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11 134 B. Sudden Infant Death Syndrome ......................................................................... 152 C. Teratologic. Destructive. and Neurobeh:wioral Effects ..................................... VII. Conclusion.., and Scope of Future lnvestigatiom, ..................................................... 154 Acknowledgments ........................................................ :. ..................................................... 154 References .................................................................................................... ....................... 155 I. INTRODUCTION Cocaine (benzoylmethylecgonine) is an alkaloid derived from the leaves of the plant Erythro.D'lon coca. which grows in Peru. Chile. and Bolivia. It is marketed as a pure hydrochloride. "'Crack". a vernacular expression for cocaine base. is formed by mixing cocaine hydrochloride, baking soda. and warm water in ~uitahle r~ropnrtions. The resulting .~o==O Oa~e t~treet name. "'rock") i~ broken off and smoked by users of illicit drugs? The name "'crack" is possibly derived from the crackling noise made when "'rock" is heated.~ Smoking "'rock" or "'crack" may cause a euphoric rush within seconds and a high that lasts for l0 to 12 min. After nasal insufflation, plasma concentrations of cocaine reach peak values in about 15 to 60 min.: The eupboda induced by smoking cocaine has possibly cona'ibuted to its illicit use. One of the serious and growing problems which will have an impact on the health and well- being of pregnant women is cocaine/crack abuse? It is estimated that 11% of the U.S. population regularly use cocaine:~ 2 to 3% are believed to use cocaine during pregnancy. A survey in 16 states and the District of Columbia involving 50.000 people indicates that women of childbearing age ~ 18 to 34 years) constitute 15% of all regular users of cocaine? The human fetus is dependent upon the maternal environment for its safety, health, growth, and develop- ment. Cocaine and other abused drugs ingested by pregnant women may damage the devel- opment of the fetus by many mechanisms.' ( l ~ Cocaine and its metabolites may interfere with normal physiological processes of pregnancy, r~sulting in fetal loss, prematurity, and obstet- rical complications threatening to both maternal and infant health, f2) Cocaine and/or its metabolites may enter the placenta and interfere with placental transport of nutrients to the fetus. Thus. they cut the maternal supply line to the developing fetus. ~3) Cocaine and/or its metabolites cross the placenta and interfere with growth and development, both physical and mental, causing reduced birth weight, birth detects, learning and behavioral disorder, and newborn distress. The immature enzyme systems in the developing fetus cannot detoxi~' drugs. Therefore, cocaine use may cause complications due to its effects on the mother, placenta, fetus, and newborn infant. A. EFFECTS OF COCAINE USE DURING PREGNANCY The adverse effects of cocaine use by pregnant women can be attributed to its well-known pharmacological effects, which are accentuated by pregnancy. Cocaine is hydrolyzed by plasma and liver cholinesterases to water-soluble metabolites tbenzoylecgonine and e.cgonine) ~hich are excreted in urine. Plasma cholinesterase activity may decrease in pregnancy. resulting in decreased metabolic clearance of cocaine and enhancing its pharmacological effects." Cocaine blocks the reuptake of the neurotransmitters norepinephrine and dopamine 2fter their release by the nerve terminals. Reuptake is the major mechanism by which the actions of norepinephrine and dopamine are terminated. Increased levels of these neurotrans- mitters at their receptors result in the stimulation of the sympathetic nervous system, causing vasoconstriction, tachycardia, hypertension, and cardiac dysrhythmia.

135 The full implications of cocaine use during pregnancy remain unknown. However. a complications in pregnancy, and the risks to their t~tuses and off,spring.~ The hazards of cocaine specific tk~r pregnant women include placental abrupfion, premature rupture ~I" mem- branes, spontaneous abo~ion, abno~al labor, and several general medical risks. I. Abrupto Placenta .%|aterna~ and fetal mortalities approach as high as 10 and 95%. respectively, in severe :ompiete placental abruption. Chasnoff et al." first reported the association between cocaine use and placental abruption. Since then. several reports have been published on this topic. They were reviewed by Lindberg et al.-~ and Slutsker.-~ Placental abruption occurs more frequently in cocaine users than in nonusers? Women who use cocaine throughout pregnancy are more likely to suffer placental abruption than those who stop cocaine use aRer the first trimester." It is likely that cocaine users who do not receive prenatal care have a higher frequency of placental abruption than cocaine users who receive prenatal care."' Several in~ e.,,tigator., ~ ho controlled prenatal care rbund that cocaine use is an independent risk factor for placental abruption.' t.z: Histological studies of placentas of cocaine users have failed to reveal any specific morphologic alterations. No biochemical studies have been conducted on placentas of cocaine-addicted women,t-~ However. repeated findings of elevated risk support a relationship betw-een cocaine use and placental abruption? 2. Premature Rupture of Membranes The risk of in fection for the t~tus increases with premature rapture of membranes t PROM).ta The incidence of PROM is elevated in cocaine users with positive tests for cocaine in urine.': Combined use of cocaine and opiates further increases the risk of PROMJ~ If cocaine users received prenatal care. there is no increased risk compared to nonusers,t: In summary., the data linking PROM and cocaine use are inconsistent.'~ 3. Spontaneous Abortion Spontaneous abortion is nonihduced separation of the products of conception before the period of viability, generally 20 to 24 weeks of gestation. One study found no increased risk of spontaneous abortion with cocaine useJr while others reported increased risk.m,~ There is insufficient evidence currently available to link cocaine use with spontaneous abortion.: B. GENERAL MEDICAL RISKS: HYPERTENSION General medical risl~s due to use of cocaine in pregnant women include ( 1 ) enhancement of pregnancy-induced hypertension,ts (2) elevated risk of precipitating deliveryJt.~') and (3) fetal death.;" THe available evidence does not convincingly support the role of cocaine in pregnancy-induced hypertension, precipitate delivery, or fetal death in humans. Studies of pregnant cocaine users are generally conducted in large inner-city hospitals. There are too many variables for the selection of suitable subjects. The subject variables include socioeco- nomic status, race. culture, education, income, nutrition, and prenatal care. Often. subjects have used more than one drug. Suitable animal models have to be employed to evaluate the risks of cocaine use in pregnancy. The role of cocaine to induce hypertension has been studied by Woods et al.:t)--': using pregnant dn,d oopi~orectomized nonpregnant e,.~,e~, lntravenou.,, cocaine t 1,2 m~kg~ increased >.vstolic. diastolic, mean arterial, and pulse pressures by a higher degree in pregnant ewes 129,6%. 48.7% ~ than in nonpregnant ewes ~ 15.6%. 27.7% ~ within 5 min.'-" This means that the vascular system of the pregnant ewe is about 76 to 90% more sensitive to the effect of cocaine than that of the nonpregnant ewe. The same intravenous doses of cocaine ~ 1. 2 mg/kgl increa.~ed uterine va>cular re.,,i.~tance b.~ t)f)t~ and I t)~' i in the pregnant e~s'e of I 15 to 120 da.~ s

136 Plavental T,,rz,',,h,...v II. METABOLISM OF COCAINE The distribution and metabolism of cocaine in the dog and rabbit following intravenous. subcutaneous, and oral administration ~10 to 30 mg/kg~ have been studied by Woods etal.",~ The plasma concentrations are dependent on the route of administration. The total amount of dru~ ~ hich appears in the urine i~ highly varmt~le and represent~ 1 to l 2% of the injected drug after 24 h in the dog. About t% of the drug is excreted in urine in the rabbit. Most of the cocaine is metabolized in the liver or plasma. Not all the metabolites of cocaine have been completely identified. Liver is the primary site for detoxication of radioactive cocaine in the rat.:~ Radioactive cocaine is metabolized fairly rapidly, and only small quantities t l to 1.5%) are excreted free in urine and feces. The excretion of metabo|ites, as indicated by the total radioacti~,ity values. continues for several days. There are only minor differences in the excretion of free cocaine or total radioactivity in urine from acutely and chronically treated rats.-'a The metabolites of cocaine in plasma and urine can be divided into two groups: ¢I~ major metabolites which are chemically identified in the plasma or urine of mammals with clearly delineated metabolic pathways and ~2~ minor mstabotims which are derived from the hydroxy- lation of the phenyl nucleus of cocaine with enzymatic pathways for their formation in mammalian tissues. Due to small yields, minor metabolites have not been definitely identified by chemical methods. A. M.-MIOR .METABOLITES OF COCAINE: EFFECTS OF" PREGNANCY Cocaine is transformed into four major metabolites in mammals: norcocaine. benzoylecgonine, ecgonine methyl ester, and ecgonine tFigure IL Each is derived from a separate metabolic process. Norcocaine arises from the action of an N-demethytase present i'n adult human liver. Benz6ylecgonine appears spontaneously or after hydrolysis of the methyl group by nonspecific esterases. Ecgonine methyl ester results from the action of cholines- terases and/or tropinesterase. Ecgonine (tropine carboxylic acidl may arise fromenzymatic hydrolysis of either benzoylecgonine or ecgonine methyl ester. Norcocaine is oxidized to .V-h.vdroxynornicotine. which is further oxidized to norcocaine nitroxide. The major metabolites of cocaine exhibit se~'eral oharmacoloo_ical acfivitie,~ ~Table I ~. lr~ .-ome actt,, tire.,, me.,, are more potent titan cocmne. Pregnancy and progesterone enhance the ef*.'ec:~ of ~om.e metabolites. Cocaine is par~iall.~ mct,tboiized ~20c~ s b.~ .',.'-i*t*ted*t.',.iatiotl to norcocaine."2 which is more effective than cocaine for inhibiting norepinephrine uptake.:¢' The remaining 80% of cocaine and norcocaine is metabolized by liver microsomal monooxygenases and liver and plasma esterases.~ Pregnancy alone decreases liver cytochrome P450 concen- trations by 25% and specific activities of glucuronyl transferase-" and monooxygenase:'~ in rats and rabbits. Progesterone increases enzymatic demethylation-'~ and vascular reactivity to cz-adrenergic receptor agonists. These observations suggest that pregnancy increases cocaine sen.-itivity by increasing formation of not'cocaine and decrea.,,ing norcocaine metabolism. Pseudococaine tdextrococaine_ i.~ococaine~ is a distereomer of cocaine with greater local anesthetic activity than the natural substance, levo-cocaine..~'' It interacts with Na- channels)t its pharmacological actions in pregnant animals are not known. Benzoylecgonine and benzoytnorecgonine form Ca- complexes and may interfere with Ca- function in the cell..~: Benzo.vlecgonine induces convulsion.,, in mice after intracisternal administration.:.: It also