General Child Neurology
May. 31, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Cocaine is one of the most addictive and frequently abused illicit drugs. Maternal abuse of cocaine during pregnancy is common and is associated with a host of neurologic and developmental abnormalities in offspring. In this updated article, the authors describe the pathological effects of cocaine on the developing brain and explain how cocaine-induced changes in maternal behavior may contribute to the neurodevelopmental deficits of prenatally exposed children.
• Maternal cocaine abuse during pregnancy is common and is associated with a host of neurologic and developmental abnormalities in the offspring.
• Cocaine is a potent vasoconstrictor, and many of the medical and neurologic problems of children exposed to cocaine in utero are due to compromised blood flow through placental and cerebral vasculature.
• Cocaine can interact with the monoaminergic synapses in the developing brain to induce short-term and long-term changes in neurophysiology and anatomy.
• Cocaine can alter maternal behaviors, thus, disrupting maternal-fetal interactions, which may contribute to the neurodevelopmental problems of the offspring.
Cocaine is benzoylmethylecgonine, an alkaloid derived from the leaves of the coca shrub (Erythroxylon coca), which grows wild and is cultivated in South American and Central American countries (44). Cocaine is available either as cocaine hydrochloride or as the highly purified (free base form) cocaine alkaloid. Cocaine hydrochloride is water soluble but heat labile and is most commonly administered by nasal insufflation (“snorting”). In contrast, cocaine alkaloid is water insoluble but heat stable and is typically administered by inhalation (smoking). Because the alkaloid preparation produces a popping sound when the crystals are heated, it has acquired the name “crack.”
In light of cocaine’s widespread use among pregnant women, the effect of the drug on the fetus is an issue of major public health importance. It is widely accepted that cocaine can be deleterious to the fetus and that the fetal brain is particularly vulnerable. However, several factors have made the study of cocaine’s effects on the human fetus difficult to conduct and interpret.
Foremost among these difficulties is the inescapable fact that a cocaine-exposed fetus is often exposed to many additional deleterious confounding variables during prenatal and postnatal life (78; 83). A pregnant woman who abuses cocaine may also drink alcohol, smoke cigarettes, and abuse other illicit drugs. She may transmit to the fetus a congenital infection, such as HIV or syphilis. Following birth, the child of a cocaine-abusing mother may receive inadequate nutrition and grow up in a poor social environment (119).
During the 1980s, a plethora of papers described wide ranging and highly negative outcomes among children exposed to cocaine in utero. The alarm sounded in the medical literature and lay press that an entire generation of deeply disabled “crack babies” was being produced. It later became evident that physicians, scientists, journalists, and politicians had overreacted in the face of the data and that cocaine did not necessarily have as profound and far reaching consequences for the fetus as had been feared. This overreaction was due, in large part, to the failure of the physicians and scientists to appreciate the many confounding variables accompanying fetal cocaine exposure. It is now appreciated that cocaine can damage a fetus, sometimes with permanent consequences, but that the damage is typically either circumscribed in nature or subtle in severity, and the impending onslaught of multiply injured crack babies is a myth (26; 27).
A second issue that has complicated the study of fetal cocaine exposure relates to the choice of outcome measure. Cocaine may adversely affect neural systems involved in complex neurologic and behavioral functions, such as motivation, attention, social interaction, and intelligence, which are difficult to measure, particularly during infancy. Because many children prenatally exposed to cocaine are in chaotic home environments, locating the children for long-term follow-up studies is often difficult.
A third methodological difficulty relates to accurately identifying the exposed fetuses and children and determining the degree and timing of the exposure. Because cocaine use is illegal and carries moral implications when used during pregnancy, women lie about their use of the drug. Testing for cocaine metabolites in urine, meconium, amniotic fluid, umbilical cord tissue, and brain identifies some, but not all, exposed fetuses, and the issues of dose and timing of exposure remain. The nature and severity of the teratogenic and destructive effects of cocaine on the fetus probably depend on the gestational timing and magnitude of exposure (122; 40). Thus, the imprecise measure of these crucial variables has limited the ability to determine cocaine’s effect on the developing brain.
Although cocaine’s adverse fetal effects are real, these methodologic issues lead to overestimation of the incidence and impact of prenatal cocaine. It is important for clinicians and others to avoid unjustified negative conclusions and assumptions about children who were prenatally exposed to cocaine as these false inferences can enhance harmful and unwarranted stigma against them (84).
The clinical manifestations of intrauterine cocaine exposure fall into the following 3 major categories: (1) maternal-fetal effects, (2) physical and neurologic effects noted at birth, and (3) long-term behavioral consequences.
Maternal-fetal effects. Cocaine use during pregnancy can produce a variety of serious obstetrical complications, many of which are injurious to the developing fetus and dangerous to the mother. Cocaine can produce preterm delivery and premature and prolonged rupture of the membranes (116; 02). Additional cocaine-related complications in pregnancy include hypertensive crisis, spontaneous abortion, and abruptio placentae (01; 37; 05).
Cocaine use greatly increases the likelihood of maternal hypertension and the obstetric complications associated with that disorder. Cocaine dependence prior to the pregnancy is strongly associated with hypertensive disorders of pregnancy, even if the woman abstains from cocaine use during the pregnancy. This ongoing predisposition to hypertension is believed to be due to heightened vascular reactivity to sympathetic/noradrenergic stimulation precipitated by the prior chronic cocaine exposure (99).
Cocaine is a potent vasoconstrictor that can compromise placental blood flow. Animal models have demonstrated that small doses of cocaine can substantially decrease uterine artery blood flow and increase uterine vascular resistance (93; 131). These changes can be accompanied by marked fetal hypoxemia, hypertension, and tachycardia. Following a single dose of cocaine, these effects typically persist for 15 minutes. Fetal acidosis and increased catecholamine levels induced by compromised uterine circulation may underlie the premature induction of labor.
Cocaine affects not only the flow of blood through the placenta, but adversely affects the placenta itself. The vasoactive effects of cocaine can lead to placental infarctions and placental abruptions. These negative effects on placental integrity can have major and persistent effects on the fetus. In pregnancies complicated by cocaine exposure, the state of placental health has been significantly correlated with fetal outcome and with severity of withdrawal symptoms in the newborn (38).
The effects of cocaine on the mother and the secondary effects on the offspring occur not only prenatally, but postnatally, as well (128). Cocaine addiction during pregnancy can disrupt the mother’s ability to care optimally for her child. Early dysfunctional mother-infant interactions probably contribute to adverse effects of prenatal cocaine exposure. Evidence has emerged that disruption of maternal oxytocin systems underlies this aberrant maternal behavior.
Cocaine-using women are less attentive and sensitive to infant cues. They show less interest and more hostility to their babies. Oxytocin is a neuropeptide that is released from the hypothalamus into the maternal blood stream in response to infant-produced stimuli. Both acute and chronic cocaine exposure can substantially alter maternal oxytocin signaling, and the effects can be long lasting. These changes in oxytocin signaling have been correlated with dysfunctional maternal behaviors, which have been correlated with aberrant social behaviors and diminished learning potential in the offspring. Thus, infants may suffer from alterations in maternal behavior that are mediated by cocaine-induced changes in maternal oxytocin signaling (128).
Animal models have provided interesting insight into the adverse effects of cocaine on maternal behaviors. Studies utilizing mice have shown that prenatal exposure to cocaine alters both prepartum and postpartum maternal behaviors. Cocaine-exposed mothers build shallower and smaller nests and less frequently provide warmth for the offspring. In addition, cocaine-exposed mothers spend less time sniffing the environment and rearing up, thus, reflecting less time exploring the environment to determine the safety that surrounds her young. These effects are dose-related, yet the worst effects are seen when the cocaine exposure occurs chronically throughout pregnancy, even if the daily chronic dose is lower than a dose restricted to later pregnancy. These observations suggest that the chronicity of cocaine exposure during pregnancy may be more important than the dose of cocaine in disrupting maternal behaviors (108).
The use of cocaine might negatively alter maternal behaviors, not only when the cocaine exposure occurs during pregnancy, but even when it occurs before pregnancy. In a study utilizing experimental animals, adult female rats self-administered cocaine prior to breeding. Even following at least 30 days of cocaine abstinence following exposure, the quality of maternal behaviors was negatively affected. The previously exposed mothers spent less time with their pups and had an excess of maladaptive maternal behaviors. These findings are worrisome, as they suggest that some adverse maternal behaviors may persist, even if the mother stopped cocaine use prior to pregnancy (43).
Prenatal cocaine can alter not only placental physiology, but fetal physiology as well. Immediately following an acute maternal dose of cocaine, the fetus may manifest tachycardia, extreme baseline heart rate variability, abnormal elevation of respiratory rate and tidal volume. The respiratory abnormalities noted in utero continue in the newborn period, may be due to autonomic dysfunction, and may underlie the increased incidence of sudden infant death syndrome in prenatally exposed infants (125; 126; 24).
Prenatal cocaine also alters fetal behaviors. Serial ultrasound studies of cocaine-exposed fetuses (Hume et al 1989) have revealed abnormal sleep states, prolonged eye scanning, vigorous or continuous sucking, and excessive fetal movements, all of which may persist into the neonatal period.
Exposed fetuses may also have withdrawal signs while in utero. Indeed, fetuses withdrawing from cocaine display symptoms similar to their withdrawing mothers, including irritability, repetitive yawning, and abnormal arousal. The disorganization of fetal behavior has been correlated with the magnitude of maternal cocaine use.
Until recently, it was unclear whether cocaine could directly affect the fetal brain or whether all effects were manifested through the fetal and placental vasculature. However, a study utilized PET to demonstrate that in third trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism (17). This finding, along with the known presence of functional monoaminergic synapses at which cocaine may exert its actions in the fetal brain, strongly suggests that cocaine is pharmacologically active in the human fetal brain (42).
Physical and neurologic effects at birth. Most infants exposed in utero to cocaine appear normal, at least on a standard newborn examination. However, maternal cocaine use during pregnancy can produce abnormalities detectable at birth in many of the infants. These include abnormalities of morphology, physiology, and behavior.
Cocaine exposure during pregnancy can interfere with somatic growth of the fetus. As a result, newborns with prenatal cocaine exposure often have reduced birth weight and are small for gestational age (49). Maternal cocaine use decreases fetal somatic growth by nearly two thirds (63%) of a standard deviation (10). The potential public health impact of cocaine-induced intrauterine growth retardation is high because low birth weight is a key risk factor for infant morbidity and mortality (86).
Even more disturbing than its effect on somatic growth is cocaine’s deleterious effect on brain growth. Prenatal cocaine exposure is associated with microcephaly among the offspring of cocaine-abusing mothers. Furthermore, the severity of the brain growth restriction may exceed the impairment of body growth, producing asymmetrical growth retardation with a brain-wasting pattern (74; 12).
Because mothers who abuse cocaine also expose their fetuses to other factors that can impair growth (such as tobacco smoking, other drugs, and undernutrition), the possibility exists that the fetal growth disturbance is due to these confounding factors and not to cocaine per se. However, an animal study has demonstrated that maternal exposure to cocaine alone reduces fetal birth weight (19). Furthermore, although the fetal brain is selectively spared in undernutrition, it is particularly vulnerable in cocaine exposure, suggesting that microencephaly in cocaine-exposed newborns is due to the cocaine and not to undernutrition.
One of the most dramatic effects of acute cocaine exposure in the newborn period is perinatal cerebral infarction. A report in 1986 described an infant born at term following maternal cocaine use 15 hours before delivery (21). On admission to the hospital, the mother was disoriented and had slurred speech. At birth, the infant was tachycardiac and had a right-sided hemiparesis. Neuroimaging demonstrated a left posterior parietal infarction. Since this report, numerous cases have been published of cocaine-exposed infants with perinatal strokes.
In addition to inducing ischemic strokes in the perinatal period, cocaine also induces intracerebral hemorrhages in the neonate (115). In premature newborns, cocaine increases the risk of intraventricular hemorrhage (112). In addition, in both premature and full-term newborns, cocaine increases the incidence of subependymal hemorrhage and the formation of subependymal cysts (114).
Probably due to its vasoconstrictive effects, cocaine induces numerous malformations notable in the newborn period. A report in 1990 described 9 infants with congenital limb reduction defects and intestinal atresia, or infarction (53). The limb-reduction defects included missing digits and unilateral atypical ectrodactyly. The report also noted increased incidence of pulmonary atresia, pulmonary stenosis, atrial septal defects, and ventricular septal defects. Furthermore, cocaine-exposed infants have an increased incidence of genitourinary abnormalities, including hydronephrosis, hypospadias with chordee, undescended testicles, and ambiguous genitalia (22).
Abnormal autonomic function is also seen in infants prenatally exposed to cocaine. Cocaine-exposed infants have less heart rate variability than do infants exposed to other drugs or unexposed infants (88). Newborns exposed to cocaine are also at increased risk for tachyarrhythmias, including isolated atrial flutter (46). These abnormalities in heart rate variability and vagal tone often persist when the infants are retested at 2 to 6 months of age (87).
Heart rates in cocaine-exposed infants are abnormal not only at baseline but also in response to environmental changes. Newborns prenatally exposed to cocaine have a delayed and prolonged heart rate reaction to orthostatic stress (59). Furthermore, abnormalities in heart rate responses persist in 7-month-old infants during tasks that illicit positive or negative affect (109). These early autonomic changes are clinically relevant, as they may underlie the increased risk of SIDS in infants exposed to cocaine in utero (124; 39). Furthermore, they may signify later life cardiovascular problems. In experimental rodents, prenatal cocaine reprograms coronary myogenic tone, increases the risk of coronary autoregulatory dysfunction, and increases the incidence of cardiac events as adults (135; 133). Therefore, at least in experimental animals, early cocaine use may impact later cardiac health.
In addition to morphology and physiology, the neurobehavior of infants may also be altered by prenatal cocaine exposure. Singer and colleagues performed neurobehavioral assessments on infants heavily exposed, lightly exposed, or unexposed to cocaine in utero (111). They found that jitteriness, attention problems, tone abnormalities, and sensory asymmetries increased in a dose-response pattern. Additional studies have suggested that cocaine may increase other neurobehavioral abnormalities, including irritability, impaired interaction, poor habituation, and diminished arousal (25; 64; 13).
Commonly, infants prenatally exposed to cocaine have also been exposed to other potential teratogens and other negative maternal factors that could influence newborn behavior. Thus, the possibility exists that many or all of the behavioral abnormalities in cocaine-exposed newborns are due to these confounders. However, new and sophisticated statistical methods have dissociated cocaine’s effects from these potential confounding variables. Das and colleagues utilized a multivariate repeated measures statistical approach to model multiple central and autonomic nervous system signs in newborns as a function of cocaine exposure and other covariates (32). They found that cocaine-exposed newborns manifest multiple neurologic signs, even after controlling for interdependence among signs and such potential confounders as race, gestational age, socioeconomic status, and prenatal exposures to tobacco, alcohol, and marijuana. These multiple nervous system signs included hypertonia, jitteriness, abnormal cry, inconsolability, and irritability.
Newborns prenatally exposed to cocaine have a greatly increased incidence of prenatally acquired infection. Hepatitis, syphilis, and human immunodeficiency virus are all substantially more common among cocaine-exposed infants than among controls (13). However, prenatally exposed infants do not have a higher rate of postnatally acquired infections (47). Therefore, the increased incidence of infection in prenatally exposed infants likely represents a difference in maternal behavior, including exposure to sexually transmitted diseases, rather than an impaired immune response in the infant. Early recognition of these infections is important, as they are associated with increased morbidity and can substantially complicate the care of these already compromised newborns.
Thus, cocaine may induce a wide variety of physical, physiological, and behavioral abnormalities in the newborn. The extent to which each of these abnormalities is due to cocaine’s vasoactive properties, toxic effects, and pharmacologic effects remains unknown.
Long-term developmental effects. There are many reasons for presuming that prenatal cocaine impairs cognition and development, thus leading to permanent physical, mental, and emotional disabilities. Cocaine affects monoaminergic neurotransmitter systems that are important for the development of neuronal circuitry (122; 82). It can cause vasospasm of cerebral and umbilical arteries, thus leading to generalized and cerebral fetal ischemia. The drug has been linked to prematurity, premature rupture of membranes, microcephaly, low birthweight, and newborn behavioral abnormalities (12; 10; 49). All of these perinatal and neonatal complications are risk factors for adverse developmental outcome.
Despite the preponderance of theoretical arguments that cocaine may cause permanent disabilities, evidence that cocaine actually does so was slow to emerge. Multiple studies conducted during the 1980s demonstrated long-term neurologic and behavioral manifestations of prenatal cocaine exposure. However, others failed to replicate the findings and argued that the apparent effects of prenatal cocaine exposure on children were due to confounding variables. It has become clear that cocaine has negative long-term developmental effects after the publication of multiple high-quality and well-controlled studies (75; 90).
This controversy regarding long-term neurodevelopmental sequelae of prenatal cocaine exposure has induced strong opinions and controversial actions within the medical, legal, and lay populations. For example, medical personnel have turned over the names of obstetric patients testing positive for cocaine metabolites to police, who have arrested the women for drug possession and child abuse (100). Community organizations have offered financial incentives to accept long-acting contraception and sterilization to women with a history of illegal drug use (98; 45). The popular press has fueled fear of an epidemic of “cocaine babies” and “crack kids” that are costly to society and impossible to educate (31; 127). No issue regarding fetal cocaine exposure has generated greater controversy than the issue of cocaine-induced neurodevelopmental sequelae.
Because of the controversy surrounding the long-term effects of prenatal cocaine exposure, Frank and colleagues conducted a meta-analysis examining the postnatal outcomes of children exposed to cocaine in utero (45). They examined 5 domains, including physical growth, cognition, language skills, motor skills, and behavior. After controlling for confounders, they found no strong evidence that prenatal cocaine exposure adversely impacts any of these domains outside of the neonatal period. These authors concluded that many of the adverse outcomes once attributed specifically to in utero cocaine exposure were actually due to other correlated factors, including prenatal exposure to alcohol and tobacco and a poor childhood environment.
Other studies, however, have found strong evidence that fetal cocaine exposure can specifically and substantially impair neurodevelopmental processes in children. In particular, Singer and colleagues prospectively studied a large cohort of cocaine-exposed infants born at a large urban county hospital (111). They compared the cocaine-exposed infants with unexposed infants from the same population. Using standardized normative measures of cognitive and motor development, they tested the children at 2 years of age and found substantial cognitive deficits among the cocaine-exposed children. The exposed children were twice as likely as the unexposed children to have developmental delay. Importantly, because the study design controlled for prenatal exposure to other drugs, gestational age and size at birth, and a variety of caregiver characteristics, many of the confounding variables that plagued earlier studies were eliminated. Thus, the cognitive deficits observed in the cocaine-exposed children probably were truly attributable to cocaine.
Likewise, prenatal cocaine exposure can have a negative and long-term impact on language skills. A longitudinal study from 4 months to 3 years of age revealed that cocaine-exposed children had poorer language skills than unexposed children (96). This longitudinal effect remained significant, even after elimination of potential confounding influences, including sociodemographic factors and prenatal exposure to other substances. A second longitudinal study confirmed that expressive and receptive language skills remain impaired at ages 4 and 6 years in children prenatally exposed to cocaine (71). Furthermore, children do not appear to outgrow these language deficits. A study conducted on late adolescents found that prenatal cocaine has lasting negative impact on many language-related functions, including word reading, reading comprehension, as well as semantic and grammatical processing (66).
Additional studies have demonstrated that negative effects of prenatal cocaine exposure on neurodevelopment endure well into childhood. In utero exposure to cocaine reduces IQ and verbal reasoning scores (16), delays language development (35; 11; 71), increases the incidence of learning disabilities (97), impairs procedural learning (81), and impairs behavioral regulation and attention (52; 07) in preschool and school-aged children.
In addition to impairing cognitive and language development, prenatal cocaine exposure may also lead to aggressive behavior. Multiple animal studies have shown that prenatal cocaine disrupts social behaviors and leads to long-term increased aggression during stressful, competitive tasks (60; 61; 130).
Based on these results in animal models, Bendersky and colleagues examined the impact of prenatal cocaine exposure on childhood aggression (15). They found that prenatal cocaine exposure significantly increased aggressive behaviors at the age of 5 years, especially in boys and in children raised in poor home environments. Prenatal cocaine exposure is also associated with long-term increases in risk-taking behavior and substance use and abuse. Teenagers (ages 15 to 17) who were prenatally exposed to cocaine are twice as likely as nonexposed teens to use tobacco and marijuana and to have a substance use disorder at age 17 (91). The increased risk-taking may be due to long-term cocaine-induced deficits in the feedback processing that helps people to avoid consequences of negative behavior. Indeed, physiologic correlates of feedback-related negativity are decreased in adolescents who were prenatally exposed to cocaine (94).
On a physical basis, the long-term behavioral problems and cognitive deficits resulting from prenatal cocaine exposure may reflect disruptions in cortical connections, due to abnormalities in white matter structure. In support of this notion, Morie and coworkers have utilized diffusion tensor imaging to show reductions in anisotropy in select white matter tracts among adolescents with prenatal cocaine exposure. The findings suggest that the long-term behavioral and learning deficits of prenatal cocaine exposure could be due to disruptions in the transmission of signals among various cortical regions that are necessary for cognition, information processing, and self-control (95).
The findings that prenatal cocaine exposure appears to permanently impair learning ability and behavioral control, led Rivkin and colleagues to examine whether cocaine permanently alters the size of the brain and its components (103). In a volumetric MRI study, these authors found that children 10 to 14 years of age who were prenatally exposed to cocaine had lower volumes of cortical gray matter and total parenchymal volumes than did matched controls. The cocaine-exposed children also had smaller head circumferences. Furthermore, these adverse effects of cocaine on brain growth were exacerbated by prenatal exposure to alcohol, tobacco, and marijuana. These findings suggest that prenatal cocaine does permanently reduce brain volume and that the drug may act cumulatively with other abused substances to permanently impair brain size and volume.
The more time that passes after a prenatal exposure, the more difficult it is to conduct a study examining the effects of that exposure. As a result, studies examining the effects of prenatal cocaine exposure on adolescents are few in number and have tended to be small in scale. Despite these shortcomings, several well-controlled studies have demonstrated that prenatal cocaine exposure does have negative consequences that can be detected in adolescents. In particular, adolescents with prenatal cocaine exposure have a substantially increased likelihood of having impulsivity, aggression, and rule-breaking behavior (75; 90). Teenagers who were prenatally exposed to cocaine are also more likely to engage in early and risky sexual behavior (89).
Prenatal exposure to certain drugs can permanently alter the neural systems involved in drug addiction and lead to addictive behaviors later in life. For example, prenatal alcohol and tobacco exposure increase the risk of alcohol (08; 03) and tobacco use later in life (62; 28; 29; Al Mumun et al 2006). Animal studies have suggested that this same phenomenon may occur with cocaine. Experiments using laboratory mice and rats have shown that prenatal cocaine exposure increases adult self-administration of cocaine (63; 51; 104) and increases the reward potency of cocaine in adulthood (73; 80). Research in experimental animals suggests that maternal consumption of cocaine can increase the propensity for later cocaine abuse in the offspring, even if the cocaine exposure occurred before conception. In a study utilizing experimental rats, Fant and colleagues allowed female adult rats to self-administer cocaine for several months, followed by at least 1 month of abstinence from cocaine, before the dams became pregnant (43). This ensured that all cocaine and its metabolites were cleared from the dams prior to pregnancy. Despite the clearance of cocaine before pregnancy, the male progeny of these dams had an increased self-administration of cocaine during adulthood. Although the previous cocaine exposure increased cocaine reinforcing efficacy in the offspring, it did not impair learning or anxiety-like behaviors. These findings suggest that preconception cocaine consumption can selectively enhance cocaine consumption in offspring, even if it does not diminish other forms of learning or behavior. One possibility is that the preconception cocaine induces epigenetic changes in the oocytes, resulting in changes in the developmental trajectory (43).
Evidence suggests that this propensity for later abuse also occurs in humans. A prospective, longitudinal, cohort study showed that people exposed to cocaine prenatally or during early postnatal life are substantially more likely to use cocaine at 14 years of age (33). Because the study controlled extensively for child, parent, and community risk factors, the results suggest that it was the cocaine itself that increased the risk for future use. Additionally, published studies have found that prenatal cocaine exposure substantially increases the likelihood that an adolescent will use and abuse tobacco, alcohol, and marijuana (90; 92). Thus, prenatal cocaine exposure not only damages the developing brain, but it also renders that brain more vulnerable to cocaine and other addictions later in life.
Research has revealed that prenatal cocaine exposure can have adverse behavioral effects that last into adulthood. In a longitudinal study of individuals born to women who were recruited during pregnancy, Richardson and colleagues compared those who were exposed to cocaine with unexposed controls and followed the offspring at multiple time points throughout life, all the way to 21 years postpartum (101). The exposed and unexposed controls were matched for a variety of potential confounding variables. The research revealed a direct association between prenatal cocaine exposure and early initiation of marijuana use, as well as emotion regulation problems, arrest history, and conduct disorder at 21 years of age. Those who were prenatally exposed to cocaine were 3 times more likely to have been arrested and were twice as likely to have been diagnosed with conduct disorder than unexposed controls. Importantly, the research strongly suggested that the adverse outcomes at 21 years of age were a direct consequence of the prenatal cocaine exposure and were not mediated by adolescent delinquent behaviors. This is the first report to demonstrate that associations between prenatal cocaine exposure and later substance abuse and externalizing behavior problems can persist into adulthood and that the young adult outcomes are not merely a consequence of earlier behavior problems.
The long-term effect of prenatal cocaine exposure is a subject of much debate. Unquestionably, a large proportion of children who were prenatally exposed to cocaine have a poor neurodevelopmental outcome (34; 35; 111; 96). Many will have developmental delay, mental retardation, attention deficits, behavior disorders, or a combination thereof. Children who were prenatally exposed to cocaine are more likely to require special education and support services when they reach school age (70). They may also have disrupted growth (10; 30). The debate centers not on whether or not these children tend to do well, but on what the role of cocaine, per se, is in this guarded prognosis. Many children prenatally exposed to cocaine are raised in dysfunctional families and have mothers that are polydrug abusers. The outcome of many children prenatally exposed to cocaine may be related more to their poor environment than to the biological effects of the previous cocaine exposure (57).
The patient was the 2020 g product of a 38-week gestation, born to an 18-year-old gravida 1 para 1 unmarried woman. The pregnancy was complicated by maternal substance abuse, including “crack” cocaine and occasional binge alcohol consumption during the first 4 months of the pregnancy. The patient’s mother also smoked 1 pack of cigarettes per day during the first 5 months of the pregnancy and one-half pack per day during the remainder of the pregnancy. Prenatal care was not sought until the sixth month of gestation, and at that time a chlamydia trachomatis infection of the genital tract was diagnosed and treated successfully with erythromycin. All other routine maternal testing, including a test for HIV infection, was negative or normal.
Ultrasound examination at 6 months’ gestation revealed intrauterine growth retardation and a small biparietal diameter. However, no dysmorphic features were noted by ultrasound, and the placenta appeared normal.
The mother stated that she abstained from cocaine use from the end of the 18th week until the 38th week of gestation, at that time she smoked crack cocaine daily for 3 consecutive days. Several hours after smoking the cocaine on the third day, the mother noted some partially clotted bleeding from the vagina. Ultrasound examination revealed a partially abrupted placenta. The fetal heart rate was adequate at 130 beats per minute but showed poor variability.
The mother was immediately transported to the operating room, and the infant was delivered by cesarean section. Apgar scores were 5 at 1 minute and 7 at 5 minutes of age. After receiving moderate tactile stimulation, the infant made good respiratory efforts and, aside from his small gestational-age size, he appeared well. He was admitted to the intermediate care nursery.
Ballard maturity rating suggested a gestational age of 38 weeks. However, he had symmetrical growth disturbance with body weight, body length, and head circumference all less than fifth percentile for gestational age.
The newborn remained stable in the nursery until 14 hours of age when he had focal motor seizures consisting of rhythmic jerking of the right arm and leg. The seizure was stopped with phenobarbital. A head CT scan revealed an extensive area of low attenuation in the left middle cerebral artery distribution, highly suggestive of an acute ischemic stroke.
Urine toxicology screens for both the infant and his mother were positive for cocaine metabolites. Further work-up for the ischemic stroke, including coagulation studies, chest x-ray, echocardiogram, complete blood count, electrolyte profile, and tests of liver and kidney function were normal. It was noted that the timing of the cerebral infarction, as well as the placental abruption, corresponded to the timing of the cocaine exposure during the days prior to delivery.
The infant’s seizures were initially well controlled with phenobarbital, and he was discharged from the hospital into foster care at 7 days of age. At 9 months of age, he was seen in the child neurology clinic because of recurrent focal seizures involving the right arm and leg that occurred several times per day despite increasing doses of phenobarbital. Developmentally, the child was progressing normally. He was able to sit unattended and was beginning to pull himself to a standing position. However, examination revealed a right hemiparesis and hyperreflexia. In addition, he was microcephalic, with a head circumference below the fifth percentile, despite weight and length at the 50th percentile. Head CT scan revealed an extensive area of encephalomalacia in the left hemisphere, corresponding to the previous stroke.
The infant’s medication was switched from phenobarbital to carbamazepine, which controlled the seizures better. When the child was re-evaluated at 3 years of age, his seizure disorder was well controlled on carbamazepine. However, he was delayed in the acquisition of social-interpersonal skills and in language, despite a normal hearing evaluation. At 6 years of age, the child was impulsive, hyperactive, and required special education.
Although cocaine remains an illegal drug, it is readily available on the street in all major cities and throughout the school systems. Cocaine is available in several forms, including pure cocaine, cocaine adulterated with a variety of substances, and crack cocaine. Cocaine is injected intravenously, smoked as crack, or inhaled as a powder (58). All routes of administration produce sufficient drug levels to adversely affect fetal well-being.
Several distinct mechanisms underlie cocaine’s damaging effects on the developing fetus. These mechanisms include disruption of developing neurotransmitter systems, alteration in the structure of neurons and their circuitry, and hypoxia-ischemia due to cocaine’s vasoconstrictive actions.
Many brain regions, including the cerebrum, diencephalon, and brainstem utilize monoamines as neurotransmitters or are the targets of monoaminergic neurons. Derangement of monoaminergic neurotransmission is cocaine’s principal mechanism of action in the adult brain. Monoamines appear early in brain development and have critical regulatory roles in the development of neuronal circuitry. Thus, disturbances in these neurotransmitter systems could have far-reaching negative effects.
In experimental systems, acute and long-term abnormalities have been detected in tissue dopamine levels, receptor-binding densities, receptor-binding affinities, and subcellular receptor location (110; 117; 102). Male, but not female, adolescent rats prenatally exposed to cocaine have altered dopamine receptor binding in the striatum and nucleus accumbens (110). This sexually dimorphic long-term effect of prenatal cocaine exposure may underlie the behavioral abnormalities consistently seen in male, but not female, children and adolescents.
In addition to altering monoaminergic systems, prenatal cocaine also corrupts GABAergic systems. In the prenatal brain, cocaine reduces GABAergic inhibition and reduces the ratio of GABAergic-to-projection neurons in the cerebral cortex (85). These physiological changes impair the balance between excitatory and inhibitory neurotransmission, enhance epileptogenicity, and lead to long-term changes in synaptic plasticity (76).
The cerebral cortex is not the only site at which prenatal cocaine exposure alters the GABA system. In the striatum, prenatal cocaine pathologically enhances GABA interneuron function, which depresses corticostriatal activity. This leads to imbalances within the striatal microcircuitry, which has adverse effects on motor control, cognition, and learning (123).
Another important physiologic change that cocaine produces in the developing brain is a delay in the maturation of glutamatergic synaptic transmission (14). Cocaine produces this effect by inhibiting dopamine transporters on the dopaminergic neurons in the ventrotegmental area, which project to and enhance the maturation of glutamatergic neurons throughout the cortex. This finding demonstrates how a teratogenic agent that acts on the receptors of one neurotransmitter system in a localized brain region can disrupt the actions of multiple neurotransmitter systems throughout the brain.
Prenatal cocaine alters not only the physiology of neurons, but their structure as well. Unlike alcohol and heroin, which diminish dendrite outgrowth, exposure of the developing neurons to cocaine can induce an exuberant overgrowth of cortical neuron dendrites. The dendritic trees of cortical neurons exposed to cocaine have greater branch length and branch number (50; 77). Exposure of developing neurons to cocaine can induce an exuberant overgrowth of cortical neuron dendrites (50). This dendritic overgrowth occurs selectively in cortical regions receiving strong dopaminergic innervation and is likely mediated by altered dopaminergic neurotransmission (118). Experimental animals are impaired in behaviors specifically mediated by cortical areas receiving strong dopaminergic innervation, indicating a correlation between excessive neurite outgrowth and abnormal behavior (106; 50).
In addition to altering the shape of neurons, prenatal cocaine exposure can also disrupt neuronal migration. During brain development, especially during the second trimester, newly formed neurons undergo a migration that takes them to their ultimate location in the developed functioning brain. Cortical neurons originate from the subventricular zone, adjacent to the lateral ventricles, and migrate radially and tangentially to their mature location in the cerebral cortex. Cocaine exposure in primates can cause neocortical cytoarchitectural abnormalities. However, these abnormalities in cortical architecture are observed only when the cocaine exposure occurs in the second trimester (72). These disruptions in cortical architecture are due to a disturbance in the radial and tangential migration of neocortical neurons (69). The findings that cocaine alters neuronal migration and disrupts cortical architecture only when the exposure occurs in the second trimester demonstrates that the pathophysiology and outcome of prenatal cocaine exposure in humans likely depends strongly on the gestational age of the fetus at the time of exposure.
Cocaine exposure also induces abnormal wiring of neural circuitry (20). This effect may be mediated by changes in the expression of axon guidance molecules, which play key roles in directing axons toward their target cells and in the establishment and stability of synapses. Cocaine substantially alters the expression of multiple families of axon guidance molecules, including the Semaphorins, Ephs, Ephrins, and neuropilins, within the mesolimbic dopamine system (09).
Prenatal cocaine decreases the number of neurons by decreasing both neuronal survival and proliferation. Cocaine induces apoptosis in brain regions by altering Bcl-2, Bax, and other apoptotic proteins and subsequently activating the caspase 3, caspase-8, and caspase-9 apoptotic signaling cascades (36; 134). Cocaine inhibits neuronal proliferation by arresting the cell cycle (54) at the G1-to-S transition (67). Reductions in neuronal number, both as a result of neuronal death and decreased proliferation, likely contribute to neurodevelopmental and cognitive deficits. In addition, the decreased neuronal number likely underlies the permanent brain growth deficits observed in volumetric MRI studies of children prenatally exposed to cocaine (103).
Cocaine may also exert some of its neuroteratogenic effects via epigenetic mechanisms. Insulin-like growth factor II (Igf-II) is an imprinted gene that plays an important role in learning and memory. In a mouse model, prenatal cocaine exposure altered the methylation status of Igf-II and decreased expression of the gene in the hippocampus (136). These molecular changes were accompanied by impaired performance on the Morris water maze and open field tasks. Furthermore, the cognitive deficits were reversed through the hippocampal injection of recombinant Igf-II. Thus, epigenetic changes in gene expression may underlie at least some of the neurobehavioral deficits of prenatal cocaine exposure.
Epigenetic changes induced by cocaine can occur not only in the fetus during pregnancy, but also in sperm prior to pregnancy. Mouse models of paternal cocaine abuse have shown that offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity (129). This appears to be due to epigenetic changes in histone proteins regulating NMDA receptors in the hippocampus of progeny mice. If these findings in mice similarly occur in humans, then this has profound implications, as it would demonstrate that the adverse effects of cocaine are due not only to maternal cocaine use during pregnancy, but also to paternal use prior to pregnancy.
Excitotoxicity also contributes to the neuronal injury of fetuses exposed to cocaine. Catecholamines, through their actions as glutamate agonists, can induce neuronal cell death (107). This is especially true in dopaminergic neurons and their projection targets. Further evidence that cocaine interacts with glutamatergic systems to induce excitotoxic effects lies in the observation that glutamate receptor antagonists can substantially reduce cocaine-induced convulsions and death in experimental animals (105).
Evidence suggests that prenatal cocaine induces at least some of its damaging effects on the developing brain by triggering the endoplasmic reticulum stress response (121). The endoplasmic reticulum plays an important role in processing and folding newly synthesized proteins. A variety of chemicals and drugs can disrupt endoplasmic reticulum protein folding, which can lead to an endoplasmic reticulum stress response. The endoplasmic reticulum stress response activates a set of signaling pathways that aim to promote cell survival. However, the endoplasmic reticulum stress response, when prolonged and unresolved, can also promote apoptosis. In addition, when the endoplasmic reticulum stress response in neural tissue is initiated at high intensity or for prolonged periods, it can lead to aberrant neuronal differentiation and impaired dendritic outgrowth. Gene profiling studies in the developing brain have shown that cocaine upregulates endoplasmic reticulum stress genes, which leads to disruption of glutamate and dopamine receptor activation. In addition, cocaine-induced endoplasmic reticulum stress inhibits neural progenitor proliferation, causing premature neuronal differentiation and microglial cell death (68).
In addition to binding catecholamine receptors, cocaine specifically interacts with other cellular proteins to exert its teratogenic effects. In particular, cocaine binds to sigma receptors, which are endoplasmic reticular proteins (120). Via this interaction, cocaine dissociates certain cytoskeletal adaptor proteins that are important for protein trafficking, membrane protein clustering, dendrite growth, and the morphological maintenance of neurons. In this way, cocaine may permanently change neuronal structure and physiology.
Fetal cocaine exposure may induce substantial destructive lesions of the developing brain. These destructive lesions are due to infarction, reflecting cocaine-induced vasospasm. Application of cocaine to pial arteries of neonatal piglets and fetal and neonatal lambs induces a constriction in vessel diameter and a decrease in cerebral blood flow (122).
Prior to the 1970s, cocaine was not a frequently abused drug in the United States. Cocaine use in the United States spiked in the 1970s and 1980s, as it became a vogue component of the disco culture and the drug of choice within many inner cities. Cocaine use remained high through 2006, when it began to decline considerably. The decline in cocaine use in the United States reflected both a waning interest in the drug and effective antidrug strategies in Colombia, its major source. However, since 2012, cocaine use in the United States has been surging again. Both the number of users and the number of deaths from cocaine overdose increased steadily between 2012 and 2015 (55). In 2016, global use of cocaine increased by 7%, reflecting its use by 18.2 million people, or 0.4% of the world population aged 15 to 64. The use of cocaine is highest in North and South America, Western and Central Europe, and Oceania, especially Australia and New Zealand (132).
In the United States, cocaine use underlies many acute medical problems. Forty percent of emergency department visits that are related to substance abuse are associated with cocaine, making cocaine the leading cause of emergency room visits that are due to illicit drug use (113).
Both cocaine and crack are widely used in American society, including by pregnant women. In 2015, cocaine was the second most commonly used illicit substance by pregnant women (behind marijuana). In that year, 3.4% of pregnant women had used cocaine in the past month. Pregnant women who use crack or cocaine tend to be older, African American, and of low socioeconomic status. Among pregnant women, cocaine use is the leading cause of antepartum hospitalizations for substance use (113).
Prevention is contingent on abstinence from drug use. Unfortunately, the highly addicting properties of cocaine render abstinence difficult for many former users. In a series of long-term follow-up studies, patients were enrolled in a comprehensive prenatal drug treatment program in an attempt to abstain from drug use during pregnancy (23; 06). In this program, women were informed that they would be tested for drug use during their pregnancy. Despite the rigor of this program, an abstinence rate of only 40% could be achieved. Thus, even in this highly controlled setting, it was difficult to achieve ongoing abstinence from cocaine.
Prenatal and perinatal cerebral infarctions may be due to (1) coagulation disturbances, such as antithrombin III deficiency or congenital deficiency of protein C or protein S, (2) polycythemia with secondary sludging of blood in cerebral arteries or veins, (3) bacterial meningitis with secondary vasculitis, or (4) emboli, presumably from degenerating placental vessels or the recently activated pulmonary vascular bed.
Microcephaly and intrauterine growth retardation suggest (1) fetal alcohol syndrome, (2) congenital infection with toxoplasmosis, rubella, cytomegalovirus, human immunodeficiency virus, or lymphocytic choriomeningitis virus, or (3) chromosomal abnormalities.
Jitteriness during the neonatal period may be associated with (1) hypoglycemia, (2) withdrawal from alcohol or opiates, (3) hypocalcemia, or (4) hypoxic-ischemic encephalopathy.
The diagnostic evaluation for intrauterine cocaine exposure includes a urine test and a meconium analysis for cocaine and its metabolites. The urine test is sensitive to recent cocaine exposure, but cocaine metabolites may be cleared from the urine within days. In contrast, meconium may remain positive for cocaine following exposure of a fetus weeks or months earlier in gestation. Thus, the use of meconium may capture a broader window of cocaine exposure (18).
Meconium is a viscous, semisolid tar-like substance and is not homogeneous. Thus, although meconium offers the advantage of a broad window of exposure assessment, the testing of meconium samples is often cumbersome and technically challenging. In response to these challenges, a new method for analyzing cocaine metabolites and other drugs of abuse in meconium has been introduced (48). This technique, which utilizes ceramic homogenizers prior to salt-assisted liquid-liquid extraction and liquid chromatography tandem-mass spectrometry, may greatly expedite and improve the methodology of meconium testing.
In addition to infant urine and meconium, several other specimens can potentially identify infants prenatally exposed to cocaine. These include infant hair, maternal hair, amniotic fluid, and umbilical blood. Of course, maternal self-report of cocaine use can also identify prenatally exposed infants. However, the accuracy of self-reporting may be low because users tend to deny use due to guilt or fear of consequences (79).
A study compared the sensitivity of a private, structured, nonthreatening interview regarding maternal drug-use history with laboratory testing of amniotic fluid, cord blood, infant urine, meconium, and maternal hair in identifying cocaine-exposed newborns (41). The study found that no single method could reliably identify all exposed infants. However, the method that maximally identified cocaine exposure was the maternal interview. Thus, maternal drug-use interviews that are thorough and nonthreatening may be the most reliable way of diagnosing prenatal cocaine exposure.
When an infant has a known exposure to cocaine, imaging of the CNS at birth is beneficial to determine if any CNS lesions have occurred. Neuroimaging is particularly indicated if microcephaly is present. Because of the association of cocaine exposure with renal disease, specifically hydronephrosis, an ultrasound of the kidney is recommended. The association with cardiac defects is small. Thus, clinical judgment should determine which children need cardiovascular evaluation.
The management of intrauterine cocaine-exposed infants usually revolves around the associated medical problems, including preterm delivery, respiratory distress, sepsis, and intrauterine growth retardation. For those infants sustaining significant withdrawal symptoms of jitteriness and irritability, the use of sedatives may be indicated. Phenobarbital at 4 mg/kg per day divided into 2 daily doses, or Valium at 0.3 mg/kg per day divided every 8 hours may be considered.
Because congenital cocaine syndrome is due to fetal cocaine exposure, the syndrome is inextricably linked to pregnancy. Many of the effects of cocaine on the fetus, such as later learning disabilities and disorders of language development, are not observed when people are postnatally exposed. Other adverse effects, such as strokes and hypertension, can occur as a result of cocaine at any stage of life – whether pregnant or not.
Complications on the pregnant woman of cocaine use during pregnancy are many and include multiple organ systems. Among the most important are cardiovascular complications, including hypertension and myocardial infarction, hepatic rupture, renal failure, stroke and transient ischemic attack, and maternal death.
Pregnant women who abuse cocaine are at increased risk for multiple adverse perinatal outcomes, including preterm delivery, low birth weight, and small for gestational age infants. Maternal cocaine use also increases the risk of vertical transmission of hepatitis, syphilis, and HIV (113).
Children prenatally exposed to cocaine do not react differently to anesthesia than do other children.
Acute cocaine intake can precipitate several obstetric emergencies, including placental abruption. Delivery of the fetus is usually the treatment of choice for placental abruption. However, acute cocaine intoxication greatly complicates the choice and use of anesthesia in these cases. This is due to the facts that pregnancy enhances the cardiovascular toxicity of cocaine and that cocaine can induce combative behavior, altered pain perception, thrombocytopenia, and hypertension. Both regional and general anesthesia in the cocaine-intoxicated parturient may be associated with serious complications for both the mother and baby (65).
Michael V Johnston MD
Dr. Johnston of Johns Hopkins University School of Medicine has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
General Child Neurology
May. 31, 2021
General Child Neurology
May. 31, 2021
May. 04, 2021
General Child Neurology
Acute cerebellar ataxia is a relatively common disorder among children and is usually observed following an acute viral illness or vaccination. The usual
Apr. 05, 2021
Mar. 29, 2021
The association between obstructive sleep apnea and neuropsychological functioning has been documented in adults, and although studies show a similar
Mar. 28, 2021
General Child Neurology
Toxoplasma gondii is an important cause of congenital infections. When the infection occurs during pregnancy, the parasite can cross the placenta and
Mar. 24, 2021
Mar. 21, 2021