Journal of Toxicology: Clinical Toxicology

ISSN: 0731-3810 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx19

Cocaine Exposure in utero: Perinatal Development and Neonatal Manifestations - Review Zeev N. Kain, Tatiana S. Kain & Emile M. Scarpelli To cite this article: Zeev N. Kain, Tatiana S. Kain & Emile M. Scarpelli (1992) Cocaine Exposure in utero: Perinatal Development and Neonatal Manifestations - Review, Journal of Toxicology: Clinical Toxicology, 30:4, 607-636, DOI: 10.3109/15563659209017946 To link to this article: http://dx.doi.org/10.3109/15563659209017946

Published online: 25 Sep 2008.

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CLINICAL TOXICOLOGY, 30(4), 607-636 (1992)

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COCAINE EXPOSURE IN UTERO PERINATAL DEVELOPMENT AND NEONATAL MANIFESTATIONS - REVIEW

Zeev N. Kain, M.D., Tatiana S. Kain, M.D. and Emile M. Scarpelli, M.D., Ph.D. Departments of Anesthesiology and Diagnostic Imaging Yale University School of Medicine, New Haven, Connecticut, Perinatology Center, The New York Hospital. Cornell University Medical Center, New York, New York

Cocaine is widely recognized as one of the most frequently used illicit drugs in use today. This review examines animal and clinical data concerning in utero cocaine exposure and its effect on the development of the fetus and newborn infant. (Key Words: cocaine; abnormalities, drug induced; teratogens; substance abuse; neonatal abstinence syndrome; fetal development; review.)

A HISTORICAL NOTE The earliest evidence of cocaine use by humans dates back to 600 A.D., as evidenced by the findings of coca leaves in the tombs of natives of Peru (1-3). With the establishment of the Inca Kingdom, the habit seems to have spread across large parts of South America. Local tribes used leaves of the plant Emythroxylon Coca for religious, mystical, stimulant and medical

Address reprint requests to: Dr. Zeev Kain, Department of Anesthesiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510. 607 Copyright

1992 by Marcel Dekker, Inc.

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purposes (4-6). Soon after the European discovery of the new world, export of coca leaves began in small quantities. Centuries later, in 1855, the active coca alkaloid was isolated, chemically defined, and named cocaine (1). The local anesthetic quality of cocaine and its application to clinical ophthalmic practice was noted some 20 years later (7-8) and, in 1884, Freud published a report on the properties of cocaine as a local anesthetic and central nervous system (CNS) stimulant (1). Freud’s comprehensive description of cocaine remained an authoritative source for the next few decades. Cocaine is one of the first alkaloids to be synthesized chemically; its molecular structure was defined in 1955 (9). The dangers of cocaine have long been recognized, so that by 1891 200 reports of cocaine intoxication could be documented (10). Cocaine’s activity as a CNS stimulant gained popularity in the early 20th century. In the last decade cocaine addiction became epidemic.

EPIDEMIOLOGY Epidemiologic data indicate that cocaine abuse is gaining worldwide popularity. It is now estimated that some 30 million Americans have tried cocaine at least once, and that 5 million of them have become regular users (11-12). About 14%of the US population has tried cocaine at least once, as compared with about 1 million in 1979 (0.5%) and some 100 OOO in 1959 (0.06%) (9). The National Institute of Drug Abuse reported that in 1986 cocaine abuse became the most frequent cause of drug-related emergency department visits, surpassing alcohol and narcotics (13). According to one survey, the age group most likely to abuse cocaine is 20-25 y 0 , with the next most likely group 26-35 y o (14). Women cocaine users have an average age of 25 and 67%of them have used the drug for five years or longer (15). The prevalence of cocaine abuse during pregnancy has been reported as 10-15%(16). In inner city hospitals 18-20% of pregnant women had urine metabolites suggesting cocaine use (17). The high use, easy availability, low cost and addictive nature of cocaine has lead to mounting concern about the effect of the drug on exposed fetuses.

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PHARMACOLOGY Cocaine is an alkaloid derived from the leaves of the South American plant Erythroxylon Coca (1). Commercially, the coca alkaloids are hydrolyzed to obtain ecgonine, which is then benzoylated and methylated to the base cocaine (8). The conversion to cocaine hydrochloride forms a water soluble salt which can be marketed as crystals, granules or white powder. About 8996 of the commercial product is in the hydrochloride form. Cocaine hydrochloride decomposes at high temperatures and melts at 195OC. Cocaine in the alkaloid form (free base) is lipid soluble and can be produced by mixing cocaine hydrochloride salt with an alkali. The free base is odorless, colorless and has a molecular weight of 303.36 (2). Cocaine free base ("crack") is more stable on heating, vaporizes readily and has a very high bioavailability when smoked. It is estimated that 40% of addicts use cocaine intranasally, 30% by free base smoking, 20% by injection and 10% by combined use. Cocaine is rapidly absorbed from mucous membranes including those of the upper respiratory tract. Most rapid absorption occurs after inhalation of free base cocaine, with peak absorption into the circulation in the time of four breaths (18). Tachycardia and intense euphoria occur within 5 to 10 min, which is comparable to the effect from intravenous administration (19,20). Peak serum concentration is reached 3 to 5 min after injection and 15 to 20 min after nasal absorption (21). Cocaine is still detectable on nasal mucosa 3 h after application and in the plasma for up to 6 h. The bioavailability of cocaine from nasal route is about 60% (22) and peak plasma concentration is proportional to the dose administered. Cocaine is a potent vasoconstrictor and may limit its own absorption; fluctuating degrees of local vasoconstriction may explain the variability of absorption rate (22). Since cocaine is lipophilic, it readily crosses the blood brain barrier and accumulates within the CNS. This results in brain concentrations about four times the peak plasma concentration (18). Less than 5% of cocaine is excreted unchanged in urine; the rest is metabolized to ecgonine methyl ester (EME), benzolyecgonine and norcocaine. EME and benzoylecgonine constitute over 80% of cocaines

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metabolites and have a half life of four to six h (23-25). Hydrolysis by liver and plasma esterases plays a major role in the metabolism of cocaine. A minor but significant N-demethylation of cocaine to norcocaine occurs in the liver. Norcocaine is the only cocaine metabolite with a significant pharmacologic activity. Several factors may operate to produce higher than expected levels of cocaine and pharmacologically active norcocaine in the fetus for any given intake by the mother: 1) Since cocaine crosses the placenta rapidly, fetal and maternal serum levels may tend to equilibrate. 2) Pregnant females reportedly metabolize cocaine by the N-demethylation pathway (to norcocaine) to a much greater extent than non-pregnant females (26). 3) The concentrations of serum esterases are diminished in maternal serum during pregnancy (8). 4) Fetal serum is also relatively deficient in esterases as compared with non-pregnant adult levels (27,28). As a result, a given dose of cocaine in a pregnant female, as compared to a non-pregnant female, may produce higher and more sustained blood levels (28). Conversely, cocaine may be metabolized by placental esterases, which may, in part, counteract the effect of serum esterase deficiency (29). Additional research is required in this area. The pharmacologic actions of cocaine are generally described under three main headings: local anesthetic, sympathomimetic, and CNS stimulant. The local anesthetic effect is produced by inhibition of impulse generation and conduction within nerve cells. Cocaine prevents the rapid increase of cell membrane permeability to sodium ions during depolarization by binding specific membrane receptors within the sodium channel (30,31). Like other local anesthetics, cocaine also produces a negative inotropic and chronotropic effect on heart muscle (8). The sympathomimetic effects of cocaine, which usually mask the effects on myocardium, result from interference with presynaptic catecholamine uptake leading to catecholamine accumulation at the postsynaptic site. An additional postsynaptic action of cocaine is to increase the maximal response of effector cells to stimulation, thereby enhancing the sympathomimetic effect. The CNS effect of cocaine is expressed as brief but intense behavioral stimulation in the form of arousal and euphoria from enhanced activation of the so-called "pleasure pathway"

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of the brain (32). The mechanism appears to be stimulation of dopamine release in the mesolimbic and/or mesocortical pathways (33). Additional mechanisms may also be involved, including release of serotonin and/or blockade of its re-uptake (32). The neuropharmacologic and cardiovascular effects of cocaine resemble those of amphetamines (32). Sympathetic stimulation results in tachycardia, increased myocardial contractility, vasoconstriction, bronchodilation, pupillary dilation and muscle tremors (8,30,34). Temperature may rise, arousal and euphoria may be followed by dysphoria, anxiety, violence and drug craving.

TERATOGENESIS There continues to be some debate over the definition of teratogenesis. Wilson defines it as lethal malformations, growth retardation or abnormal function in the fetus as a result of early insult (35). There is now general agreement that the term "growth abnormality" should replace growth retardation so as to include both inhibited and abnormally accelerated growth, e.g., macrosomia. Vulnerability of the embryo-fetus is a function of the developmental stage at the time of insult, the most sensitive period being the period of organogenesis (embryogenesis). In order to evaluate cocaine teratogenicity, studies of both animal models and of human case histories will be considered. Cocaine administration to CF-1 mice during the period of organogenesis produced a wide variety of fetal malformations, including both increased resorption rate and significantly higher incidence of skeletal defects, anencephaly, eye malformations, hydronephrosis ,cryptorchidism and delayed ossification of the skull (36). In a more recent study, Finnel el al. investigated the teratogenicity of cocaine in two inbred mouse strains (37). A dose related effect on the frequency of induced malformations was found. The anomalies included dilated or immaturely developed cerebral ventricles, hydronephrosis, dilated or cystic ureters and grossly distended bladders. There was a statistically significant relationship between dilated cerebral ventricles and genitourinary defects and increasing dosage of cocaine.

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Abnormalities of the limbs occurred sporadically, mainly flexion deformities and reduction of digits. Gastrointestinal defects included ileal atresia predominantly and also abnormalities of the pylorus and colon. Cardiovascular defects were frequently observed in the cocaine exposed fetuses, the most common being pulmonary stenosis, transposition of great arteries, and hemopericardium. Vascular defects resulting in intra-abdominal or mesenteric arterial hemorrhage and cerebral hematoma were also observed. Some miscellaneous abnormalities such as a cleft lip were described. This study is of particular importance because it revealed the wide range of possible cocaine teratogenicity and the significant dose-related effects on cerebral ventricular and genitourinary development. Webster et al. found that cocaine is teratogenic to rats only during late organogenesis or the post organogenesis period (38). Cocaine exposure induced hemorrhage and edema in the developing fetus with subsequent necrosis or disruption of existing and developing structures, particularly the limbs. Church ez aE. (39) found an increased incidence of edematous, hemorrhagic fetuses with anophthalmia and microphthalmia. Other animal models have failed to show a significant increase in internal and external malformations (40). The difference may be attributed to different routes of exposure and different strains of experimental rodents. The dose-response curve may explain the wide variability in the incidence and type of congenital malformations reported. The limited number of human reports makes it difficult to draw firm conclusions regarding in uzero cocaine exposure. This problem is not unique to cocaine. Given the obviously tenuous circumstances for making controlled observations in humans involved with illicit drugs, it is often difficult if not impossible, to determine the time and dose of drug exposure. For the same reason, precise determination of exposure to other drugs and teratogens may be thwarted. Several of the studies of in utero cocaine exposure reported concomitant use of marijuana, alcohol and cigarettes (41-46). Alcohol and marijuana are known teratogens, while cigarettes have been associated with small-for-gestational-age babies (47-49). In 1985, Chasnoff et al. reported the occurrence of prune belly syndrome, hydronephrosis and cryptorchidism in a group of infants exposed

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to cocaine in utero (45). Two years later, two additional studies of in utero cocaine exposure described malformations of the cardiac, neural tube, gastrointestinal and genitourinary systems as well as bone defects (41,44). The human studies indicate that cocaine may have a teratogenic effect on almost every system of the body, although a recent meta-analysis which examined many of the human reports did not confirm a significant effect

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Possible Underlving Mechanisms Cocaine-induced sympathetic activity, as described earlier in this review, may result in generalized maternal vasoconstriction, hypertension and tachycardia. Whereas uterine blood vessels are normally dilated, operating at near maximum hemodynamic efficiency (51) increased sympathetic tone may cause spasm of the uterine vessels and consequent impairment of oxygen and nutrient transfer to the fetus. In gravid ewes maternal administration of cocaine elevates blood pressure and decreases uterine perfusion rate with a pronounced dose-dependent effect (52). Uterine vascular resistance was increased by 52 to 168% depending on the dose. The fetal effects included elevated blood pressure, increased heart rate, and a marked fall of arterial oxygen content and oxygen pressure (Pao,). These responses can be explained both by the effect of cocaine on the uterine vascular bed and by maternal hypoxia; the lowering of fetal PaO, related directly to the reduction of uretroplacental blood flow (53). Fetal hypoxia secondary to maternal cocaine usage has been confirmed repeatedly in studies of humans, rats and ewes (52-57). Precedent research provides some insight into fetal consequences of hypoperfusion and hypoxia. Hypoperfusion or interruption of blood flow to the developing embryo may result in infarctions, hematomas, or ablation of the developing vasculature and developing structures. For example, vascular disruption following either acute or chronic reduction of blood flow has been linked to transverse limb reduction defects and VATER-like anomalies (58,59). It is likely that the nature of the cocaine-induced defect(s) reflects the timing during fetal development of the insult and the location of the vascular injury or hemorrhage. For example, disruption of the superior mesenteric artery in early gestation will result in intestinal atresia. If the

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same disruption happens in late gestation, the result may be intestinal infarction (60). Hemorrhage and consequent ischemia may also follow a rapid increase of fetal systemic and cerebral blood pressure similar to that noted in cocaine exposed adults (61,62). Hemorrhage may also accompany the hyperthermia associated with cocaine abuse. Indeed, hyperthermia has been shown to produce a teratogenic effect as a consequence of associated hemorrhages (63). Some investigators have also reported placental thrombi in association with maternal cocaine use (64). The significance of this finding is unclear, but may be related to the thrombi serving as a source of thromboembolism. The possibility that cocaine may have a direct toxic effect on developing tissues cannot be excluded and needs to be studied. Obstetric complications related to cocaine use are numerous and extend throughout pregnancy. Clinical Correlates There is a significant increase in the incidence of spontaneous abortions, abruptio placentae and pre-term labor (4-46,65-68). An increased number of stillbirths and chorioamnionitis has also been reported in women using cocaine during pregnancy (41,45,69). Complications at delivery include an increase in meconium staining in up to 20% of all deliveries of cocaine abusers and a 1.5 fold higher incidence of premature rupture of membranes (42). The tonic sympathetic stimulation related to cocaine may result in acute maternal hypertension, which may then lead to abruptio placentae. In addition, stimulation of the myometrium results in increased uterine contractility and, an enhanced risk of premature rupture of membranes and preterm labor (70). Uteroplacental insufficiency has also been associated with such fetalneonatal problems as reduced birth weight, intrauterine growth retardation and fetal intolerance to labor (14,17,41,42,44,67,68,71). Intrauterine growth retardation and low birth weight may be related to the length and the timing of in #em cocaine exposure. A study conducted in infants exposed prenatally to cocaine indicates that only exposure throughout pregnancy will result in lower birth weight, birth length and head circumference while exposure limited to the first trimester produces no change in birth weight (72). Decreased intrauterine growth may be related to the intermittent

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diminution in placental blood flow associated with maternal cocaine use. In utero cocaine exposure is also associated with depressed neonatal fat stores and diminished body mass (73). In the past, these effects were associated with maternal malnutrition (74). However, even after maternal weight and height at conception and pregnancy weight gain were controlled, the findings in cocaine users were sustained. The phenomenon of decreased fat and body mass are consistent with the effects of compromised uterine blood flow and transfer of nutrients. Moreover, the high catecholamine levels of the fetus may increase fetal metabolism and thus cause depletion of fetal nutrients.

CARDIOVASCULAR SYSTEM Cardiac abnormalities associated with cocaine exposure in utero are listed in Table 1 (41,75,76). A retrospective comparison of 214 infants who tested positive for cocaine metabolites and 314 infants who tested negative indicated the rate of central cardiovascular anomalies to be significantly higher in the positive infants (75). Another study showed that the rate for cocaine positive infants to be significantly higher than the published rates for the general population of infants (77). Structural defects among the cocaine positive infants included peripheral pulmonic stenosis, patent ductus arteriosus, atrial septal defect, ventricular septal defect and prolapse of an aortic valve leaflet. Animal studies also show a wide variety of anomalies (37). The most frequent include pulmonary stenosis, transposition of the great arteries and hemopericardium. Organogenesis of the cardiac system is essentially completed by the sixth to eight week of fetal life. Normal cardiac organogenesis depends on adequate fetal blood flow and myocardial oxygenation. Any insult during this critical period may result in structural anomalies (78). Cocaine may produce its effect through fetal hypoxia secondary to uterine vessel constriction. Since fetal hypoxia stimulates the release of catecholamines from fetal chromaffm tissue, (79) chronic catecholamine excess could also be a stimulus for cardiac hyperplasia and hypertrophy (80). In addition, cocaine induced vasoconstriction may lower intracardiac blood flow locally and inhibit development of specific regions of the heart (81).

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TABLE 1 Cardiac Abnormalities Associated with In Utero Cocaine Exposure In Humans

Pulmonary Atresia Pulmonary Stenosis

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Atrial Septal Defect Ventricular Septal Defect Aortic Valve Leaflet Prolapse

Hypoplastic Heart Syndrome Biventricular Hypertrophy Right Sided Valve Changes Patent Ductus Arteriosus Conduction Defects

Other cardiac abnormalities such as conduction defects, voltage abnormalities and transient ventricular tachycardia have been reported in cocaine-exposed infants (75,82). These rhythm abnormalities can be attributed either to enhanced beta adrengeric stimulation or to a direct toxic effect of cocaine. When administered to gravid animals, cocaine produces a dosedependent increase in maternal heart rate and blood pressure and a decrease in uterine blood flow (53). The fetus responds to maternal cocaine consumption with tachycardia and elevated blood pressure (52,53,56). Most reports of human infants confirm increased heart rate and blood pressure following cocaine exposure (83,84). Cardiac output and stroke volume fall, possibly in response to increased plasma norepinephrine level (54,84,85). In most reports all the hemodynamic parameters tend to return to normal after the first day of extrauterine life.

UROGENITAL SYSTEM Development of the urogenital systems in humans is underway at 5 weeks gestation (86). Since the serial reports of Mahalit ez al. (36) and Chasnoff et al. (43, there have been a number of studies to certify the wide variety of urogenital developmental abnormalities that are closely associated with cocaine in the gravid female (37,42,44,71,87,88). The reported abnormalities are listed in Table 2.

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TABLE 2 Urogenital Abnormalities Associated With in Utero Exposure

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Prune Belly Syndrome Hypospadias Hydroureter Hernia Hydronephrosis Cryptorchidism Horseshoe Kidney

Undescended Testes Enlarged Bladder Renal Agenesis Bifid Scrotum Retrovesical Fistula Pseudohermaphroditism (82)

Etiology and pathogenesis of prune belly syndrome are unclear. The syndrome includes but is not restricted to prostatic hypoplasia, enlarged bladder, hydroureteronephrosis and cryptorchidism (89), each of which can be linked to vascular compromise around the twelfth week of gestation. A possible construct for pathogenesis is the following: Cocaine induced prostatic vasoconstriction may be followed by either atrophy or hypoplasia of the prostatic stroma (86). These effects produce obstruction leading to bladder distention and subsequent inhibition of further development of the urinary tract. Indeed, the most common pathologic finding in children with prune belly syndrome is prostatic hypoplasia (90,91). Similarly cocaine induced spasm of ureteral vessels may lead to fibrosis and flaccidity of this structure thereby producing hydronephrosis (86). Cryptorchidism, which could be related to the poor intra-abdominal pressure in these children, has not been analyzed in terms of fetal development and cocaine exposure (92). Since cocaine may also play a role in the utilization and availability of ionized calcium (30), it has been suggested that interference with Ca+* metabolism may reduce effective ureteral peristalsis, thereby facilitating development of hydronephrosis (93). The question of maternal cocaine use during early pregnancy as a risk factor for urogenital anomalies was addressed specifically in a recent clinical study (88). Maternal cocaine use during early pregnancy was defined as "reported use at any time from one month prior to pregnancy to the end of the first trimester." The study identified 276 babies with urinary tract and

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791 with genital anomalies. There were 2835 and 2973 respective controlbabies, without birth defects, randomly selected through birth certificates. The investigators reported a significant association between cocaine use and risk of urologic defects. The estimated crude odds ratio was 4.4 for urologic anomalies, including hydronephrosis, prune belly sequence, ureteral and renal agenesis, ambiguous genitalia and a unilateral ectopic fallopian tube (86). There was no statistically significant association between in zuero cocaine exposure and intrinsic defects of the genitalia. The results of this study support the hypothesis of precedent clinical and animal studies regarding the teratogenic effect of cocaine. In contrast two other studies did not support this association (94,95). However, one of the studies examined only full term well babies, while the other used renal ultrasonography only in a small sub-population of the patients. Along with the structural defects of the urinary tract, other anomalies have been reported: a high incidence of urinary tract infection was described in infants exposed to cocaine in uero (96). The frequency of urinary tract infection was as high as 20%,as compared with 0.5 to 3 % in normal preterm and term infants. A recent preliminary report suggested an association between cocaine exposure in utero and persistent, subclinical hyperchloremic metabolic acidosis (97). In a group of 149 infants with a history of in utero cocaine exposure (97), evaluation of renal function showed normal serum creatinine and low urinary sodium excretion. Given the many possible effects of cocaine on the structure of urinary system, it is clear that functional development needs to be evaluated further. CENTRAL NERVOUS SYSTEM (CNS) CNS complications in adult cocaine abusers include cerebrovascular accidents, hyperpyrexia, seizures, cerebritis and abnormal electroencephalogram (EEG)(9,98-100). Over the past few years several groups have reported a number of CNS complications in infants exposed to cocaine in utero (41,45,46,65,41,71). Chasnoff et al. noted increased tremulousness, deficient interactive behavior and disturbed state organization among cocaine exposed infants (45).

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On0 and Dixon described a neurologic behavioral pattern typical of infants born to addicted mothers, including sleep pattern disturbances, tremors, feeding difficulties, hypotonia, vomiting, sneezing, high pitch cry and hyperreflexia (46). Other investigatorshave described jitteriness, irritability, poor feeding, increased muscle tone, impaired motor ability, seizures, apathy and decreased orientation (14,45,71,101-103). Most but not all neurobehavioral disturbances after delivery probably follow the direct neurotoxic effect of cocaine rather than withdrawal, because clinical signs disappear as the cocaine metabolite disappear from urine. The fetal response to cocaine has also been investigated (104). A group of fetuses was followed by ultrasonography in Uero and later assessed as newborns. Manifestations of acute fetal intoxication included hyperflexia and prolonged periods of scanning eye movements during vigorous sucking. The fetus appeared to experience physiologic and behavioral effects concordant with maternal responses to cocaine. The newborns in this study had autonomic instability including excessive tremulousness and unexplained tachypnea. Disturbed state organization was signalled by hyperresponsiveness and by difficulty in arousal. These characteristics were termed "all or nothing", i.e., difficult to arouse and inconsolable when aroused with only brief or no periods of quiescence. The fetal and neonatal behavioral abnormalities were present even if exposure was limited to the first trimester. The authors suggested that neurobehavioral response deficiencies occur among cocaine exposed infants, whether the mother stopped cocaine use in the first trimester or used cocaine throughout pregnancy (71). Neurobehavioral scores of two infant groups exposed to cocaine during different times in pregnancy were similar (71). Larger prospective studies are needed to resolve this issue. One study indicates that by one month of age drug exposed newborns have improved significantly but are still functioning below drug-free controls in terms of interactive capabilities and state regulation (105). Belcher and Wallace evaluated children between 5 and 30 months of age after exposure to cocaine in wero (106). Fine motor skills were delayed in 4 2 2 , while 36% had suspect or delayed gross motor skills. Neuromuscular dysfunction was present in 24% of the infants.

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Longer term follow-up is necessary to determine the full developmental impact of intrauterine cocaine exposure. While "clusters of abnormal signs" on neonatal neurological examinations may be indicative of later developmental problems, neonatal neurological examinations are also known for their high rate of "false positives." It is also possible that the nervous system may develop compensatory mechanisms and that signs of dysfunction may not be detectable at the time of follow-up (107,108).

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Phonation "High pitch cry" was identified in the past as characteristic of infants exposed to psychoactive drugs in wero (109). From a study that showed depressed neurobehavioral function in the neonate, it was suggested that the depression explained fewer cry utterances, longer first cry utterances (poor cry inhibition), and less variable vocal tract responses (depressed neural input to phonation) in these babies (109). In a second study, cry, which was analyzed twice during the first 48 h of life (110), did not change in a nonexposed (control) group, while fundamental frequencies dropped markedly for some drug-exposed infants. Cry of the exposed infants lacked harmonic structure, and was bitonal with glottic roll and glide. These characteristics could account for the typical "squealing" quality of the cry. &el2

It has been suggested that cocaine may disrupt the arousal mechanisms particularly during sleep (111). A study to determine sleep maturation after cocaine exposure in wero found that sleep among the cocaine exposed infants was poorly organized and disrupted, and that most of the sleep time was spent in active sleep (111). Disrupted sleep may be a factor in the poor behavioral outcome associated with cocaine exposure. Hearing

Animal studies indicate that cocaine has a toxic effect on both the cochlea and brain stem auditory system (112). Central neural conduction patterns recorded from skin electrodes following auditory stimulation are the "auditory brain stem response" (ABR)and the "brain stem transmission time" @TI'). The ABR of newborns exposed to cocaine in utero is abnormal (112114); the specific ABR pattern suggests an abnormality within the brain stem.

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The BTT, along with ABR, has also been reported to be abnormal (112,114). Prolonged BTT associated with intrauterine cocaine exposure may indicate that the myelinization process is either impaired or retarded (115). However, long-term studies show that the prolonged BTT may become normal by 52 to 65 weeks of age (1 15,116). Maturation of axonal elements, principally myelin deposition, is commonly offered to explain age-related "temporary" abnormalities of ABR and BTT as seen in the exposed babies, (115) a concept that is consonant with animal studies (117). Evaluation of the peripheral auditory nervous system of infants exposed to cocaine in utero shows a particular vulnerability of critically ill, less than 30 weeks gestation infants to peripheral auditory dysfunction (107). Two recent reports suggest that the effect on the auditory system is mediated by the secondary asphyxia, low birth weight and/or CNS injury induced by cocaine (1 18,119). Electroencephaloeram E E G l EEG patterns in adult cocaine users can show increased electrical amplitude and beta activity that may be related to clinical seizures (120). Administration of cocaine to animals also promotes the spread of epileptiform discharges in subcortical limbic structures (121). An attempt to correlate neonatal clinical neurologic impairment with EEG abnormalities (101) found that transient neurologic abnormalities are most evident on the third day of life and improve without specific therapy in most cocaine-exposed infants. The EEG was abnormal in 17 of 38 of these infants and was characterized by cerebral irritation with bursts of sharp waves and spikes. The abnormal EEG did not correlate with severity of neurologic signs or with maternal factors. By three to twelve months of age, most of the previously abnormal tracings had normalized. The authors concluded that EEG abnormalities are transient and may be the result of changes in neurotransmitter availability and function. CNS Growth and DeveloDment Average birth weight, head circumference and birth length are reduced in infants exposed to cocaine during pregnancy. Interestingly, neonates who are malnourished in uzero, and are exposed to toxic drugs, usually preserve

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brain growth at least partially (122). This relative sparing of brain growth at the expense of body growth is also seen in other mammals. In contrast, infants exposed to teratogens in utero may lack this sparing effect. These infants may develop a variety of CNS problems, e.g., asymmetric growth and microcephaly (123). Prenatal alcohol exposure was reported in the past to be associated with brain growth retardation both in humans and in animal models (124,125). A study of 801 neonates exposed to cocaine in ufero and 67 infants exposed to alcohol (126) showed that asymmetric growth retardation (i.e. disproportionally small head circumference for body weight at birth) was comparable in both groups, i.e., that head circumference did not differentiate the teratogens. Postnatal assessment of intracranial pathology by ultrasonography, however, provides specific information about cocaine exposure in utero (127). Over one third of 32 term infants exposed in utero were abnormal with ultrasonographic evidence of white! matter cavities, white matter densities, acute infarction, intraventricular hemorrhage, subarachnoid hemorrhage, subependymal hemorrhage and ventricular enlargement. The prevalence of abnormal findings was significantly higher in the cocaineexposed group than in normal infants. Most of the lesions were in the basal ganglia, frontal lobes, and posterior fossa. Ultrasonographic abnormalities were not predictable by standard neonatal assessment, probably because damage to the frontal lobes and basal ganglia generally becomes evident only after the first year of life when more complex visual motion and cognitive tasks can be tested (128). It is believed that the cerebral infarction and brain hemorrhage described in cocaine-exposed infants may be caused by intrauterine and postnatal hypertension just as in adults (65,88). This hypothesis is supported by a number of reports of increased mean arterial pressure in the immediate postnatal period (81,119,120). The choroid plexus has been suggested as the site of hemorrhage, since it is known to be particularly vulnerable in infants, especially when oxygen and carbon dioxide tensions are abnormal (121). This vulnerability in cocaine-exposed fetuses may be related to the relatively high vasoconstriction in the plexus area secondary to the absence of a mature blood brain barrier at this site with enhanced local accumulation of the drug is enhanced.

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Cerebral blood flow velocity and mean arterial blood pressure are elevated during the first day of life in cocaine- exposed infants (103). High velocity may be due to increased cerebral flow and/or cerebral vasoconstriction. The latter is the normal autoregulatory response to increased blood pressure. It may also reflect a direct effect of cocaine. Cocaine was shown to cause vasoconstriction of cerebral vessels of newborn piglets and of cerebral arteries of perinatal lambs (129,130). This vasoconstrictor effect is mediated either through adrenergic receptors or through Naf and K+ channels (129,131). Much of the developmental impairment of the CNS in cocaineexposed infants can be explained by the vasoconstrictor effect of cocaine, for example, on the middle cerebral artery, which supplies basal ganglia and frontal horns. These vessels are relatively well muscularized early in development of the fetal brain, making them more vulnerable to drug-induced constriction. Other possible explanations include placental thromboembolism and impaired cerebral vasodilation in response to hypercarbia and hypoxia (64,129).

GASTROINTESTINAL SYSTEM In utero cocaine exposure is associated with a variety of gastrointestinal anomalies both in animal studies and in clinical reports (17,44,36,132,133). Reports of infants exposed to cocaine in utero contain a fearsome spectrum of developmental anomalies including jejunal atresia, imperforate anus with midcolonic atresia, anal atresia, ileal atresia, and widespread infarction of the bowel (17,44,71,86,88,132). The vasoconstrictor effect of cocaine, can account for some of these abnormalities. Similar lesions have been described following in utero ligation of branches of the superior mesenteric arteries in canine fetuses (60)and after embryonic disruption of the omphalomesenteric artery in humans (134). Necrotizing enterocolitis (NEC) is a common serious gastrointestinal problem of neonates requiring intensive care for a variety of diseases. Recently NEC was shown to be associated with prenatal exposure to cocaine as well (132,135-138). Experimental data show that ischemic or

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postischemic events can produce injury resembling NEC (135). It is reasonable to conclude that increased mesenteric vascular resistance induced by cocaine results in ischemia of the fetal bowel wall and vulnerability of the bowel to bacterial infection resulting in NEC-like disease and bowel perforation (139). It is likely that the various gastrointestinal anomalies reflect differences in timing, location and relative severity of the induced vasoconstriction. For example, disruption of the superior mesenteric artery in early gestation can lead to infarction and necrosis; with time tissue resorption will occur; and intestinal atresia may result. However, should the same vascular disruption occur in late gestation, it may lead to bowel infarction and NEC-like disease.

RESPIRATORY SYSTEM Clinical studies aimed at establishing an association between in urero cocaine exposure and neonatal respiratory distress syndrome (RDS) are conflicting (138,140-143).Some report that cocaine decreases the incidence of RDS, others disagree. Similarly, in vivo animal studies suggest that cocaine enhances production of pulmonary surfactant, while in vitro studies do not (144,145). The difficulty can be related to both the uncertainties in clinical studies and the fact that lung maturation is affected by multiple variables in vivo. Kain et al. addressed the question of lung maturation in an animal model, eliminating many of the maternal factors that would be unknown in clinical studies (140). Fetal rabbits were exposed in ufero by injecting the pregnant dams with cocaine on d 24 through 26 of gestation. Fetuses were delivered prematurely on d 27. Exposure to cocaine was associated with increased lung distensibility and stability, as a result of accelerated morphologic maturation and enhanced surfactant function. Each of these changes is consistent with enhancement of lung development and maturation. The effect was explained on the basis of cocaine-induced increase of cortisol and catecholamine levels, both of which promote lung maturation and have been associated with in ucero cocaine exposure (140).

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Sudden Infant Death Syndrome tSIDS) A number of reports suggest an association between SIDS and in utero exposure to cocaine (42,146-152).However,individual case reports are often difficult to interpret because of concurrent maternal problems, including the use of alcohol, marijuana and other illicit drugs, and deficient prenatal and postnatal care. An early retrospective study concluded that SIDS was the cause of death in 10 of 60 infants exposed to cocaine in utero (147). However, a prospective study of 32 infants exposed to cocaine failed to identify any case of SIDS (146). A large prospective cohort study which involved 1014 mother-infant pairs reported that the risk of SIDS was 5.6 in loo0 among cocaine exposed infants, and 1 to 3 in lo00 among the general population (151). A review of all SIDS deaths in the City of New York, from 1979 to 1989,(149)found an incidence among exposed infants of 4.1 in lo00 versus 1.3 in lo00 in non-exposed infants (rate ratio of 3.1). The association between cocaine exposure and increased incidence of SIDS is tentative at this time. Chasnoff et al. documented apnea and periodic breathing in 38% of a group of 32 infants exposed to cocaine in utero (147). Gibson et al., in a prospective study, evaluated the prevalence of apnea in cocaine exposed term and preterm infants (152). They found that 26% of the cocaine group had abnormal breathing patterns, principally central apnea and also periodic breathing. The possibility that impaired arousal from sleep is a mechanism that increases risk to SIDS or to morbid prolongation of apnea was tested in infants less than one week of age. Two tests were employed (153): The first was arousal during induced hypoxia and the other was ventilatory response to carbon dioxide. Of 24 infants exposed to cocaine in utero, 21 had abnormal arousal to the hypoxia challenge and 15 had abnormal response to carbon dioxide. A cellular basis for this effect, which can only be conjectural at present, should take into account cocaine's action on norepinephrine as the primary neurotransmitter of the putative "arousal center" (154)and other respiration-related brain stem regions (155).

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THE EYE Abnormalities of the eye and vision have been noted in infants exposed to cocaine in utero. The vessels of the iris can appear tortuous and dilated (156), a condition that may presage permanent damage to the iris. However, vascular and tissue abnormalities regressed spontaneously with time, leaving no apparent residual effects. Several explanations were considered: (1) Vascular changes are secondary to a primary but transient effect of cocaine on mesodermal development. (2) Vasodilatation may be a rebound response from cocaine-induced vasoconstriction as the levels of cocaine and its metabolites decrease after birth. (3) Vasoconstriction may be limited to peripheral segments of the iris vessels, thereby reducing outflow from the vessels and dilating the proximal segments. Retinopathy was described in an immature infant exposed to cocaine in uferowithout other known risk factors for the retinal pathology (157). On the basis of this observation, the interesting possibility was raised that regular exposure to cocaine in utero may lead to sustained retinal hypoxia through both the direct effect of cocaine and the induced hypoxia itself. Impetus for additional research on peripheral and central visual effects of cocaine in ufero is provided by a report showing the significantly lower scores of exposed infants in tests of animate and inanimate visual orientation (45).

SUMMARY The question of whether cocaine exposure in utero increases the risk of major structural malformations remains controversial. Most animal studies have demonstrated that cocaine can have a teratogenic effect. The ultimate association between cocaine exposure and fetal development must be inferred from human data. The relative effects of cocaine exposure, exposure to other illicit drugs and alcohol and deficient prenatal care are difficult to assess. Little specific information is available about the amount, duration, and timing of cocaine use during the nine months of pregnancy. Unlike the case with many other teratogens, cocaine exposure at any point in pregnancy can result

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in some abnormality. The extent of damage and the organ involved depend on the particular stage of morphogenesis. A large scale prospective human study is needed to confirm the suggested teratogenic effects. Since it involves an illicit drug such a study is obviously difficult to perform.

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Cocaine exposure in utero: perinatal development and neonatal manifestations--review.

The question of whether cocaine exposure in utero increases the risk of major structural malformations remains controversial. Most animal studies have...
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