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The effects of intrauterine cocaine exposure: Transient or teratogenic?
Archives of Clinicd Neuropsychology. Vol. 6. pp. 133-146. Printed in the LISA. All rights reserved.
1991 Copyright
0887-6177191 $3.00 + .OO 0 1991 National Academy of Neuropycblogy
The Effects of Intrauterine
Cocaine
Exposure: Transient or Teratogenic? Loretta F. Allen, Ronald S. Palomares, Paula DeForest, Brenda Sprinkle, and Cecil R. Reynolds Texas A&M University
The use of cocaine and its smoked derivative, crack, is increasing in America. Among those affected are neonates of women who use cocaine during pregnancy. This paper examines the potential effects of maternal cocaine use upon the developingfetus emphasizing neuropsychological and behavioral effects including those that typically persist into early childhood and beyond. Empirical research should continue to explore the effects of maternal cocaine use focusing on whether or not the many detrimental effects of cocaine use during pregnancy are transient. directly teratogenic, or indirect and due to prolonged hypoxia.
Cocaine, in various forms, is a drug of choice used by an increasing segment of the population each year. Tragically, countless unborn infants are forced to suffer the effects of cocaine upon their developing bodies and minds. We have only recently begun to study the effects of cocaine and still do not fully understand or comprehend the consequences of cocaine use during pregnancy. There are numerous research studies published and in process detailing the consequences of cocaine use in the human body, but there is little information that details the direct effects of maternal cocaine use upon a fetus. Some research findings that are available suggest that the effects of intrauterine cocaine exposure are only transient (Madden, Payne, & Miller, 1986; Doberczak, Shanzer, Senie, & Kandall, 1988; Fame1 & Macphail, 1982). Other research suggests cocaine is teratogenic, resulting in more permanent abnormalities (Mannino & Trauner, 1983). Whether the effects of cocaine are merely transient or more long term has yet to be concluded, particularly with regard to fetal cocaine exposure. Results of Requests for reprints should be sent to Cecil R. Reynolds, Dept. Of Educational Psychology, Texas A&M University, College Station, TX 77843. 133
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TABLE 1 Abnormal Behaviors Observed in Toddlers and Preschoolers Exposed to Cocaine Prenatally Abnormal Play Patterns
Less Representitional Play Less Variation in Play Disorganization of Play Interactional Dilkultics with Both Peers and Adults Hyperactive Behavior
the first study of possible teratogenic effects of cocaine (Fame1 & MacPhail, 1982) showed no evidence of teratogenicity in rats. More recently, the field of teratology has been broadened beyond a study of visible malformations of the neonate to include behavioral anomalies as well that may result from exposure to a drug or other toxic substance during gestation (Grimm, 1987). The effect of a teratogen on an organism is influenced by several factors-the organism’s stage of development at the time of exposure, the chronicity and intensity of the exposure, any genetic predisposition of the organism, and the state of the mother’s physical and emotional well-being (Grimm, 1987). Evidence of the neural effect of a teratogen may be less than obvious because a disruption of the development of one system may secondarily lead to disruption of the normal development of other parts of the central nervous system. This deviation from normal development ultimately may affect the organism’s ability to respond to and to interact with its environment (Spear et al., 1989). Howard (1989) has reported evidence of atypical behaviors found in preschool children who were subjected to intrauterine cocaine exposure. No information was provided concerning the amount or duration of fetal exposure, but when compared with other high-risk toddlers who had not been exposed to drugs prenatally, differences in the children’s play and social interactions were observed. The play of the drug-exposed toddlers appeared disorganized and lacked representational and symbolic elements normally observed in young children. They had a difficult time with fantasy play and appeared to be unable to participate in sustained play with toys. Their play more often consisted of batting at or scattering toys and simply picking up and putting down toys. She also found their lack of organization seemed to extend beyond play into their interpersonal relationships as it was more difficult for these children to relate to peers as well as adults. Regulation of affect was also poor for these children (Howard, 1989). A summary of abnormal behaviors observed in toddlers and preschoolers exposed to cocaine prenatally can be found in Table 1. Similar reports of behavioral abnormalities are also appearing in the news media in articles describing these children. They are being seen in special pro grams for infants and toddlers with special needs, and teachers in these programs describe their behavior as primitive almost limited to “instinctual”
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responses. They sometimes are withdrawn and have trouble interacting with other children through play or conversation. Caretakers have reported that these children are not cuddly and often do not respond when touched or hugged (Sunde, 1990, Feb. 26). A few special programs like the Salvin Special Education School in Los Angeles are being set up around the country in efforts to help remediate some of the apparent deficits of these children (Kantrowitz, Wingert, De La Pena, Gordon & Padgett, 1990, Feb. 12). This paper compiles existing information about the effects of intrauterine cocaine exposure on the fetus, the neonate, and the young child. A brief history of cocaine use is presented along with recent reports of the incidence of cocaine use. The effects of maternal cocaine use on the mother, the fetus, and the newborn are examined. Research is cited that suggests the effects of fetal exposure to cocaine are transient, and evidence of the possibility that cocaine acts as a teratogen will be explored. HISTORY Cocaine is believed to have been used over five thousand years ago by the Incas for religious and medicinal purposes through the practice of burning and smoking parts of the coca plant (Siegel, 1987). It was not until the 19th Century that cocaine was derived as a distinct, concentrated agent from the coca plant, and its use then became widespread in Europe and North America. Cocaine’s medicinal use flourished during this time with much of its perceived popularity having been attributed to Sigmund Freud. Freud is reported to have touted the use of cocaine as a local anesthetic, free of addictive properties (Estroff, 1987), advocating its use as a “cure” for morphine addiction (Commissaris, 1989). However, it was quickly recognized that cocaine was not a safe or nonaddictive drug, and thus the sale of cocaine in the United States was banned by the Harrison Act in 1914 (Pitts & Marwah, 1989). Since the early 1970s cocaine has returned to the forefront of abused drugs with its use becoming more widespread and more serious. Currently, a very rapid and easy method of self-administration of cocaine has become popular. It involves the inhalation of the volatilized alkaloidal form of cocaine through smoking or “free basing” of “crack” (Pitts & Marwah, 1989). Crack is produced by mixing cocaine hydrochloride powder with water and bicarbonate of soda and then drying the mixture in a microwave. The process results in hardened pieces of the drug that can then be smoked in pipes. This method has reduced the price of the drug, making it accessible for all segments of the population. The purity of the drug in combination with the larger absorptive area of the lung causes blood levels to be much higher than those resulting from intranasal cocaine use (Udell, 1989). Consequently, the euphoric effects increase along with the addictive potential and resulting medical complications. Crack can be bought on the street in vials containing tiny chunks or “rocks” at a price ranging
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between $5 and $15 each, and “Crack 19th Century, are becoming common 1989). Smoking “crack” cocaine had over one-third of all the callers to the (Washton, 1989).
Houses,” similar to the opium dens of the throughout the United States (Washton, become the preferred method of use for 800-COCAINE National Hotline by 1989
INCIDENCE The use of cocaine is widespread throughout the population, and it has been estimated that those addicted to cocaine range in age from 9 to 65 years. Cocaine’s impact is spreading from the rich, who were previously the only ones who could afford it, to those less affluent since crack has become so readily available. The actual percentage of the population that uses or is addicted to cocaine cannot be clearly defined. Even attempts to record accurately the number of deaths related to cocaine use have been complicated by the wide variations in the investigations conducted by the medical examiner-coroner systems (Wetli, 1989). Toxicological testing is not always used because of its prohibitive cost and equipment needs. Yet, the increased use of cocaine is evidenced by the fact that by 1986, the death rate due to cocaine in Dade County, Florida, had risen from two per month to nearly two per week (Wetli, 1989). One nationwide survey of Americans (Adlaf, 1986) found that cocaine is being used by 28% of the population between the ages of 18 and 25, as well as by 9% of those 26 and older. Nicholi (1984) reports findings that cocaine use increased in the United States from 9 million in 1972 to 33 million in 1984 in college-aged individuals. Thirty-three percent of young adults in another study (Newcomb, Bentley, & Fahy, 1987) reported the use of cocaine within the six months prior to the study. Other national surveys (National Institute on Drug Abuse-NIDA, High School Senior Survey, National Household Survey, and Drug Abuse Warning Network-DAWN) concur that the incidence of cocaine use is rising, and its fastest growth is occurring among young adults from 18 to 25 years of age (Grabowski & Dworkin, 1985). The use of cocaine by women, including those in their prime child-bearing years is also on the rise (Newcomb, Bentley, & Fahy, 1987; Chasnoff, Lewis, Griffith, & Willey, 1989). Consequently, studies of the women who use illegal drugs during pregnancy are also increasing. During the first six months of 1989, Chasnoff and his colleagues tested the urine of pregnant women who visited private physicians or public health clinics for the presence of drugs. In a sample of 715 women, they found a prevalence rate of 14.8% who had positive urine toxicologies. Of those, the drugs most commonly found were cocaine and marijuana (Chasnoff, 1989). In another survey of hospitals across the United States, it was found that 11% of the women who delivered babies in those hospitals had used illicit drugs at some point during their pregnancies. Again, cocaine was the drug
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most commonly found with some hospitals reporting that 25% of the women delivering babies showed positive results in urine screening for cocaine (Chasnoff et al., 1989). In another study of mothers who had used illicit drugs while pregnant, of those who admitted using cocaine, 85% reported using freebase (crack) cocaine (Fulroth, Phillips, & Durand, 1989).
Effects of h4aternal Use When a pregnant woman uses cocaine, she puts not only herself at risk for cardiovascular and central nervous system problems, but she places her fetus in danger as well. Cocaine use causes an intense vasoconstriction to occur, which in turn causes a sudden increase in the mother’s blood pressure and may be accompanied by cardiac arrhythmias (Bingol, Fuchs, Diaz, Stone, & Gromisch, 1987). A result of this acute hypertension is a decrease in the placental blood flow (Chasnoff & Griffith, 1989). It has been hypothesized that this interruption of the blood supply to the fetus may interfere with its ability to develop normally (Bingo1 et al., 1987). This reduction of blood flow may also reduce the oxygen received by the fetus (Woods, Plessinger, & Clark, 1987). Additionally, cocaine has an anorexic effect that may prevent the mother from receiving the proper nutrition that would ensure a normal growth rate for the fetus (Bingo1 et al., 1987). Cocaine is metabolized in the body by the enzyme cholinesterase. The duration of the effects of cocaine depends on the ability of the plasma cholinesterase to break down the drug (Rivkin & Gilmore, 1989). The levels of cholinesterase are lower than normal in the bodies of pregnant women, fetuses, and neonates, thus enhancing the toxic properties of cocaine in these individuals (Oro & Dixon, 1987). Evidence of cocaine or its metabolites can be found in urine samples of adults for up to 72 hours following intranasal use. However, in the neonate, a major metabolite of cocaine has been found to persist in urine samples for as many as four days either due to immaturity of the system or to the deficiency of cholinesterase in the newborn (Chasnoff, Bussey, Savich, & Stack, 1986). Udell (1989) has cited evidence of cocaine metabolites for up to two weeks in a very premature baby.
Apparent Effects in the Newborn Women who use cocaine during pregnancy experience a greater incidence of preterm labor and delivery, and the number of stillbirths is greater for these women (Dow-Edwards, 1988). Babies who have been exposed to cocaine in utero often suffer from retarded intrauterine growth and are generally intolerant of labor. Many have a lower gestational age at the time of delivery with lower birth weights and often are still considered small for their gestational age (MacGregor et al., 1987). These babies also have small head circumferences, and Dow-Edwards (1988) found increasing evidence of skull defects. Chasnoff
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Aberrant
Behaviors
TABLE 2 Observed in Newborns Cocaine In Uferu
Exposed to
Tremulousness Muscular Rigidity Irritability Poor State Regulation Abnormal Sleep Pattcms Poor Consolability Depressed Interactive Abilities Poor Organizational Responses Tendency to Become Overloaded bv Environmental Stimuli
et al. (1989) used the Brazelton Neonatal Behavioral Assessment Scale to examine behavior of newborns who had been exposed to cocaine. These babies were found to be significantly depressed in their ability to organize responses to environmental stimuli, findings consistent with earlier noted patterns of abnormality of play in the early years (also see Table 1). It was difficult for them to proceed through the various states of arousal required for testing, and they had difficulty attending to and actively engaging auditory and/or visual stimuli. They were easily overloaded by stimuli in their environment because of their overexcitable nervous systems, and caretakers often found it necessary to assist them in maintaining a level of equilibrium (Chasnoff et al., 1989). State changes in cocaine babies have often been found to be inappropriate for the level of stimulation being provided. Besides high excitability and irritability, these babies show tremulousness and hypertonicity (Chasnoff, Burns, Schnoll, & Burns, 1985; Chasnoff et al., 1986; DowEdwards, 1988). Infants who had been exposed to crack showed muscular rigidity as well (Dow-Edwards, 1988). The aberrant behaviors observed in newborns exposed to cocaine in utero are summarized in Table 2. Upon reexamination after one month, the babies in the study done by Chasnoff et al. (1989) had improved in their ability to interact with their environments and to control their arousal states. However, when compared with the infants who had not been exposed to cocaine, they were still not as adequately developed in their regulation of arousal states, nor were they as adequately developed in their ability to remain alert over extended periods without becoming overloaded by stimuli (Chasnoff et al., 1989). In a single case study by Chasnoff et al. (1985), the baby was monitored up to three months of age following the identification of a cerebral infarction evident at birth. Except for small head circumference and some hypotonia, the infant was reported to be alert and interactive. Udell (1989) reported babies in his study became more normal over a two-week period demonstrating only abnormal sleep patterns. Chasnoff et al. (1985) reported in a 1985 article that the 23 infants examined in his research would be included in long-term followup. Reports on results of such long-term research are not yet found in the literature.
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Transient Effects of Cocaine
Just as cocaine was not initially deemed to be highly addictive or particularly dangerous to frequent users, cocaine’s effect on the newborn has been believed to be transient. In reporting results of their study, Madden et al. (1986) were relieved that the cocaine-exposed babies in their study did not require the same level of extensive care after birth as babies who had been born to heroin addicts. They did, however, acknowledge the difficulty of assessing newborns for such things as intense craving for the drug, prolonged sleep periods with suppressed rapid eye movement, fatigue, loss of energy, depression, and hyperphagia which are symptoms exhibited by adult cocaine users who abruptly cease chronic use (Madden, Payne, & Miller, 1986). A study by Doberczak et al. (1988) of infants born to mothers who used cocaine during pregnancy provided evidence of an association between neure logical dysfunction and abnormal electroencephalograph readings. Their study confirmed signs of clinical neurological dysfunction that had been found in other studies such as irritability, tremulousness, abnormal sleep patterns, poor feeding, and difficulty with interactive and organizational responses. The clinical signs were reported to be transient since they disappeared with the disappearance of cocaine or its metabolites in the urine. Doberczak et al. (1988) determined the neurobehavioral responses were probably a result of the neure toxic effect of the cocaine rather than withdrawal from the drug. Permanent Effects of Cocaine
Dixon and Bejar in a later study (1989) used echoencephalography to assess abnormalities in neonates who had positive toxicology results at birth. They reported finding evidence of infarctions with areas of cavitation, suggestive of brain injury that had probably occurred before birth. Their findings were similar to those of infants who had been deprived of oxygen before birth. The infants in their study had uncomplicated birth processes with no other obvious causes of cerebral injury (Dixon & Bejar, 1989). The lesions found by Dixon and Bejar (1989) were such that they may not have been manifested behaviorally in either infancy or early childhood. Evidence of damage to the frontal lobes or basal ganglion appears only when more complex processing tasks involving visual-motor skills and social cognition are required of the young child. Consequently, these seemingly normal infants would be sent home to environments that would probably be less than adequate for a child’s psychosocial development. When these same children then reach school age, their deficits in neurological, cognitive, and behavioral development would become apparent and problematic (Mannino & Trauner, 1983; Dixon & Bejar, 1989). By then a host of intervening environmental factors have affected the child’s behavior, and determining causes for the problematic behavior becomes almost impossible (Grimm, 1987).
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Corgfounding Factors The issue of causality is complicated from the time of the child’s conception by other factors, in addition to the cocaine that could impact fetal development. The mothers who use cocaine often use tobacco, alcohol, and other drugs in conjunction with the cocaine, and the combination of these could have a synergistic effect on the fetus. Mothers who abuse crack have reported smoking cigarettes containing a mixture of tobacco, marijuana, and cocaine (Fulroth, Phillips, & Durand, 1989). A study by Oro and Dixon (1987) showed the combination of narcotics and cocaine used prenatally to be harmful to infants, and cocaine and heroin taken together were shown to have an additive morbidity in babies in research conducted by Fulroth et al. (1989). The cocaine itself may have been adulterated with other contaminants that could be harmful to the fetus (Chasnoff, Bums, Schnoll, & Burns, 1985). Such known teratogens as strychnine are even used on some occasions to “cut” cocaine and other amphetaminelike drugs popular among cocaine abusers. Continued drug use, poor nutrition, and a failure to seek prenatal care could further threaten normal fetal develop ment (Chasnoff & Griffith, 1989). While the mothers themselves are the best source of information about the prenatal period, obtaining reliable reports from them of how much, how often, and how long cocaine was used during pregnancy is often difficult (Fulroth, Phillips, & Durand, 1989). Few studies examined the time during the pregnancy that cocaine was used, and none included specific information about the amounts of cocaine used. Chasnoff and Griffith (1989) concluded that exposure to cocaine during the first trimester of pregnancy was the most dangerous to the fetus even if cocaine use was discontinued after that time. It has also been recognized that the samples of pregnant women included in those studies represent a select portion of the population of women that use cocaine during pregnancy. They are women who at least sought prenatal care, and the concern is that the baby born to women who use cocaine and receive no prenatal care may have an even poorer outcome than the infants being studied (MacGregor et al., 1987). Evidence of Teratogenic Effects If cocaine is to be considered a teratogen, its impact on the development of the fetus, and specifically the neurological development, needs to be explored. Because of the complexity of neurodevelopment, the use of a teratogenic sub stance could alter the normal formation of the anatomical structures of the brain, the neurochemical system, or the patterns of blood flow throughout the brain. Additionally, an increased sensitivity to cocaine due to a kindling effect could result. Evidence for each of these possibilities will be examined. Neuroanatomical Alterations The first system to begin developing
in the body is the central nervous
sys-
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tern. It begins with the appearance of neural epithelium about 15-17 days after fertilization and continues in various stages until well after birth (Grimm, 1987). Because of the specificity of certain cells migrating and organizing at definite times, it would be expected that the introduction of a toxic agent, such as cocaine, would disturb the proper development of certain groups of cells. Furthermore, it has been shown that an early insult to the developing brain significantly affects areas of the brain beyond those directly damaged by the insult (Kolb & Fantie, 1989). Dow-Edwards (1988), in her study of the effects of maternal cocaine use on rat pups, showed that exposure to cocaine during critical developmental periods can produce permanent changes in brain function. It then follows that impaired neurobehavioral capabilities in the neonate are a manifestation of abnormal development of the brain (Kolb & Fantie, 1989; Chasnoff & Griffith, 1989). In 1987, Grimm conducted studies with rats in order to search for the mechanism imposed by perinatal anoxia and the introduction of other toxins. Her findings lead to the suggestion that prenatal and perinatal deprivation of oxygen in the middle of human pregnancy may disrupt or at least slow down the generation of cholinergic synapses in the frontal cortex. This retardation of synaptogenesis could then cause other neurochemical mechanisms of the central nervous system to compensate in order to correct some of the abnormality, thus affecting the organism’s ability to deal with complex demands of the environment at a later point in life (Grimm, 1987). These discoveries are pertinent to neonates exposed to cocaine while in utero because of the reduction of transplacental oxygen delivery. Another mechanism by which the structure of the brain may be affected or altered by cocaine use is through cerebral infarctions that occur prenatally. These may be the result of vasoconstriction, hypertension, and subsequent hemorrhage caused by cocaine exposure (Chasnoff, Bussey, Savich, & Stack, 1986). The time of the cocaine exposure to the fetus, as well as the intensity and chronicity of the exposure would affect the location of lesions. Dixon and Bejar (1989) hypothesized vessels that develop early on may be more vulnerable to the vasoconstriction that results from cocaine exposure. The branches of the middle cerebral artery, which supply blood to the basal ganglion and the frontal horns, are vessels that could become damaged (Dixon & Bejar, 1989). They concluded that structural brain lesions that occurred before birth because of cocaine exposure and go unnoticed may be located in what they called “ ‘silent areas’ of the brain” (Dixon & Bejar, 1988, p. 1226A). Again, babies who have sustained a cerebrovascular accident before birth may appear normal both neurologically and developmentally. Difficulties may arise only when they reach school age when cognitive dysfunction such as learning disabilities and attention deficits become more apparent flrauner & Mannino, 1986). Alterations of the Neurochemical System
Cocaine acts to prevent the presynaptic uptake of norepinephrine and dopamine in the central and autonomic nervous system. This produces an excess
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of these neurotransmitters that is thought to be responsible for vasoconstriction, tachycardia, and the abrupt rise in blood pressure (Chasnoff, Burns, Schnoll, & Bums, 1985; Cregler & Mark, 1986; Mody, Miller, MacIntyre, Cobb, & Goldberg, 1988; Rivkin & Gilmore, 1989). Chronic cocaine use causes the brain to adapt and decrease the production of dopamine for the central nervous system, thus decreasing neurotransmission even without the presence of cocaine (Farrar & Keams, 1989). The depletion of dopamine has been hypothesized to be the reason for the intense dysphoria experienced during withdrawal from cocaine and the resulting intense craving for more of the drug (Cregler & Mark, 1986). As the normal human fetus develops, some of the first neurotransmitters evident are noradrenaline, serotonin, and dopamine. They have been shown to be present in the fetus as early as the third or fourth month. Since the blood-brain barrier has not developed completely at that time, cocaine can readily act on fetal brain neurotransmitters (Chasnoff & Griffith, 1989). If chronic use in adults can alter the normal dopaminergic pathways (Farrar & Kearns, 1989), then the possibility may exist for the fetal dopaminergic pathways to be affected permanently as they are altered during development. Alterations in Cerebral Blood Flow It has been shown that chronic cocaine use can cause changes in cerebral blood flow, possibly because of its direct effect on vessels themselves or as a response to the disruption of the normal neurotransmitter mechanism. A study by Volkow et al. (1987) on the effects of cocaine on cerebral blood flow showed continued evidence of abnormal cerebral blood flow following 10 days of cocaine withdrawal. They hypothesized that disturbances of cerebral function may be more long term after chronic cocaine abuse. With the decrease in uterine and placental blood flow in pregnant women who use cocaine, fetal cerebral perfusion may also be compromised. The immaturity of the central nervous system of the fetus leaves it without the ability to regulate responses to abrupt variations in blood supply and blood flow (Dixon & Bejar, 1989). Seizures and the Kindling Effect Seizures commonly result from cocaine use to such an extent that physicians are alerted to consider the possibility of cocaine use in patients who present with unexplained seizure activity (Farrar & Kearns, 1989). Cocaine seems to lower the seizure threshold when used by adults (Chasnoff & Griffith, 1989), and current information about neonatal seizures is conflicting. In a study by Doberczak et al. (1988), of 39 infants who had been exposed to cocaine in utero, none experienced seizures. One of the possible explanations offered for this was that dendritic development in infants has not advanced to the point where a single neuron beginning epileptic activity can efficiently connect with enough other
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neurons to complete a seizure discharge (Doberczak, Shanzer, Senie, & Kandall, 1988). In a later study by Chasnoff and Griffith (1989), 6 of 52 infants did experience seizures. Though cocaine or its metabolites had been present in the urine of those infants at the time of birth, the seizure activity did not necessarily coincide with the presence of cocaine in the system (Chasnoff & Griffith, 1989). Studies with rats have shown long-term cocaine use can progressively increase the sensitivity to cocaine, particularly the excitatory effects of cocaine on the central nervous system. This phenomenon, known as the “kindling effect,” may be responsible for a continuation of hyperactive behavior and an increased occurrence of seizure activity even when cocaine is not present in the system (Cregler & Mark, 1986; Fulroth, Phillips, & Durand, 1989; Karler, Petty, Calder, & Turkanis, 1989). Corgfounding Injluences
Studying abnormal behaviors of children who were exposed to cocaine before birth in search of etiology is confounded by the environments in which they live. Particularly if the mother continues to use cocaine, addiction will probably cause a craving for the drug that supersedes all other considerations (MacGregor et al., 1987). She may fail to care for the infant or young child or even abuse the child if an intolerable stress level is reached as a result of her strong craving for more cocaine (Udell, 1989). Poverty may result or continue as her money is used primarily to support her cocaine needs. She may be emotionally absent to her child, or she may be physically incapacitated by her drug use (MacGregor et al., 1987). Additionally, exposure of the infant to cocaine itself may continue as evidence has been cited of infants’ exposure to cocaine through breast milk (Chasnoff, Douglas, & Squires, 1987; Chaney, Franke, & Wadlington, 1988). More recently in the literature have come reports of infants and toddlers who received medical attention for neurological symptoms including drowsiness, unsteadiness of gait, and seizures. Evidence of cocaine was found in toxicological studies of the urine of these children. No other medical causes for the abnormal behavior were evident and there were no indications that the children had directly ingested cocaine. Each of the children had been exposed to cocaine through inhalation of the smoke from the use of freebase cocaine or crack by their caretakers (Bateman & Heagarty, 1989). One incident has been reported in which an infant was seen in an emergency room following the sudden onset of seizures after she had ingested cocaine found on the floor of her home (Rivkin & Gilmore, 1989).
SUMMARY
The use of cocaine was popular in the 19th Century, and since the early 1970s its use has again been on the increase. Cocaine and its harmful effects are
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a broader segment of the population because a more inexpensive form Just as the dangers of cocaine use were originally not recognized, the dangerous and long-term effects of intrauterine cocaine exposure have only recently begun to be explored. Evidence seems to indicate that chronic and intermittent use of cocaine by a pregnant woman has the potential to impact the development of the fetal brain to such an extent that long-term neurobehavioral effects will result (Fulroth, Phillips, & Durand, 1989). It is possible that alterations may occur in the development of the anatomical structures, the neurotransmitters, and/or the blood flow patterns of the brain. A hypersensitivity of the central nervous system may also result. Behavioral manifestations of the alterations caused by cocaine exposure are not always evident at birth, but problems may become more obvious as the child matures and enters school. It appears that cocaine does have a more teratogenic effect on the fetus. Additional studies are necessary in which time and intensity of fetal exposure to cocaine is correlated with observations of neurologic and behavioral abnormalities throughout infancy, childhood, and even continuing into adolescence and early adulthood (LeBlanc, Parekh, Naso, & Glass, 1987). At present, it appears that the most prominent, or at least the best documented, behavioral abnormalities seen in newborns of women who used cocaine during pregnancy are tremulousness and irritability (Chasnoff et al., 1985; Oro & Dixon, 1987; Dow-Edwards, 1988), poor state regulation (Chasnoff, Burns, S&troll, & Bums, 1985; Chasnoff, Lewis, Griffith, & Willey, 1989), depressed interactive abilities (Chasnoff et al., 1985), and a tendency to become overloaded by environmental stimuli (Chasnoff et al., 1989). The toddlers and preschoolers who were exposed to cocaine in utero continue to demonstrate difficulties in interpersonal relationships. Their play is also affected in that it is sparse and disorganized, consisting of less representational and fantasy play than that of children born to mothers free of drugs. Many of these children also exhibit hyperactive behavior. As more and more of the children who have been exposed to cocaine before birth reach school age, it is imperative that we look more carefully at the evidence that cocaine does have a teratogenic effect and consider more fully the neurological implications. Infants known to have been exposed to cocaine in utero should be closely followed. Long-term studies including neuropsycho logical evaluations of these children as they reach school age and beyond are necessary in order that the neurological effects of intrauterine cocaine exposure can be recognized. As the manifestation of a head injury in childhood changes the child matures into adolescence and adulthood, so may the manifestation of intrauterine cocaine exposure change with the maturation of the affected organism. More and more it is becoming clear that taking a patient’s drug history is insufficient; the mother’s drug history may be of major importance as well. known as crack is now available.
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REFERENCES Adlaf, R. M. (1986). Self-reported cocaine reactions among social-recreational users: A factor analytical study. Drug and Alcohol Dependence, l&204-212. Bateman, D. A., & Heagarty, M. C. (1989). Passive freebase cocaine (‘crack’) inhalation by infants and toddlers. American Journal ofDisease in Children, 143,25-27. Bingol, N., Fuchs, M., Diaz, V., Stone, R. K. & Gromisch, D. S. (1987). Teratogenicity of cocaine in humans. The Journal of Pediatrics, 110,93-96. Chaney, N. E., Franke, J., & Wadlington, W. B. (1988). Cocaine convulsions in a breast-feeding baby. The Journal of Pediatrics, 112, 134-135. Chasnoff, I. J. (1989). The incidence of cocaine use. In K. V. Sprout (Ed.), Special currents: Cocaine babies (p. 1). Columbus, OH: Ross Laboratories, P.L. Chasnoff, I. J., Bums, W. J., Schnoll, S. H., & Burns, K. A. (1985). Cocaine use in pregnancy. The New England Journal of Medicine, 313,666669.
Chasnoff, I. J., Bussey, M. E., Savich, R., & Stack, C. M. (1986). Perinatal cerebral infarction and maternal cocaine use. The Journal ofPediauics, 108,4X-459. Chasnoff, I. J., Douglas, E. L., & Squires, L. (1987). Cocaine intoxication in a breast-fed infant. Pedialrics, 80,836-838.
Chasnoff, I. J., & Griffith, D. R. (1989). Cocaine: Clinical studies of pregnancy and the newborn. Annals of New York Academy of Science, 562,2&I-266.
Chasnoff, I. J., Lewis, D. E., Griffith, D. R., & Willey, S. (1989). Cocaine and pregnancy: Clinical and toxicological implications for the neonate. Clinical Chemistry, 35, 12761278. Commissaris, R. L. (1989). Cocaine pharmacology and toxicology. In K. K. Redda, C. A. Walker, & G. Bamett (Eds.), Cocaine, marijuana, designer drugs: Chemistry, pharmacology, and behavior (pp. 71-81). Boca Raton, FL: CRC Press, Inc. Cmgler, L. L., & Mark, H. (1986). Special report: Medical complications of cocaine abuse. The New EnglandJournal of Medicine, 315, 1495-1500. Dixon, S. D., & Bejar, R. (1988). Brain lesions in cocaine and methamphetamine exposed neonates. Pediatric Research, 23, 1226A.
Dixon, S. D., & Bejar, R. (1989). Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: Incidence and clinical correlates. The Journal of Pediatrics, 115,77O-778. Doberczak, T. M., Shanzer, S., Senie, R. T., & Kandall, S. R. (1988). Neonatal neurologic and electro encephalographic effects of intrauterine cocaine exposure. The Journal of Pediauics, 113, 354-358.
Dow-Edwards, D. L. (1988). Developmental effects of cocaine. In D. Clovet, K. Asghar, & R. Brown (Eds.), Mechanisms of cocaine abuse and toxicify (pp. 290-303). NIDA Research Monograph 88, Dept. of Health and Human Services: National Institute of Drug Abuse, Division of Preclinical Research. Estroff, T. W. (1987). Cocaine smoking: Nature and extent of coca paste and cocaine free-base abuse. In A. M. Washton, & M. G. Gold (Eds.), Cocaine: A clinician’s handbook (pp. 23-32). New York: Guilford Press. Fantel, A. G., & Macphail, B. J. (1982). The tentogenicity of cocaine. Teratology, 26, 17-19. Farrar, H. C., & Kearns, G. L. (1989). Cocaine: Clinical pharmacology and toxicology. The Journal of Pediaaics, 115.665675. Fulroth, R., Phillips, B., & Durand, D. J. (1989). Perinatal outcome of infants exposed to cocaine and/or heroin in utero. American Journal of the Diseased Children, 143,905-910. Grabowski, J., & Dworkin, S. I. (1985) Cocaine: An overview of current issues. The International Journal of the Addictions, 20.1065-1088.
Grimm, V. E. (1987). Effects of teratogenic exposure on the developing brain: Research strategies and possible mechanisms. Developmental Pharmacologic Therapy, 10.328-345.
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Howard, J. (1989). Long-term effecls of infants exposed prenatally to drugs. In K. V. Sproat (Ed.), Special currents: Cocaine babies (pp. l-2). Columbus, OH: Ross Laboratories. Karler, R., Petty, C., Calder, L., & Turkanis, S. A. (1989). Preconvulsant and anticipated effects in mice of acute and chronic treatment with cocaine. Neuropharmacology, 28709-714. Kantrowitz, B. K., Wingert, P., De La Pena, N., Gordon, J., & Padgett, T. (1990, February 12) The crack children, Newsweek, pp. 62-63. Kolb, B., & Fantie, B. (1989). Development of the child’s brain and behavior. In C. R. Reynolds & E. Fletcher-Janzen (Eds.), Ilandbook of clinical child neuropsychology (pp. 17-39). New York: Plenum Press. LeBlanc, P. E., Par&h, A. J., Naso, B., & Glass, L. (1987). Effects of intrauterine exposure to alkaloid cocaine (‘crack’). American Journal of Diseases of Children, 141,937-938. MacGregor, S. N., Keith, L. G., Chasnoff, I. J., Rosner, M. A., Chisum, G. M., Shaw, P., & Minogue, J. P. (1987). Cocaine use during pregnancy: Adverse pcrinatal outcome. American Journal of Obstetrics and Gynecology, 157,686690.
Madden, J. D., Payne, T. F., & Miller S. (1986). Matcmal cocaine abuse and effect on newborns. Pediatrics, 11,209-211.
Mannino, F. L., & Trauner, D. A. (1983). Stroke in neonates. The Journal of Pediatrics, 102(4), 605610. Mody, C. V., Miller, B. L., McIntyre, H. B., Cobb, S. K., & Goldberg, M. A. (1988). Neurologic complications of cocaine abuse. Neurology, 38,1189-l 193. Newcomb, M. D., Bentley, P. M., & Fahy, B. (1987). Cocaine use and psychopathology: Associations among young adults. The fnrernational Journal of the Addictions, 22,1167-1188. Nicholi, A. M. (1984). Cocaine use among the college age group: Biological and psychological effects. Clinical and laboratory research findings. Journal of American College Health, 32, 258-261. Oro, A. S., & Dixon, S. D. (1987). Perinatal cocaine and mcthamphetamine exposure: Maternal and neonatal correlates. The Journal of Pediatrics, 11,571-578. Pitts, D. K., & Marwah, J. (1989). Autonomic actions of cocaine. Canadian Journal of Physiological Pharmacology, 67,1168-l 176.
Rivkin, M., & Gilmore, H. F. (1989). Gcneralizcd seizures in an infant due to environmentally acquired cocaine. Pediatrics, 84, 1101-1102. Siegel, R. K. (1987). Medical and biological conscqucnccs of cocaine abuse. In A. M. Washton, & M. S. Gold (Eds.), Cocaine: A clinician’s hund6ook (pp. 175-191). New York: Guilford Press. Spear, L. P., Kirstein, C. L., Bell, J., Yoottanasumpun, V., Grecnbaum, R., O’Shea, J., Hoffmann, H., & Spear, N. E. (1989). Effects of prenatal cocaine exposure on behavior during the early postnatal period. Neurotoxicology and Teratology, 11.57-63. Sunde, S. (1990, February 26). A generation in doubt, Dallas Times Herald, pp. A-l, A-12. Trauner, D. A., & Mannino, F. L. (1986). Neurodevelopmental outcome after neonatal cerebrovascular accident. The Journal of Pediatrics, 108,459461. Udell, B. (1989). Crack cocaine. In K. V. Sproat (Ed.), Special currents: Cocaine babies (pp. 5-8). Columbus, OH: Ross Laboratories. Volkow, N. D., Gould, K. L., Mullani, N., Addles, S., & Krajewsky, K. (1987). Changes in cerebral blood flow of chronic cocaine users. Journul of Cerebral Blood Flow and Metabolism, 7(l), S292.
Washton, A. M. (1989). Cocaine addiction. New York: W.W. Norton & Co. Wetli, C. V. (1989). Fatal reactions to cocaine. In A. M. Washton (Ed.), Cocaine addiction (pp. 33-54). New York: W.W. Norton & Co. Woods, J. R., Plessinger, M. A., & Clark, K. E. (1987). Effect of cocaine on uterine blood flow and fetal oxygenation. Journal of the American Medical Association, 257,957-961.
1991 Copyright
0887-6177191 $3.00 + .OO 0 1991 National Academy of Neuropycblogy
The Effects of Intrauterine
Cocaine
Exposure: Transient or Teratogenic? Loretta F. Allen, Ronald S. Palomares, Paula DeForest, Brenda Sprinkle, and Cecil R. Reynolds Texas A&M University
The use of cocaine and its smoked derivative, crack, is increasing in America. Among those affected are neonates of women who use cocaine during pregnancy. This paper examines the potential effects of maternal cocaine use upon the developingfetus emphasizing neuropsychological and behavioral effects including those that typically persist into early childhood and beyond. Empirical research should continue to explore the effects of maternal cocaine use focusing on whether or not the many detrimental effects of cocaine use during pregnancy are transient. directly teratogenic, or indirect and due to prolonged hypoxia.
Cocaine, in various forms, is a drug of choice used by an increasing segment of the population each year. Tragically, countless unborn infants are forced to suffer the effects of cocaine upon their developing bodies and minds. We have only recently begun to study the effects of cocaine and still do not fully understand or comprehend the consequences of cocaine use during pregnancy. There are numerous research studies published and in process detailing the consequences of cocaine use in the human body, but there is little information that details the direct effects of maternal cocaine use upon a fetus. Some research findings that are available suggest that the effects of intrauterine cocaine exposure are only transient (Madden, Payne, & Miller, 1986; Doberczak, Shanzer, Senie, & Kandall, 1988; Fame1 & Macphail, 1982). Other research suggests cocaine is teratogenic, resulting in more permanent abnormalities (Mannino & Trauner, 1983). Whether the effects of cocaine are merely transient or more long term has yet to be concluded, particularly with regard to fetal cocaine exposure. Results of Requests for reprints should be sent to Cecil R. Reynolds, Dept. Of Educational Psychology, Texas A&M University, College Station, TX 77843. 133
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TABLE 1 Abnormal Behaviors Observed in Toddlers and Preschoolers Exposed to Cocaine Prenatally Abnormal Play Patterns
Less Representitional Play Less Variation in Play Disorganization of Play Interactional Dilkultics with Both Peers and Adults Hyperactive Behavior
the first study of possible teratogenic effects of cocaine (Fame1 & MacPhail, 1982) showed no evidence of teratogenicity in rats. More recently, the field of teratology has been broadened beyond a study of visible malformations of the neonate to include behavioral anomalies as well that may result from exposure to a drug or other toxic substance during gestation (Grimm, 1987). The effect of a teratogen on an organism is influenced by several factors-the organism’s stage of development at the time of exposure, the chronicity and intensity of the exposure, any genetic predisposition of the organism, and the state of the mother’s physical and emotional well-being (Grimm, 1987). Evidence of the neural effect of a teratogen may be less than obvious because a disruption of the development of one system may secondarily lead to disruption of the normal development of other parts of the central nervous system. This deviation from normal development ultimately may affect the organism’s ability to respond to and to interact with its environment (Spear et al., 1989). Howard (1989) has reported evidence of atypical behaviors found in preschool children who were subjected to intrauterine cocaine exposure. No information was provided concerning the amount or duration of fetal exposure, but when compared with other high-risk toddlers who had not been exposed to drugs prenatally, differences in the children’s play and social interactions were observed. The play of the drug-exposed toddlers appeared disorganized and lacked representational and symbolic elements normally observed in young children. They had a difficult time with fantasy play and appeared to be unable to participate in sustained play with toys. Their play more often consisted of batting at or scattering toys and simply picking up and putting down toys. She also found their lack of organization seemed to extend beyond play into their interpersonal relationships as it was more difficult for these children to relate to peers as well as adults. Regulation of affect was also poor for these children (Howard, 1989). A summary of abnormal behaviors observed in toddlers and preschoolers exposed to cocaine prenatally can be found in Table 1. Similar reports of behavioral abnormalities are also appearing in the news media in articles describing these children. They are being seen in special pro grams for infants and toddlers with special needs, and teachers in these programs describe their behavior as primitive almost limited to “instinctual”
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responses. They sometimes are withdrawn and have trouble interacting with other children through play or conversation. Caretakers have reported that these children are not cuddly and often do not respond when touched or hugged (Sunde, 1990, Feb. 26). A few special programs like the Salvin Special Education School in Los Angeles are being set up around the country in efforts to help remediate some of the apparent deficits of these children (Kantrowitz, Wingert, De La Pena, Gordon & Padgett, 1990, Feb. 12). This paper compiles existing information about the effects of intrauterine cocaine exposure on the fetus, the neonate, and the young child. A brief history of cocaine use is presented along with recent reports of the incidence of cocaine use. The effects of maternal cocaine use on the mother, the fetus, and the newborn are examined. Research is cited that suggests the effects of fetal exposure to cocaine are transient, and evidence of the possibility that cocaine acts as a teratogen will be explored. HISTORY Cocaine is believed to have been used over five thousand years ago by the Incas for religious and medicinal purposes through the practice of burning and smoking parts of the coca plant (Siegel, 1987). It was not until the 19th Century that cocaine was derived as a distinct, concentrated agent from the coca plant, and its use then became widespread in Europe and North America. Cocaine’s medicinal use flourished during this time with much of its perceived popularity having been attributed to Sigmund Freud. Freud is reported to have touted the use of cocaine as a local anesthetic, free of addictive properties (Estroff, 1987), advocating its use as a “cure” for morphine addiction (Commissaris, 1989). However, it was quickly recognized that cocaine was not a safe or nonaddictive drug, and thus the sale of cocaine in the United States was banned by the Harrison Act in 1914 (Pitts & Marwah, 1989). Since the early 1970s cocaine has returned to the forefront of abused drugs with its use becoming more widespread and more serious. Currently, a very rapid and easy method of self-administration of cocaine has become popular. It involves the inhalation of the volatilized alkaloidal form of cocaine through smoking or “free basing” of “crack” (Pitts & Marwah, 1989). Crack is produced by mixing cocaine hydrochloride powder with water and bicarbonate of soda and then drying the mixture in a microwave. The process results in hardened pieces of the drug that can then be smoked in pipes. This method has reduced the price of the drug, making it accessible for all segments of the population. The purity of the drug in combination with the larger absorptive area of the lung causes blood levels to be much higher than those resulting from intranasal cocaine use (Udell, 1989). Consequently, the euphoric effects increase along with the addictive potential and resulting medical complications. Crack can be bought on the street in vials containing tiny chunks or “rocks” at a price ranging
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between $5 and $15 each, and “Crack 19th Century, are becoming common 1989). Smoking “crack” cocaine had over one-third of all the callers to the (Washton, 1989).
Houses,” similar to the opium dens of the throughout the United States (Washton, become the preferred method of use for 800-COCAINE National Hotline by 1989
INCIDENCE The use of cocaine is widespread throughout the population, and it has been estimated that those addicted to cocaine range in age from 9 to 65 years. Cocaine’s impact is spreading from the rich, who were previously the only ones who could afford it, to those less affluent since crack has become so readily available. The actual percentage of the population that uses or is addicted to cocaine cannot be clearly defined. Even attempts to record accurately the number of deaths related to cocaine use have been complicated by the wide variations in the investigations conducted by the medical examiner-coroner systems (Wetli, 1989). Toxicological testing is not always used because of its prohibitive cost and equipment needs. Yet, the increased use of cocaine is evidenced by the fact that by 1986, the death rate due to cocaine in Dade County, Florida, had risen from two per month to nearly two per week (Wetli, 1989). One nationwide survey of Americans (Adlaf, 1986) found that cocaine is being used by 28% of the population between the ages of 18 and 25, as well as by 9% of those 26 and older. Nicholi (1984) reports findings that cocaine use increased in the United States from 9 million in 1972 to 33 million in 1984 in college-aged individuals. Thirty-three percent of young adults in another study (Newcomb, Bentley, & Fahy, 1987) reported the use of cocaine within the six months prior to the study. Other national surveys (National Institute on Drug Abuse-NIDA, High School Senior Survey, National Household Survey, and Drug Abuse Warning Network-DAWN) concur that the incidence of cocaine use is rising, and its fastest growth is occurring among young adults from 18 to 25 years of age (Grabowski & Dworkin, 1985). The use of cocaine by women, including those in their prime child-bearing years is also on the rise (Newcomb, Bentley, & Fahy, 1987; Chasnoff, Lewis, Griffith, & Willey, 1989). Consequently, studies of the women who use illegal drugs during pregnancy are also increasing. During the first six months of 1989, Chasnoff and his colleagues tested the urine of pregnant women who visited private physicians or public health clinics for the presence of drugs. In a sample of 715 women, they found a prevalence rate of 14.8% who had positive urine toxicologies. Of those, the drugs most commonly found were cocaine and marijuana (Chasnoff, 1989). In another survey of hospitals across the United States, it was found that 11% of the women who delivered babies in those hospitals had used illicit drugs at some point during their pregnancies. Again, cocaine was the drug
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most commonly found with some hospitals reporting that 25% of the women delivering babies showed positive results in urine screening for cocaine (Chasnoff et al., 1989). In another study of mothers who had used illicit drugs while pregnant, of those who admitted using cocaine, 85% reported using freebase (crack) cocaine (Fulroth, Phillips, & Durand, 1989).
Effects of h4aternal Use When a pregnant woman uses cocaine, she puts not only herself at risk for cardiovascular and central nervous system problems, but she places her fetus in danger as well. Cocaine use causes an intense vasoconstriction to occur, which in turn causes a sudden increase in the mother’s blood pressure and may be accompanied by cardiac arrhythmias (Bingol, Fuchs, Diaz, Stone, & Gromisch, 1987). A result of this acute hypertension is a decrease in the placental blood flow (Chasnoff & Griffith, 1989). It has been hypothesized that this interruption of the blood supply to the fetus may interfere with its ability to develop normally (Bingo1 et al., 1987). This reduction of blood flow may also reduce the oxygen received by the fetus (Woods, Plessinger, & Clark, 1987). Additionally, cocaine has an anorexic effect that may prevent the mother from receiving the proper nutrition that would ensure a normal growth rate for the fetus (Bingo1 et al., 1987). Cocaine is metabolized in the body by the enzyme cholinesterase. The duration of the effects of cocaine depends on the ability of the plasma cholinesterase to break down the drug (Rivkin & Gilmore, 1989). The levels of cholinesterase are lower than normal in the bodies of pregnant women, fetuses, and neonates, thus enhancing the toxic properties of cocaine in these individuals (Oro & Dixon, 1987). Evidence of cocaine or its metabolites can be found in urine samples of adults for up to 72 hours following intranasal use. However, in the neonate, a major metabolite of cocaine has been found to persist in urine samples for as many as four days either due to immaturity of the system or to the deficiency of cholinesterase in the newborn (Chasnoff, Bussey, Savich, & Stack, 1986). Udell (1989) has cited evidence of cocaine metabolites for up to two weeks in a very premature baby.
Apparent Effects in the Newborn Women who use cocaine during pregnancy experience a greater incidence of preterm labor and delivery, and the number of stillbirths is greater for these women (Dow-Edwards, 1988). Babies who have been exposed to cocaine in utero often suffer from retarded intrauterine growth and are generally intolerant of labor. Many have a lower gestational age at the time of delivery with lower birth weights and often are still considered small for their gestational age (MacGregor et al., 1987). These babies also have small head circumferences, and Dow-Edwards (1988) found increasing evidence of skull defects. Chasnoff
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Aberrant
Behaviors
TABLE 2 Observed in Newborns Cocaine In Uferu
Exposed to
Tremulousness Muscular Rigidity Irritability Poor State Regulation Abnormal Sleep Pattcms Poor Consolability Depressed Interactive Abilities Poor Organizational Responses Tendency to Become Overloaded bv Environmental Stimuli
et al. (1989) used the Brazelton Neonatal Behavioral Assessment Scale to examine behavior of newborns who had been exposed to cocaine. These babies were found to be significantly depressed in their ability to organize responses to environmental stimuli, findings consistent with earlier noted patterns of abnormality of play in the early years (also see Table 1). It was difficult for them to proceed through the various states of arousal required for testing, and they had difficulty attending to and actively engaging auditory and/or visual stimuli. They were easily overloaded by stimuli in their environment because of their overexcitable nervous systems, and caretakers often found it necessary to assist them in maintaining a level of equilibrium (Chasnoff et al., 1989). State changes in cocaine babies have often been found to be inappropriate for the level of stimulation being provided. Besides high excitability and irritability, these babies show tremulousness and hypertonicity (Chasnoff, Burns, Schnoll, & Burns, 1985; Chasnoff et al., 1986; DowEdwards, 1988). Infants who had been exposed to crack showed muscular rigidity as well (Dow-Edwards, 1988). The aberrant behaviors observed in newborns exposed to cocaine in utero are summarized in Table 2. Upon reexamination after one month, the babies in the study done by Chasnoff et al. (1989) had improved in their ability to interact with their environments and to control their arousal states. However, when compared with the infants who had not been exposed to cocaine, they were still not as adequately developed in their regulation of arousal states, nor were they as adequately developed in their ability to remain alert over extended periods without becoming overloaded by stimuli (Chasnoff et al., 1989). In a single case study by Chasnoff et al. (1985), the baby was monitored up to three months of age following the identification of a cerebral infarction evident at birth. Except for small head circumference and some hypotonia, the infant was reported to be alert and interactive. Udell (1989) reported babies in his study became more normal over a two-week period demonstrating only abnormal sleep patterns. Chasnoff et al. (1985) reported in a 1985 article that the 23 infants examined in his research would be included in long-term followup. Reports on results of such long-term research are not yet found in the literature.
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Transient Effects of Cocaine
Just as cocaine was not initially deemed to be highly addictive or particularly dangerous to frequent users, cocaine’s effect on the newborn has been believed to be transient. In reporting results of their study, Madden et al. (1986) were relieved that the cocaine-exposed babies in their study did not require the same level of extensive care after birth as babies who had been born to heroin addicts. They did, however, acknowledge the difficulty of assessing newborns for such things as intense craving for the drug, prolonged sleep periods with suppressed rapid eye movement, fatigue, loss of energy, depression, and hyperphagia which are symptoms exhibited by adult cocaine users who abruptly cease chronic use (Madden, Payne, & Miller, 1986). A study by Doberczak et al. (1988) of infants born to mothers who used cocaine during pregnancy provided evidence of an association between neure logical dysfunction and abnormal electroencephalograph readings. Their study confirmed signs of clinical neurological dysfunction that had been found in other studies such as irritability, tremulousness, abnormal sleep patterns, poor feeding, and difficulty with interactive and organizational responses. The clinical signs were reported to be transient since they disappeared with the disappearance of cocaine or its metabolites in the urine. Doberczak et al. (1988) determined the neurobehavioral responses were probably a result of the neure toxic effect of the cocaine rather than withdrawal from the drug. Permanent Effects of Cocaine
Dixon and Bejar in a later study (1989) used echoencephalography to assess abnormalities in neonates who had positive toxicology results at birth. They reported finding evidence of infarctions with areas of cavitation, suggestive of brain injury that had probably occurred before birth. Their findings were similar to those of infants who had been deprived of oxygen before birth. The infants in their study had uncomplicated birth processes with no other obvious causes of cerebral injury (Dixon & Bejar, 1989). The lesions found by Dixon and Bejar (1989) were such that they may not have been manifested behaviorally in either infancy or early childhood. Evidence of damage to the frontal lobes or basal ganglion appears only when more complex processing tasks involving visual-motor skills and social cognition are required of the young child. Consequently, these seemingly normal infants would be sent home to environments that would probably be less than adequate for a child’s psychosocial development. When these same children then reach school age, their deficits in neurological, cognitive, and behavioral development would become apparent and problematic (Mannino & Trauner, 1983; Dixon & Bejar, 1989). By then a host of intervening environmental factors have affected the child’s behavior, and determining causes for the problematic behavior becomes almost impossible (Grimm, 1987).
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Corgfounding Factors The issue of causality is complicated from the time of the child’s conception by other factors, in addition to the cocaine that could impact fetal development. The mothers who use cocaine often use tobacco, alcohol, and other drugs in conjunction with the cocaine, and the combination of these could have a synergistic effect on the fetus. Mothers who abuse crack have reported smoking cigarettes containing a mixture of tobacco, marijuana, and cocaine (Fulroth, Phillips, & Durand, 1989). A study by Oro and Dixon (1987) showed the combination of narcotics and cocaine used prenatally to be harmful to infants, and cocaine and heroin taken together were shown to have an additive morbidity in babies in research conducted by Fulroth et al. (1989). The cocaine itself may have been adulterated with other contaminants that could be harmful to the fetus (Chasnoff, Bums, Schnoll, & Burns, 1985). Such known teratogens as strychnine are even used on some occasions to “cut” cocaine and other amphetaminelike drugs popular among cocaine abusers. Continued drug use, poor nutrition, and a failure to seek prenatal care could further threaten normal fetal develop ment (Chasnoff & Griffith, 1989). While the mothers themselves are the best source of information about the prenatal period, obtaining reliable reports from them of how much, how often, and how long cocaine was used during pregnancy is often difficult (Fulroth, Phillips, & Durand, 1989). Few studies examined the time during the pregnancy that cocaine was used, and none included specific information about the amounts of cocaine used. Chasnoff and Griffith (1989) concluded that exposure to cocaine during the first trimester of pregnancy was the most dangerous to the fetus even if cocaine use was discontinued after that time. It has also been recognized that the samples of pregnant women included in those studies represent a select portion of the population of women that use cocaine during pregnancy. They are women who at least sought prenatal care, and the concern is that the baby born to women who use cocaine and receive no prenatal care may have an even poorer outcome than the infants being studied (MacGregor et al., 1987). Evidence of Teratogenic Effects If cocaine is to be considered a teratogen, its impact on the development of the fetus, and specifically the neurological development, needs to be explored. Because of the complexity of neurodevelopment, the use of a teratogenic sub stance could alter the normal formation of the anatomical structures of the brain, the neurochemical system, or the patterns of blood flow throughout the brain. Additionally, an increased sensitivity to cocaine due to a kindling effect could result. Evidence for each of these possibilities will be examined. Neuroanatomical Alterations The first system to begin developing
in the body is the central nervous
sys-
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Transient or Teratogenic?
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tern. It begins with the appearance of neural epithelium about 15-17 days after fertilization and continues in various stages until well after birth (Grimm, 1987). Because of the specificity of certain cells migrating and organizing at definite times, it would be expected that the introduction of a toxic agent, such as cocaine, would disturb the proper development of certain groups of cells. Furthermore, it has been shown that an early insult to the developing brain significantly affects areas of the brain beyond those directly damaged by the insult (Kolb & Fantie, 1989). Dow-Edwards (1988), in her study of the effects of maternal cocaine use on rat pups, showed that exposure to cocaine during critical developmental periods can produce permanent changes in brain function. It then follows that impaired neurobehavioral capabilities in the neonate are a manifestation of abnormal development of the brain (Kolb & Fantie, 1989; Chasnoff & Griffith, 1989). In 1987, Grimm conducted studies with rats in order to search for the mechanism imposed by perinatal anoxia and the introduction of other toxins. Her findings lead to the suggestion that prenatal and perinatal deprivation of oxygen in the middle of human pregnancy may disrupt or at least slow down the generation of cholinergic synapses in the frontal cortex. This retardation of synaptogenesis could then cause other neurochemical mechanisms of the central nervous system to compensate in order to correct some of the abnormality, thus affecting the organism’s ability to deal with complex demands of the environment at a later point in life (Grimm, 1987). These discoveries are pertinent to neonates exposed to cocaine while in utero because of the reduction of transplacental oxygen delivery. Another mechanism by which the structure of the brain may be affected or altered by cocaine use is through cerebral infarctions that occur prenatally. These may be the result of vasoconstriction, hypertension, and subsequent hemorrhage caused by cocaine exposure (Chasnoff, Bussey, Savich, & Stack, 1986). The time of the cocaine exposure to the fetus, as well as the intensity and chronicity of the exposure would affect the location of lesions. Dixon and Bejar (1989) hypothesized vessels that develop early on may be more vulnerable to the vasoconstriction that results from cocaine exposure. The branches of the middle cerebral artery, which supply blood to the basal ganglion and the frontal horns, are vessels that could become damaged (Dixon & Bejar, 1989). They concluded that structural brain lesions that occurred before birth because of cocaine exposure and go unnoticed may be located in what they called “ ‘silent areas’ of the brain” (Dixon & Bejar, 1988, p. 1226A). Again, babies who have sustained a cerebrovascular accident before birth may appear normal both neurologically and developmentally. Difficulties may arise only when they reach school age when cognitive dysfunction such as learning disabilities and attention deficits become more apparent flrauner & Mannino, 1986). Alterations of the Neurochemical System
Cocaine acts to prevent the presynaptic uptake of norepinephrine and dopamine in the central and autonomic nervous system. This produces an excess
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of these neurotransmitters that is thought to be responsible for vasoconstriction, tachycardia, and the abrupt rise in blood pressure (Chasnoff, Burns, Schnoll, & Bums, 1985; Cregler & Mark, 1986; Mody, Miller, MacIntyre, Cobb, & Goldberg, 1988; Rivkin & Gilmore, 1989). Chronic cocaine use causes the brain to adapt and decrease the production of dopamine for the central nervous system, thus decreasing neurotransmission even without the presence of cocaine (Farrar & Keams, 1989). The depletion of dopamine has been hypothesized to be the reason for the intense dysphoria experienced during withdrawal from cocaine and the resulting intense craving for more of the drug (Cregler & Mark, 1986). As the normal human fetus develops, some of the first neurotransmitters evident are noradrenaline, serotonin, and dopamine. They have been shown to be present in the fetus as early as the third or fourth month. Since the blood-brain barrier has not developed completely at that time, cocaine can readily act on fetal brain neurotransmitters (Chasnoff & Griffith, 1989). If chronic use in adults can alter the normal dopaminergic pathways (Farrar & Kearns, 1989), then the possibility may exist for the fetal dopaminergic pathways to be affected permanently as they are altered during development. Alterations in Cerebral Blood Flow It has been shown that chronic cocaine use can cause changes in cerebral blood flow, possibly because of its direct effect on vessels themselves or as a response to the disruption of the normal neurotransmitter mechanism. A study by Volkow et al. (1987) on the effects of cocaine on cerebral blood flow showed continued evidence of abnormal cerebral blood flow following 10 days of cocaine withdrawal. They hypothesized that disturbances of cerebral function may be more long term after chronic cocaine abuse. With the decrease in uterine and placental blood flow in pregnant women who use cocaine, fetal cerebral perfusion may also be compromised. The immaturity of the central nervous system of the fetus leaves it without the ability to regulate responses to abrupt variations in blood supply and blood flow (Dixon & Bejar, 1989). Seizures and the Kindling Effect Seizures commonly result from cocaine use to such an extent that physicians are alerted to consider the possibility of cocaine use in patients who present with unexplained seizure activity (Farrar & Kearns, 1989). Cocaine seems to lower the seizure threshold when used by adults (Chasnoff & Griffith, 1989), and current information about neonatal seizures is conflicting. In a study by Doberczak et al. (1988), of 39 infants who had been exposed to cocaine in utero, none experienced seizures. One of the possible explanations offered for this was that dendritic development in infants has not advanced to the point where a single neuron beginning epileptic activity can efficiently connect with enough other
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neurons to complete a seizure discharge (Doberczak, Shanzer, Senie, & Kandall, 1988). In a later study by Chasnoff and Griffith (1989), 6 of 52 infants did experience seizures. Though cocaine or its metabolites had been present in the urine of those infants at the time of birth, the seizure activity did not necessarily coincide with the presence of cocaine in the system (Chasnoff & Griffith, 1989). Studies with rats have shown long-term cocaine use can progressively increase the sensitivity to cocaine, particularly the excitatory effects of cocaine on the central nervous system. This phenomenon, known as the “kindling effect,” may be responsible for a continuation of hyperactive behavior and an increased occurrence of seizure activity even when cocaine is not present in the system (Cregler & Mark, 1986; Fulroth, Phillips, & Durand, 1989; Karler, Petty, Calder, & Turkanis, 1989). Corgfounding Injluences
Studying abnormal behaviors of children who were exposed to cocaine before birth in search of etiology is confounded by the environments in which they live. Particularly if the mother continues to use cocaine, addiction will probably cause a craving for the drug that supersedes all other considerations (MacGregor et al., 1987). She may fail to care for the infant or young child or even abuse the child if an intolerable stress level is reached as a result of her strong craving for more cocaine (Udell, 1989). Poverty may result or continue as her money is used primarily to support her cocaine needs. She may be emotionally absent to her child, or she may be physically incapacitated by her drug use (MacGregor et al., 1987). Additionally, exposure of the infant to cocaine itself may continue as evidence has been cited of infants’ exposure to cocaine through breast milk (Chasnoff, Douglas, & Squires, 1987; Chaney, Franke, & Wadlington, 1988). More recently in the literature have come reports of infants and toddlers who received medical attention for neurological symptoms including drowsiness, unsteadiness of gait, and seizures. Evidence of cocaine was found in toxicological studies of the urine of these children. No other medical causes for the abnormal behavior were evident and there were no indications that the children had directly ingested cocaine. Each of the children had been exposed to cocaine through inhalation of the smoke from the use of freebase cocaine or crack by their caretakers (Bateman & Heagarty, 1989). One incident has been reported in which an infant was seen in an emergency room following the sudden onset of seizures after she had ingested cocaine found on the floor of her home (Rivkin & Gilmore, 1989).
SUMMARY
The use of cocaine was popular in the 19th Century, and since the early 1970s its use has again been on the increase. Cocaine and its harmful effects are
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a broader segment of the population because a more inexpensive form Just as the dangers of cocaine use were originally not recognized, the dangerous and long-term effects of intrauterine cocaine exposure have only recently begun to be explored. Evidence seems to indicate that chronic and intermittent use of cocaine by a pregnant woman has the potential to impact the development of the fetal brain to such an extent that long-term neurobehavioral effects will result (Fulroth, Phillips, & Durand, 1989). It is possible that alterations may occur in the development of the anatomical structures, the neurotransmitters, and/or the blood flow patterns of the brain. A hypersensitivity of the central nervous system may also result. Behavioral manifestations of the alterations caused by cocaine exposure are not always evident at birth, but problems may become more obvious as the child matures and enters school. It appears that cocaine does have a more teratogenic effect on the fetus. Additional studies are necessary in which time and intensity of fetal exposure to cocaine is correlated with observations of neurologic and behavioral abnormalities throughout infancy, childhood, and even continuing into adolescence and early adulthood (LeBlanc, Parekh, Naso, & Glass, 1987). At present, it appears that the most prominent, or at least the best documented, behavioral abnormalities seen in newborns of women who used cocaine during pregnancy are tremulousness and irritability (Chasnoff et al., 1985; Oro & Dixon, 1987; Dow-Edwards, 1988), poor state regulation (Chasnoff, Burns, S&troll, & Bums, 1985; Chasnoff, Lewis, Griffith, & Willey, 1989), depressed interactive abilities (Chasnoff et al., 1985), and a tendency to become overloaded by environmental stimuli (Chasnoff et al., 1989). The toddlers and preschoolers who were exposed to cocaine in utero continue to demonstrate difficulties in interpersonal relationships. Their play is also affected in that it is sparse and disorganized, consisting of less representational and fantasy play than that of children born to mothers free of drugs. Many of these children also exhibit hyperactive behavior. As more and more of the children who have been exposed to cocaine before birth reach school age, it is imperative that we look more carefully at the evidence that cocaine does have a teratogenic effect and consider more fully the neurological implications. Infants known to have been exposed to cocaine in utero should be closely followed. Long-term studies including neuropsycho logical evaluations of these children as they reach school age and beyond are necessary in order that the neurological effects of intrauterine cocaine exposure can be recognized. As the manifestation of a head injury in childhood changes the child matures into adolescence and adulthood, so may the manifestation of intrauterine cocaine exposure change with the maturation of the affected organism. More and more it is becoming clear that taking a patient’s drug history is insufficient; the mother’s drug history may be of major importance as well. known as crack is now available.
Cocaine:
Transient or Teratogenic?
14.5
REFERENCES Adlaf, R. M. (1986). Self-reported cocaine reactions among social-recreational users: A factor analytical study. Drug and Alcohol Dependence, l&204-212. Bateman, D. A., & Heagarty, M. C. (1989). Passive freebase cocaine (‘crack’) inhalation by infants and toddlers. American Journal ofDisease in Children, 143,25-27. Bingol, N., Fuchs, M., Diaz, V., Stone, R. K. & Gromisch, D. S. (1987). Teratogenicity of cocaine in humans. The Journal of Pediatrics, 110,93-96. Chaney, N. E., Franke, J., & Wadlington, W. B. (1988). Cocaine convulsions in a breast-feeding baby. The Journal of Pediatrics, 112, 134-135. Chasnoff, I. J. (1989). The incidence of cocaine use. In K. V. Sprout (Ed.), Special currents: Cocaine babies (p. 1). Columbus, OH: Ross Laboratories, P.L. Chasnoff, I. J., Bums, W. J., Schnoll, S. H., & Burns, K. A. (1985). Cocaine use in pregnancy. The New England Journal of Medicine, 313,666669.
Chasnoff, I. J., Bussey, M. E., Savich, R., & Stack, C. M. (1986). Perinatal cerebral infarction and maternal cocaine use. The Journal ofPediauics, 108,4X-459. Chasnoff, I. J., Douglas, E. L., & Squires, L. (1987). Cocaine intoxication in a breast-fed infant. Pedialrics, 80,836-838.
Chasnoff, I. J., & Griffith, D. R. (1989). Cocaine: Clinical studies of pregnancy and the newborn. Annals of New York Academy of Science, 562,2&I-266.
Chasnoff, I. J., Lewis, D. E., Griffith, D. R., & Willey, S. (1989). Cocaine and pregnancy: Clinical and toxicological implications for the neonate. Clinical Chemistry, 35, 12761278. Commissaris, R. L. (1989). Cocaine pharmacology and toxicology. In K. K. Redda, C. A. Walker, & G. Bamett (Eds.), Cocaine, marijuana, designer drugs: Chemistry, pharmacology, and behavior (pp. 71-81). Boca Raton, FL: CRC Press, Inc. Cmgler, L. L., & Mark, H. (1986). Special report: Medical complications of cocaine abuse. The New EnglandJournal of Medicine, 315, 1495-1500. Dixon, S. D., & Bejar, R. (1988). Brain lesions in cocaine and methamphetamine exposed neonates. Pediatric Research, 23, 1226A.
Dixon, S. D., & Bejar, R. (1989). Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: Incidence and clinical correlates. The Journal of Pediatrics, 115,77O-778. Doberczak, T. M., Shanzer, S., Senie, R. T., & Kandall, S. R. (1988). Neonatal neurologic and electro encephalographic effects of intrauterine cocaine exposure. The Journal of Pediauics, 113, 354-358.
Dow-Edwards, D. L. (1988). Developmental effects of cocaine. In D. Clovet, K. Asghar, & R. Brown (Eds.), Mechanisms of cocaine abuse and toxicify (pp. 290-303). NIDA Research Monograph 88, Dept. of Health and Human Services: National Institute of Drug Abuse, Division of Preclinical Research. Estroff, T. W. (1987). Cocaine smoking: Nature and extent of coca paste and cocaine free-base abuse. In A. M. Washton, & M. G. Gold (Eds.), Cocaine: A clinician’s handbook (pp. 23-32). New York: Guilford Press. Fantel, A. G., & Macphail, B. J. (1982). The tentogenicity of cocaine. Teratology, 26, 17-19. Farrar, H. C., & Kearns, G. L. (1989). Cocaine: Clinical pharmacology and toxicology. The Journal of Pediaaics, 115.665675. Fulroth, R., Phillips, B., & Durand, D. J. (1989). Perinatal outcome of infants exposed to cocaine and/or heroin in utero. American Journal of the Diseased Children, 143,905-910. Grabowski, J., & Dworkin, S. I. (1985) Cocaine: An overview of current issues. The International Journal of the Addictions, 20.1065-1088.
Grimm, V. E. (1987). Effects of teratogenic exposure on the developing brain: Research strategies and possible mechanisms. Developmental Pharmacologic Therapy, 10.328-345.
146
L. F. Allen et al.
Howard, J. (1989). Long-term effecls of infants exposed prenatally to drugs. In K. V. Sproat (Ed.), Special currents: Cocaine babies (pp. l-2). Columbus, OH: Ross Laboratories. Karler, R., Petty, C., Calder, L., & Turkanis, S. A. (1989). Preconvulsant and anticipated effects in mice of acute and chronic treatment with cocaine. Neuropharmacology, 28709-714. Kantrowitz, B. K., Wingert, P., De La Pena, N., Gordon, J., & Padgett, T. (1990, February 12) The crack children, Newsweek, pp. 62-63. Kolb, B., & Fantie, B. (1989). Development of the child’s brain and behavior. In C. R. Reynolds & E. Fletcher-Janzen (Eds.), Ilandbook of clinical child neuropsychology (pp. 17-39). New York: Plenum Press. LeBlanc, P. E., Par&h, A. J., Naso, B., & Glass, L. (1987). Effects of intrauterine exposure to alkaloid cocaine (‘crack’). American Journal of Diseases of Children, 141,937-938. MacGregor, S. N., Keith, L. G., Chasnoff, I. J., Rosner, M. A., Chisum, G. M., Shaw, P., & Minogue, J. P. (1987). Cocaine use during pregnancy: Adverse pcrinatal outcome. American Journal of Obstetrics and Gynecology, 157,686690.
Madden, J. D., Payne, T. F., & Miller S. (1986). Matcmal cocaine abuse and effect on newborns. Pediatrics, 11,209-211.
Mannino, F. L., & Trauner, D. A. (1983). Stroke in neonates. The Journal of Pediatrics, 102(4), 605610. Mody, C. V., Miller, B. L., McIntyre, H. B., Cobb, S. K., & Goldberg, M. A. (1988). Neurologic complications of cocaine abuse. Neurology, 38,1189-l 193. Newcomb, M. D., Bentley, P. M., & Fahy, B. (1987). Cocaine use and psychopathology: Associations among young adults. The fnrernational Journal of the Addictions, 22,1167-1188. Nicholi, A. M. (1984). Cocaine use among the college age group: Biological and psychological effects. Clinical and laboratory research findings. Journal of American College Health, 32, 258-261. Oro, A. S., & Dixon, S. D. (1987). Perinatal cocaine and mcthamphetamine exposure: Maternal and neonatal correlates. The Journal of Pediatrics, 11,571-578. Pitts, D. K., & Marwah, J. (1989). Autonomic actions of cocaine. Canadian Journal of Physiological Pharmacology, 67,1168-l 176.
Rivkin, M., & Gilmore, H. F. (1989). Gcneralizcd seizures in an infant due to environmentally acquired cocaine. Pediatrics, 84, 1101-1102. Siegel, R. K. (1987). Medical and biological conscqucnccs of cocaine abuse. In A. M. Washton, & M. S. Gold (Eds.), Cocaine: A clinician’s hund6ook (pp. 175-191). New York: Guilford Press. Spear, L. P., Kirstein, C. L., Bell, J., Yoottanasumpun, V., Grecnbaum, R., O’Shea, J., Hoffmann, H., & Spear, N. E. (1989). Effects of prenatal cocaine exposure on behavior during the early postnatal period. Neurotoxicology and Teratology, 11.57-63. Sunde, S. (1990, February 26). A generation in doubt, Dallas Times Herald, pp. A-l, A-12. Trauner, D. A., & Mannino, F. L. (1986). Neurodevelopmental outcome after neonatal cerebrovascular accident. The Journal of Pediatrics, 108,459461. Udell, B. (1989). Crack cocaine. In K. V. Sproat (Ed.), Special currents: Cocaine babies (pp. 5-8). Columbus, OH: Ross Laboratories. Volkow, N. D., Gould, K. L., Mullani, N., Addles, S., & Krajewsky, K. (1987). Changes in cerebral blood flow of chronic cocaine users. Journul of Cerebral Blood Flow and Metabolism, 7(l), S292.
Washton, A. M. (1989). Cocaine addiction. New York: W.W. Norton & Co. Wetli, C. V. (1989). Fatal reactions to cocaine. In A. M. Washton (Ed.), Cocaine addiction (pp. 33-54). New York: W.W. Norton & Co. Woods, J. R., Plessinger, M. A., & Clark, K. E. (1987). Effect of cocaine on uterine blood flow and fetal oxygenation. Journal of the American Medical Association, 257,957-961.