the onset of labor. The vertical transmission rate is estimated to be 20% to 30%. Intrapartum transmission is thought to be the result of maternal-fetal microtransfusion during uterine contractions, fetal exposure to maternal blood, and vaginal secretions during delivery. Breastfeeding significantly increases the risk of HIV transmission to infants and is contraindicated in infected women. Breastfeeding adds a 12% to 26% risk of vertical infection over and above the risk of transmission at delivery or in utero.²⁰ HIV-infected infants have the same frequency of congenital abnormalities as those not infected, and there is no consistent pattern of defects.

A significant reduction in the vertical transmission of HIV can be achieved with treatment of HIV-infected women with highly active antiretroviral therapy (HAART), regardless of their CD4+ count or viral load. Using this regimen, mother-to-child transmission can be decreased to less than 2% as long as breastfeeding is not undertaken. Risk factors for intrapartum transmission of HIV include severity of disease (maternal viral load), prolonged rupture of membranes, chorioamnionitis, vaginal delivery, and invasive fetal monitoring.²¹ A cesarean section has the advantage of decreasing the time of contact between maternal blood and the neonate, and studies have shown a significant reduction in vertical transmission when it is combined with preoperative intravenous zidovudine infusion. Current ACOG guidelines recommend that women who have an HIV RNA level greater than 1000 copies/mL near term should undergo elective cesarean section at 38 weeks’ gestation, before the onset of labor and rupture of membranes. Intravenous zidovudine should be administered 3 hours before the cesarean section. For those women with viral loads less than 1000 copies/mL, studies have not shown that cesarean section further decreases the rate of HIV transmission to the infant. In the absence of other obstetric indications, ACOG recommends that patients with viral loads less than 1000 copies/mL may deliver vaginally with a loading dose of zidovudine followed by a continuous infusion throughout labor.^22,23 Viral load testing should be performed every 3 months during pregnancy.

Clinical Manifestations

The clinical manifestation of HIV and acquired immunodeficiency syndrome (AIDS) can be that of the viral infection itself, opportunistic infections, neoplasms, or by the antiretroviral drugs or antiopportunistic drugs used for therapy. In the early stages of the AIDS epidemic, the predominant symptoms were those of immune suppression (eg, opportunistic infections, unusual malignancies). As improvements in prophylaxis and treatment of opportunistic infections have increased longevity, it has become apparent that HIV eventually affects multiple organ systems.

CENTRAL AND PERIPHERAL NERVOUS SYSTEM ABNORMALITIES

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Non-neuraxial Labor Analgesia Hypertension of Pregnancy Anesthesia for Obstetric Procedures not Involving Delivery Drugs Commonly Used in Obstetric Anesthesia Managing the Obese Parturient Anesthetic Management of the Parturient With Neurologic/Neuromuscular Disease

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