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CLINICAL OBSTETRICS AND GYNECOLOGY Volume 00, Number 00, 000–000 r 2013, Lippincott Williams & Wilkins The Use of Narcotics and Street Drugs During Pregnancy MICHAEL K. LINDSAY, MD, MPH and ERIN BURNETT, MD Department of Gynecology and Obstetrics, Emory University, Atlanta, GA Abstract: All prenatal care providers should offer routine voluntary substance use screening to all patients. Parturients who screen positive for illicit substances require a multidisciplinary team approach to drug rehabilitation and prenatal care. This review will examine the pharmacological properties and the neonatal consequences of the use of opioids and amphetamines. Substance-abusing parturients typically abuse multiple substances simultaneously and have other comorbidities including psychosocial instability and mental illness. These comorbidities must be effectively addressed to achieve optimal health outcomes for both mother and infant. Key words: illicit substances, prenatal care, and neonatal consequences identifying, and treating substance-abusing pregnant women can improve their pregnancy outcomes and lead to more beneficial long-term health outcomes in this high-risk population. The use of street drugs and other illicit substances in pregnancy is an expensive public health problem. In 2008, drug abuse costs in the United States were estimated to be >$180 billion a year, including $605 million associated with health care costs for drug-exposed newborns.1 In addition, illicit drug use among women of reproductive age has major physical and mental health consequences and is associated with increased rates of sexually transmitted infections, including hepatitis B, human immunodeficiency virus (HIV), as well as depression, domestic violence, poverty, and significant prenatal and neonatal complications.2 The magnitude of substance abuse in pregnancy is well characterized from 2010 data from the Substance Abuse and Mental Health Service Administration that performs an annual survey on drug use the National Survey on Drug Use and Health. The 2010 survey estimated that 22.6 million (8.9%) of Americans, age 12 years and Introduction The use of illicit substances of abuse and street drugs is an emerging public health problem. The pharmacologic properties of many of these substances cause physical dependence in the user and leads to behaviors that cause adverse consequences for both mother and infant. Screening, Correspondence: Michael K. Lindsay, MD, MPH, Department of Gynecology and Obstetrics, 69 Jesse Hill Jr. Drive, SE, Atlanta, GA. E-mail: mlindsa@ emory.edu The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 00 / NUMBER 00 / ’’ 2013 www.clinicalobgyn.com | 1 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 2 Lindsay and Burnett above, were ‘‘current’’ (past month) drug abusers.3 The most commonly abused substances were marijuana, psychotherapeutic drugs, and cocaine. Data from this survey also revealed that 4.4% of pregnant women were current (past month) substance abusers. The highest prevalence of use was observed in 15 to 17 year olds (16.2%), followed by 18 to 25 year olds (7.4%), whereas the lowest prevalence of use was observed in 26 to 44 year olds (1.9%).3 Survey data, however, may grossly underestimate drug use in pregnancy. A study of inner city parturients who underwent universal drug screening revealed that 19% screened positive for Z1 substance at presentation to labor and delivery. However, only one third of those who screened positive actually gave a history of drug use.4 The underreporting of drug use by pregnant women is complex and may be attributable in part to the stigma of drug use in pregnancy and/or the fear of legal consequences and memory failure.4 All prenatal care providers should offer routine voluntary substance use screening to all patients. The goal of drug screening is to identify women for counseling and referral to drug rehabilitation. The American Congress of Obstetrician Gynecologist declares that Obstetrician Gynecologist have the moral obligation to provide routine alcohol and drug abuse screening to all prenatal patients.1 Prenatal care providers should provide prenatal substance use screening in a culturally sensitive nonjudgmental matter and should clearly convey to parturients the public health rationale for screening that is, to protect both maternal and fetal health. In addition to voluntary substance use screening, several chemical tests can be employed to detect illicit substances. Specimen used for testing exposure to illicit substances includes maternal blood and urine, and fetal cord blood, meconium, hair, and urine. However, the most commonly used test because of ease of availability for both mother and infant involves urinalysis.5 It is important to realize that false-negative test results can occur if too much or too little time has passed since drug ingestion, or if the urine is too dilute. Parturients who screen positive for illicit substances either by self-report and/ or urine drug screens require a multidisciplinary team approach to drug rehabilitation and prenatal care. This multidisciplinary team should include an obstetrician, addiction specialist or a trained addiction counselor, mental health professional, newborn specialist, and social worker. The diverse expertise of the team should allow it to effectively address the myriad of medical and psychosocial issues encountered in managing these high-risk pregnancies. This review will examine the pharmacological properties and the maternal and neonatal consequences of the use of opioids, and amphetamines in pregnancy. In many instances substance-abusing parturients abuse multiple substances simultaneously; therefore it is difficult to determine the effect of a particular substance of abuse in isolation. In addition, many substance abusers have other comorbidities including psychosocial instability and mental illness. These comorbidities must be considered and effectively addressed to achieve optimal health outcomes for both mother and infant. Opioids: Pharmacology and Epidemiology An opioid is a psychoactive chemical that works by binding to opioid receptors found principally in the central nervous system and the gastrointestinal tract.6 The receptors in these organs mediate both the beneficial and side effects of this class of drugs. There are 4 broad classes of opioids; endogenous opioid peptides produced in the central nervous system such as endorphin, and enkephelins; natural opioids which are alkaloids contained in the resin of opium poppy such as morphine, and codeine; semisynthetic www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Illicit Substances of Abuse and Street Drugs opioids created from natural opioids such as oxycodone, heroin, and buprenorphine; and fully synthetic opioids such as fentanyl, and methadone.7 The pharmacological effects of opioids analgesics are derived from the interaction of 3 opioid receptor types (m, d, k). The major pharmacological effects of opioids are decreased perception and reaction to pain as well as increased pain tolerance and feeling of euphoria, which is the major motivation for recreational use of these drugs. Their major side effects include sedation, respiratory depression, and constipation.7 These drugs can be administered by multiple routes including orally, by injection, absorbed by skin, sniffing, or smoking. Opioid addiction is characterized by physical dependence and tolerance that leads to the need for higher doses of the drug to achieve the same physiological effects.7 Once a parturient is opioid dependent, withdrawal symptoms in both the mother and infant will occur unless additional drug is obtained. With short-acting opioids, such as heroin, withdrawal symptoms can occur within 6 to 12 hours, whereas for long-acting opioids, such as methadone withdrawal symptoms can be experienced between 72 to 96 hours.7 It is difficult because of its illicit nature and transient use to obtain exact information on the prevalence of opioid use in pregnancy. Over the past decade, prevalence data have primarily originated from chemical analysis of meconium and maternal self-report. A 2004 observational study that relied on meconium analysis estimated that 7000 opiate-exposed birth occurred annually in the United States, whereas data from the 2010 National Survey on Drug Use and Health estimated 1 in 1000 pregnant women admitted to heroin use in the past 30 days.3,8 The most commonly abused opioids in pregnancy include heroin, and prescribed opioids including codeine, morphine, oxycodone, meperidine, hydromorphone, hydrocodone, fentanyl, methadone, propoxyphene, and buprenorphine.9 3 Heroin: Pharmacology and Epidemiology Heroin or diacetylmorphine is a synthetic opioid derived from the sap of the poppy seed (Papaver somniferum). It is lipid soluble and rapidly crosses the blood brain barrier where it is converted to morphine and binds to natural opioid receptors.10 Its primary route of use is intravenously but it is also occasionally snorted or smoked. Sniffing or smoking heroin has recently gained popularity because of the availability of high-purity drug coupled with the fear by users of sharing needles and contracting HIV or hepatitis B or C.11 Many current heroin users mistakenly believe that sniffing or smoking heroin will not lead to addiction. Intravenous use produces effects within seconds,10,11 whereas snorting or smoking produces effects in minutes.10,11 The duration of heroin euphoric effect is 3 to 5 hours which leads to repeated uses of this drug to maintain a high.10 The adverse maternal consequences of heroin addiction are both short and long term. The short-term adverse effects include somnolence, altered mentation, constipation, diarrhea, urinary retention, and cardiorespiratory depression. Longterm adverse effects include physiological withdrawal, liver disease, pulmonary complications, kidney disease, infectious morbidity from hepatitis B and C, sexually transmitted diseases, HIV, endocarditis, abscesses, pneumonia, and tuberculosis.10 Effects on Pregnancy Heroin passes rapidly through the placenta with limited fetal detoxification and within 1 hour accumulates in the amniotic fluid.12 The lack of in utero metabolism of heroin explains the high risk of the onset of in utero withdrawal symptoms when this opioid is not available to the mother. Chronic untreated heroin use in pregnancy has been associated with increased risk of adverse pregnancy outcomes www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 4 Lindsay and Burnett including poor fetal growth, preterm premature rupture of membranes, preterm birth, neonatal abstinence syndrome (NAS), antepartum hemorrhage, low birth weight, maternal infections, use of other illicit drugs, poor prenatal care, and social adversity.13,14 Many of these adverse effects are felt to be secondary to poor health behaviors of the mother combined with repeated episodes of in utero opioid withdrawal. Prescribed Opioids; Effects on Pregnancy Three prescribed opioids codeine, meperidine, and oxycontin are also commonly abused in pregnancy. Codeine or (3 methylmorphine) is a synthetic opiate used for its analgesic, antitussive, and antidiarrheal properties.6 Small case series and casecontrol studies have revealed an association between codeine use in pregnancy and both congenital anomalies and NAS.15,16 However, a large prospective cohort study of 2666 women who used codeine during pregnancy compared with 65,316 women who used no opioids during pregnancy after adjusting for potential confounders found no association with maternal codeine intake during pregnancy and the risk of congenital anomalies or infant survival.17 Meperidine (ethyl 1-methyl-4-phenylpiperidine-4-carboxylate) is an opioid agonist of the morphine type that is used to relieve moderate to severe pain. This drug is administered by crushing, chewing, snorting, or injecting dissolved products. Meperidine abuse in pregnancy often results in uncontrolled delivery of this drug which poses a significant risk of high drug levels, which can lead to maternal overdose and death. In addition, meperidine used within hours of delivery can create drowsiness and potential serious breathing problem in the newborn, whereas chronic use can cause NAS.18 Oxycontin or oxycodone hydrochloride, (5a-epoxy-14-hydroxy-3-methoxy methylmorphinan-6-one) is a synthetic opioid with agonist activity on m, d, k receptors.7 Oxycontin is similar in structure to codeine and morphine. This drug is among the most widely sold pain killers in the United States with $2.9 billion in sales in 2009.19 This drug is highly addictive and can be administered orally, by snorting or by injections. Oxycontin is replacing heroin as the opiate of choice in some rural regions of the country and is very popular among adolescents.20 There are little data about oxycotin use in pregnancy, however, there has been a case report linking oxycontin abuse in pregnancy with neonatal withdrawal syndrome.21 Antepartum/Intrapartum/ Considerations Screening for opioid use in pregnancy should be part of a comprehensive approach to screening for alcohol and illicit substances in pregnancy. Parturients identified as heroin and or prescription opioid users should be counseled about the potential adverse maternal and infant/ newborn impact of continued use and be referred for drug rehabilitation. There are 3 major options for the antepartum management of opioid abuse in pregnancy, methadone maintenance, buprenorphine maintenance, and detoxification. The first option and the standard of care for over 4 decades is methadone (6-[dimethylamino]-4, 4-diphenyl-3-hepatonone) maintenance. Observational studies report improved pregnancy outcomes in women maintained on methadone compared with those on no therapy. These studies report improvement in prenatal clinic attendance, better nutrition, better obstetrical outcomes including lower risk of spontaneous abortion, intrauterine growth restriction, and neonatal morbidity and mortality.22 A 2002 systematic review further confirmed the benefits of methadone maintenance in pregnancy. The review of randomized www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Illicit Substances of Abuse and Street Drugs controlled trials reported a 3-fold reduction in heroin use and a 3-fold increase in retention in treatment relative to nonpharmacologic therapy.23 However, a common side effect from methadone maintenance was neonatal withdrawal.24 The second antepartum management option for opiate abuse is the use of recently approved buprenorphine (subutex). Buprenorphine is a partial opioid agonist as opposed to heroin or methadone which are full agonists. As a partial agonist it has a lower likelihood of causing overdose or respiratory depression. This drug has the ability to suppress opioid cravings and withdrawal, blocks the effect of self-administered opioids, and decreases illicit opioid use.25 A recent randomized controlled trial found that using buprenorphine for opioid dependence during pregnancy resulted in fewer episodes of NAS than use of methadone. Both drugs were associated with similar reduction in illicit opioid use.26 However, more largescale use of buprenorphine is contingent on easier availability and currently access is limited to providers that are board certified in Addiction Medicine, Addiction Psychiatry, or licensed physicians who complete 8 hours of training. The final antepartum management option is inpatient opioid detoxification. Opioid detoxification can safely be accomplished in an inpatient setting, and it is recommended that detoxification be conducted under the supervision of physicians experienced in prenatal addiction in a perinatal unit equipped with fetal monitoring to detect signs of fetal stress or preterm labor.27,28 There are no clear guidelines for the initiation of antenatal testing in opioidabusing parturients who are not on maintenance therapy. A reasonable approach is to offer antenatal testing beginning at 32-week gestation, unless the clinical situation warrants earlier testing. Parturients who are in labor and maintained on methadone should receive standard obstetrical pain relief as maintenance doses do not provide adequate relief. These 5 parturients are candidates for both epidural and spinal anesthesia the same as nonopioid–using mothers. Opioid agonist and antagonist such as nubain, talwin, stadol, and narcan should be avoided as they can precipitate acute withdrawal symptoms.29 Postpartum Considerations Neonatal withdrawal is a well-recognized risk of maternal opioid use in pregnancy and is seen in the majority of infants exposed in utero to heroin, methadone, morphine, oxycotin, codeine, and buprenorphine. NAS is characterized by hyperactivity of the central and autonomic nervous systems. Newborn symptoms may present anytime in the first 2 weeks of life with peak in symptoms at 3 to 4 days.24 All infants born to opioid addicted mothers must be monitored closely in the nursery and treated if needed. The American Academy of Pediatrics recommends that breastfeeding should be avoided in heroin users, as breastfeeding may cause tremors, restlessness, vomiting, and poor feeding in the infants. However, methadone users are encouraged to breastfeed and breastfeeding has been found to lead to improved NAS scores.30 Amphetamines/ Methamphetamine/Ecstasy/ Bath Salts PHARMACOLOGY, EPIDEMIOLOGY, PATHOPHYSIOLOGY Amphetamines are noncatecholamine sympathomimetic drugs that stimulate the central nervous system. They are not naturally occurring but are synthetic and are structurally similar to ephedrine—a natural stimulant. Amphetamines release stores of neurotransmitters (norepinephrine, dopamine, and serotonin) from nerve endings and inhibit recycling of www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 6 Lindsay and Burnett these products. These actions increase the concentrations of these neurotransmitters in nerve spaces, promoting nerve impulse transmission.31 Physiologically, amphetamines increase alertness, euphoria, exhilaration, and decrease tiredness, and inhibition. They are highly addictive, and often only 1 use is needed for dependence to occur. Amphetamines may be smoked, injected, or taken orally. Shortterm systemic effects include tremors, hypertension, wakefulness, decreased appetite, and dilated pupils. Long-term effects include toxic psychosis, hallucination, and change in brain structure. If consumed at high enough doses they may cause retinal damage, cardiac arrhythmias, hyperthermia, toxic hepatitis, seizures, shock, stroke, or death.31 Methamphetamines (N-methyl1-phenyl-propan-2-amine) can easily be made from over-the-counter-cold medication or decongestants. Studies have shown that chronic use is associated with cerebral deterioration, most commonly in the medial temporal lobe and basal ganglia. The effects in the basal ganglia are due to increased iron concentration which exacerbates the toxicity of free radicals created from catecholamine break down. Decreased catecholamine stores in the body leads to anxiety, somnolence hallucinations, and can precipitate psychotic breaks.32 Ecstasy 3,4 methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine that is chemically similar to methamphetamine and mescaline. MDMA is taken orally as a capsule but can also be smoked, injected, or absorbed as a suppository. MDMA may exert its effects centrally via serotonin. It may cause serontonin vesicles in the neurons to release quantities of serontonin into the synapses.33 MDMA can produce confusion, depression, and drug craving. It is commonly used in night clubs settings and produces feeling of euphoria, intimacy, and decreased anxiety and warmth. Common side effects include tachycardia, and hyperthermia, rare side effects include psychosis and death. This drug was initially popular among adolescents and young adults but recently its use is becoming more widespread.34 A potential side effect from ecstasy use is a decrease in frontal gray matter, secondary to sustained local vasoconstriction.35 Bath salts are a new class of synthetic drugs with effects similar to cocaine and lyseric acid diethylamide. These chemical mixtures of principally mephedrone, methylenedioxyprova lezone, and methylone are central nervous system stimulants. Their route of administration include ingestion, sublingual, intravenous, insufflations, inhalation, and rectally. Use of these drugs can cause euphoria, alertness, and agitation. Users of these drugs may become hypertensive and experience acute neurological, cardiovascular, and psychopathologic symptoms that are felt to be mediated by the action of methylenedioxyprovalezone on monoamine inhibitor uptake.36 Bath salts are marketed and labeled not for human consumption to skirt the law and to avoid being labeled as illegal. They are sold as plant food and water cleaner in smoke shops, convenience stores, gasoline stations, on line, and on the black market.37 There are limited data on the extent of amphetamine use in pregnancy. National prevalence estimates for methamphetamine use in pregnancy vary from 0.7% to 5.2%.38 However, these figures may represent an underestimate as more pregnant women in drug treatment programs are there due to methamphetamine use than any other drug based on a review of data from the Treatment Episode Data Set. During the 12-yearstudy period (1994 to 2006), the number of parturients seeking treatment for methamphetamines abuse tripled from 8% to 24%.39 There also has been a recent epidemic of emergency room visit because of acute intoxication from bath salts. Data from the American College of Emergency Physicians clearly captures the scope of the problem. In 2010, there were 300 calls to poison control centers for bath salt ingestion while, during the first 8 months of 2011 there www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Illicit Substances of Abuse and Street Drugs were >4700 calls.37 The US Drug Enforcement Agency recently, because of the rise in emergency room visits secondary to acute intoxication from these drugs, made sales of the 3 principal chemical used to make bath salts illegal. The ban was issued on October 2011 and is in effect for 1 year, and will be reassessed in November 2012 at which time it may become permanent.40 EFFECTS ON PREGNANCY Both amphetamines and methamphetamines cross the placenta and appear to cause vasoconstriction leading to adverse consequences for both the mother and the baby.41 However, in 2005 an expert panel concluded that there was insufficient evidence to conclude that prenatal exposure to amphetamines caused adverse pregnancy outcome because the studies failed to adjust for poor prenatal care and nicotine use.42 Nevertheless observational studies have reported an association between amphetamine use and adverse pregnancy outcome including increase risk of hypertension, postpartum hemorrhage, Ob intensive care unit admission, social disruption, domestic violence, and placement of kids in foster care. Fetal and newborn risk include abruption, preterm birth, intrauterine growth restriction, low birth weight, small head circumference, congenital anomalies, learning disabilities, low 5-minute Apgars, and increased neonatal death.43,44 Infants exposed in utero to methamphetamines are at high risk of suffering from amphetamine withdrawal syndrome characterized by tremors, sleep problems, poor feeding, excessive crying, muscle spasms, and irritability.45 Parturients with first trimester ecstasy exposure are at increased risk of delivering infants with congenital anomalies. The United Kingdom Teratology Information Service using prospective data from 136 pregnancies with exposure to ecstasy found a 15.4% rate of congenital anomalies with cardiovascular and muscular skeleton anomalies being predominant.46 7 There is a paucity of information on the use of bath salts in pregnancy. There have been recent reports of bath salt use in pregnant women in Michigan and Florida. The Michigan Health Department reported use among pregnant women and a Florida Department of Law Enforcement reported 61 calls to poison centers a number of which involved pregnant women.47,48 There is no test to detect bath salts therefore health care providers must inquire during their screening for alcohol and other substances about bath salt use. ANTENATAL/INTRAPARTUM/ POSTPARTUM CONSIDERATIONS Identification of amphetamine, methamphetamine, ecstasy, and bath salt abuse during pregnancy is challenging. As with other illicit substances in pregnancy it is important to systematically inquire during prenatal registration about substance abuse. Both rehabilitation and detoxification are the gold standards for treating amphetamine and methamphetamine addiction in pregnancy. However, prospects for successful rehabilitation and detoxification are guarded because of the physiological effects of these drugs which induce an intense craving that is difficult to extinguish. Detoxification should only be attempted in consultation with a trained addiction specialist because once the parturient stops taking amphetamines she is at high risk of experiencing withdrawal symptoms with risk of depression, insomnia, and visual hallucinations. These symptoms may be managed with the use of psychotropic medications. Once the parturient is stabilized, the providers can refer the patient to trained mental health professionals for psychological healing. During the intrapartum period, amphetamine abusers are at risk of experiencing obstetrical emergencies such as fetal distress and placenta abruption. Regional anesthesia places these patients at risk for severe hypotension and response to treatment with vasopressors is unpredictable. If www.clinicalobgyn.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 8 Lindsay and Burnett general anesthesia is selected for cesarean section, potent inhalation agents such as halothane should be avoided as they may sensitize the myocardium to endogenous catecholamines.29 Finally, breastfeeding is strongly discouraged in these mothers because of the high concentration of amphetamines in breast milk and the detrimental effects on the fetus including poor sleep and irritability.49 4. 5. 6. 7. Conclusions The impact of the use of street drugs and illicit substances during pregnancy can have devastating maternal and newborn consequences. An effective strategy to address this important public health problem is for all prenatal care providers to offer routine voluntary substance use screening at the time of the obstetrical intake interview. Parturients who are identified as drug users should receive a multistep management approach that includes comprehensive counseling concerning the adverse maternal and fetal/newborn impact of continued use comprehensive prenatal care with referral to a multidisciplinary team for drug rehabilitation and a high-risk pregnancy specialist for ongoing fetal surveillance; and comprehensive postpartum follow up with referral to family planning, a primary care provider and referral to social service to insure that the newborn has a safe home environment. References 1. ACOG: At-risk drinking and illicit drug use: ethical issues in obstetric and gynecologic practice. ACOG committee opinion number 422. Obstet Gynecol. 2008;112:1449–1460. 2. Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol. 2007;19: 578–585. 3. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings. 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