i. Abstract

Cocaine is now regarded as one of the most dangerous illicit drugs available today. A disturbing trend in the pattern of cocaine use is that groups long considered unlikely to be involved in drug use, including women of childbearing age, pregnant women, the pediatric age group, fetuses, and neonates, are showing an alarming increase in cocaine exposure. Substantial data have been derived from clinical observations, clinical studies, and animal studies indicating that prenatal exposure to cocaine may have detrimental short-term and possibly long-term effects on the mother, the developing fetus, and the neonate. The effects attributed to cocaine may, however, be due to other substances (e.g., alcohol) ingested by the drug-using woman, to prematurity, or to the environmental chaos in which the infant must develop. Prospective controlled studies are needed to define further the effects of cocaine as distinct from other negative influences having an impact on the developing fetus, the newborn, or the infant.

Cocaine is considered one of the most dangerous illicit drugs available today. Recent epidemiologic data indicate that cocaine use is widespread in society. The National Institute on Drug Abuse (NIDA) estimated that 5 million Americans are regular users of cocaine, 20 to 30 million other Americans have tried the drug on at least one occasion, and 5,000 additional individuals try cocaine for the first time each day (1). The NIDA reported that for the first time during the 15 years it has been collecting data, cocaine has become the most frequent cause of drug-related emergency room visits, surpassing ethanol and opiate narcotics (2). That report also suggested that cocaine is the third most common agent identified in drug-related deaths.

I. Cocaine Use During Pregnancy

The availability and appeal of cocaine is causing a change in the profile of cocaine users. Groups long considered unlikely to be involved in drug abuse, including women of childbearing age, pregnant women, the pediatric age group, fetuses, and neonates, are showing an alarming increase in cocaine exposure (2-4). A survey of 50,000 individuals in 16 states and the District of Columbia revealed that women of childbearing age, primarily those 18 to 34 years old, constitute 15% of all regular users of cocaine (5). Other studies have substantiated this figure, reporting that 10% to 15% of high-risk pregnant women produced positive test results for cocaine during some stage of their pregnancy (6).

Chasnoff (3) reported that 10% of all newborns at Harlem Hospital in New York City had a positive urine screen for cocaine. In a study of the incidence rates of cocaine use by mothers of infants in the nurseries at Grady Memorial Hospital in Atlanta, Georgia, we examined the incidence of historical evidence of cocaine use or the incidence of a positive maternal urine screen for cocaine metabolites (e.g., benzoylecgonine). The screening test was completed in the clinical laboratory using the enzyme-mediated immunoassay technique (EMIT) (Syva Co., Palo Alto, Calif.). We reviewed the records of 263 infants admitted to the term nurseries during one 2-week period. Of this total, there was a test result (either positive or negative) or a comment about the mother's drug history found in the charts of 215 of the infants. Of these infants, 15 (7%) had either a positive test or a positive history (7). Other studies in the Special Care Nursery at Grady Memorial Hospital examined evidence of cocaine in infants admitted to this area. Urine drug screening on the infants and the mothers and drug histories obtained from the mothers were used to identify infant in utero exposure to cocaine. Twenty-three percent of infants admitted to the Special Care Nursery over the first 9 months of 1990 were found to have been exposed to cocaine in utero.

II. Screening for Cocaine Exposure

The accumulation of clinical data on cocaine use during pregnancy is fraught with problems. Obstetric services involved in research on drug exposure are frequently in hospitals for the indigent. Routine screening of body fluids on pregnant women is generally viewed as an invasion of privacy. If the screening is targeted toward a specific population (e.g., black or indigent), the practice can be viewed as discriminatory. If the women screened are more often indigent, the sample will not be representative of the population as a whole, and broad-based conclusions cannot be made from the data. Similarly, nonvoluntary screening (i.e., obligatory screening) has not been practiced because of ethical implications. Voluntary screening of pregnant women has been done, but it appears to be unreliable. In a study conducted in Detroit, a meconium sample was obtained for cocaine testing on nearly 7,000 newborn infants in 1989 (8). Of the infants tested, 42% had evidence of cocaine exposure in utero. At the same time, the mother's rate of self-reported drug use was 8%. Thus, it appears that these women grossly underreported their cocaine use.

Screening of urine for cocaine metabolites (generally benzoylecgonine) is done in many hospitals. Cocaine metabolites are present in the urine for 3 to 5 days after maternal use (9 11). The neonate, especially if premature, may also have a marked decrease in plasma cholinesterase activity and in renal function. If cocaine is used by the mother shortly before delivery, the decreased metabolism and decreased excretion of the by-products may cause persistence of drug effect for days after delivery (11-13). The amount of time that metabolic by-products are present in the urine of the newborn depends on the amount of time between maternal ingestion of the drug and delivery of the infant. Thus, a woman may have used cocaine extensively during pregnancy and have a negative screening test for cocaine if she had not used the drug within a week before delivery. The infant, while testing negative, would still be at risk for many of the problems of an infant testing positive.

Testing of hair and meconium in the neonate has been proposed as a method for detecting chronic or previous exposure to cocaine (8 10). While these tests are promising, they are expensive and not widely available. More recently, the Centers for Disease Control (CDC) in Atlanta announced the beginning of a year-long surveillance study to be done on all infants delivered in Georgia to evaluate the incidence of cocaine exposure late in pregnancy. The study will be anonymous and will be done on the blood collected routinely as part of the mandatory state screening for inherited metabolic diseases (e.g., the "PKU test"). Because of the short half- life of cocaine and its metabolites in the blood, this study will again be limited to assessing exposure close to the time of delivery.

Whether collected by history, urine screen, blood testing, or some other method, the assessment of cocaine use during pregnancy has inherent difficulties. Incidence figures must, therefore, be viewed cautiously and in light of the population tested and the manner in which the data were obtained. Any incidence figure will probably underestimate the true total population using cocaine.

III. Cocaine's Actions During Pregnancy

Pharmacologically, cocaine acts as a sympathomimetic agent and as a powerful central nervous system stimulant (14). One of the primary effects of the drug is to block the reuptake of sympathetic amines (e.g., norepinephrine, dopamine) at the neural end-plate. Because catecholamine reuptake is the mechanism by which sympathetic neural transmission is terminated, blocking reuptake can cause significant potentiation. Consequently, cocaine causes a dose-dependent inotropic and chronotropic effect on the cardiovascular system (15 16).

Cocaine also blocks fast sodium channels and inhibits neural and cardiac action potential (14). The augmentation of sympathetic activity combined with inhibition of myocardial contraction can facilitate the development of arrhythmias and contribute to the development of ventricular fibrillation (17). This effect may be combined with adrenergic stimulation to cause vasoconstriction, tissue and myocardial ischemia, and reduced oxygen delivery to critical tissues (18).

Additionally, there is evidence that cocaine may indirectly increase tissue metabolism and myocardial oxygen consumption. Stimulation of B-adrenergic receptors activates adenylate cyclase and elevates the level of cyclic AMP at the cellular level (12). The elevated levels of cyclic AMP enhance phosphorylation of a variety of regulatory proteins, including those regulating calcium channels. The result is an increase in calcium influx within the myocardium, with increased inotropism and increased myocardial cellular oxygen demand.

The effects of cocaine that have been noted clinically in pregnant women appear to be related to an increase in sympathetic amines. These effects include decreased uteroplacental blood flow, uteroplacental insufficiency, (19) placental hypoperfusion, vasoconstriction of the uterine vasculature, and substantial increases in arterial blood pressure and heart rate (2O). Cocaine- induced vasoconstriction in pregnant women can result in hypertension, and maternal hypertension due to cocaine use has been associated with an increased incidence of abruptio placentae (21 22).

The fetus may also experience detrimental effects associated with the mother's use of cocaine. The drug crosses the placenta freely and may cause problems related to teratogenicity and fetal growth (23 24). If developmental or biochemical processes are disrupted by hypoxia or drug treatment at a critical time during ontogenesis, defects in the organs developing at that time will occur (25). Mahalik et al (25) proposed that a possible mechanism of cocaine's action leading to the development of fetal abnormalities is increased levels of catecholamines induced by cocaine, which then cause vasoconstriction. The relationship between placental vasoconstriction and fetal anomalies has been demonstrated in studies involving the mechanical clamping of uterine and placental vascular flow to induce fetal malformations through decreased oxygen levels (26 27). Administration of drugs, such as morphine (28) and serotonin, (29) to bring about the same effects pharmacologically can also cause fetal abnormalities. In studies designed to examine the possible mechanisms by which cocaine exerts its effects on a fetus, Woods et al (30) demonstrated a significant, acute, dose-dependent increase in maternal mean arterial pressure and heart rate, with a decrease in uterine blood flow approaching 50% after acute cocaine administration. Fetal effects of this cocaine administration included hypoxemia and hypertension. When cocaine was administered directly to the fetus, there were no significant effects at any time in the maternal animal. Mean arterial blood pressure in the fetus increased rapidly, an effect which is characteristic of cocaine administered IV in monkeys (31) and humans (20).

Shah et al (32) demonstrated that cocaine can cross the placenta, can accumulate in fetal tissues, and can reach a level of concentration in reproductive tissues that is significantly higher than in other organs. Blood flow to reproductive tissue is reduced more noticeably than blood flow to nonreproductive tissue (33); therefore, cocaine received by a maternal animal could affect the fetus in either of two ways (30). It could impair fetal oxygenation through catecholamine- mediated vasoconstriction of uterine arteries, which would result in reduced oxygen delivery to the fetus. Moreover, several studies have shown that fetal hypoxemia stimulates the release of catecholamines (34 35). A second mechanism may be the diffusion of cocaine across the placenta into the fetus, with subsequent direct effects on the developing fetal tissues.

IV. Cocaine Use During Pregnancy - Maternal Effects

Many of the sources of information concerning cocaine's effects on human pregnancy are of the retrospective, clinical report or case study type. Evidence from these sources suggests that a pregnant woman and her developing fetus are at risk, for a host of potential problems when cocaine is present. Among the medical complications attributed to cocaine use in the pregnant woman are cardiovascular effects including acute myocardial infarction, cardiac arrhythmias, rupture of the ascending aorta, (36) central nervous system complications including cerebrovascular accidents related to abrupt increases in blood pressure, (37) and other, less frequently occurring effects such as fungal cerebritis, (29) respiratory arrest, (38) and hyperpyrexia, which may contribute to the development of seizures (39). Medical complications that may result from the life-style associated with drug use include failure to seek proper prenatal care, (40) nutritional deficits, and weight loss (41). In a study of cocaine-exposed infants admitted to the Grady Memorial Hospital Special Care Nursery between January and October 1989, 69% were born to mothers who failed to obtain adequate prenatal care. Moreover, these infants showed a high rate of exposure to sexually transmitted diseases. A greater proportion of cocaine-abusing mothers had HIV infection, syphilis, and hepatitis (42).

Another study at Grady Memorial Hospital focused on characteristics that differentiated pregnant cocaine users from pregnant nonusers, and it was found that cocaine users were older (26.4 years vs. 23.4 years) and had higher gravidity (2.92 vs. 1.89) than nonusers. In addition, opiate use among cocaine users was 7.4%, approximately four times the rate found in nonusers (1.7%), tobacco use was more prevalent among cocaine users than nonusers (47.9% vs. 20.7%), and 50% of women using cocaine also used alcohol. As a group, women who used cocaine had a significantly lower average weight gain during pregnancy than did nonusers (20.9 lb. vs. 30.1 lb.), and a higher percentage of cocaine users failed to seek prenatal care (43.1% of users vs. 24.9% of nonusers) (43). It is apparent that clinical studies, though generally valuable, are limited in that differentiation of the effects of cocaine, other drugs, and life-style issues is difficult.

Chasnoff and colleagues have conducted several clinical studies on the effects of prenatal exposure to cocaine, among them a study comparing outcomes of women enrolled in a perinatal addiction program (3). One group was composed of women who used cocaine only, and a second group consisted of those who used cocaine plus heroin. The perinatal outcomes of the two groups were compared with those of women who were former heroin users receiving methadone maintenance therapy during pregnancy and with those of women with no previous history of drug abuse. All groups were equated on factors such as maternal age, socioeconomic status, number of pregnancies, and use of nicotine, marijuana, and alcohol. The pregnant cocaine-using women had a higher rate of spontaneous abortion than did women in the other groups. Four of the cocaine-using women experienced onset of labor with abruptio placentae after intravenous self-injection of cocaine. Some cocaine-using women also reported feeling contractions and increased fetal activity subsequent to cocaine use. The results of this study suggest that infants exposed to cocaine are at risk for higher rates of congenital malformations and perinatal mortality.

V. Cocaine Use During Pregnancy - Fetal Effects

The increased incidence of abruption and prematurity associated with cocaine use exacerbates problems for a fetus already potentially damaged by in utero exposure to the drug. Clinical data indicate that the neonate exposed in utero to cocaine may have a lower gestational age at delivery, lower birth weight, and decreased body length and head circumference (22 23 44). Studies have also reported associations between cocaine use during pregnancy and the occurrence of fetal anomalies, including an increase in skull malformations such as parietal bone defects, exencephaly and interparietal encephalocele, (45) limb defects, (46) urogenital system anomalies such as "prune belly syndrome" (i.e., urethral obstruction, enlarged bladder, cryptorchidism, hydroureter, hydronephrosis, and lax abdominal muscles), second-degree hypospadias and hydronephrosis, (47-49) and neural tube defects (45). Intrauterine fetal death also occurs more frequently in pregnant cocaine users than in nonusers.

Chasnoff et al (50) examined the effects of cocaine exposure on the developing fetus and neonate as a function of the trimester during which exposure occurred. In this clinical study, the perinatal outcomes were compared for women who used cocaine only during the first trimester of pregnancy (n = 23), those who used cocaine throughout pregnancy (n = 52), and a matched obstetric group with no history or evidence of substance abuse (n = 30). The women who used cocaine throughout pregnancy had the highest rate of preterm delivery and the highest incidence of infants with low birth weight and retarded intrauterine growth. These infants also had reduced body length and smaller head circumference for their gestational age.

Abnormalities of the central nervous system have also been reported. These include bony skull defects, exencephaly, and encephalocele, (23) as well as infarction, atrophy, and cystic areas of the brain (51). Also, neural tube defects (38) and cerebral infarctions (13 52) are reportedly more common in these infants.

Problems of respiratory control are of significant long-term concern in drug-exposed infants. An increased risk of sudden infant death syndrome (SIDS) has been reported in infants of cocaine- using mothers (49 53 54). In a recent prospective study, however, Bauchner et al (55) found that the risk of SIDS in infants exposed to cocaine in utero was less than previously reported and was, in fact, equivalent to the rates found in similar socioeconomic groups. One author suggested that the apparent increase in sudden unexplained death in these infants may be related to passive inhalation of crack smoke rather than preexisting problems of respiratory or cardiac control (51).

To limit and control the confounding variables present in clinical studies, animal studies are essential to evaluate the interplay of drug doses, timing of drug administration during pregnancy, and extent of effect seen in the mother, as these factors relate to the effects seen in the fetus. In a study of cocaine's teratogenic potential at various times during gestation, Mahalik et al (25) administered a single injection of 60 mg/kg cocaine to each of six groups of rats on day 7, 8, 9, 10, 11, or 12 of gestation, respectively. When compared with control animals that received saline injections on gestational days 7 through 12 and with untreated controls, the animals that received cocaine had significantly greater occurrences of soft-tissue abnormalities, skeletal anomalies, cryptorchidism, hydronephrosis, anophthalmia, malformed or missing lenses, delayed ossification of the skull, paws, or centrum, and other skeletal defects. The investigators also studied the relationship between day of drug treatment and occurrence of defect. Findings included the following: (1) soft-tissue abnormalities occurred on each day of cocaine administration and therefore could occur at multiple times during gestation; (2) significant skeletal anomalies occurred most often when cocaine was injected on days 7, 8, and 9 of gestation; (3) significant difference in resorption and an increase in intrauterine fetal death with resorption of the dead fetus occurred when cocaine was administered on day 10; and (4) skeletal abnormalities occurred after cocaine exposure later in gestation. The occurrence of these defects closely paralleled the ontogenetic period for these structures (56). It appears from this study that detrimental effects are not limited to any particular day or period of development.

Fantel and MacPhail (23) administered repeated doses of cocaine intraperitoneally to rats. There were no significant differences in maternal weight gain or fetal condition after administration of 50 mg/kg of cocaine, though there was an increase in resorption rate as compared with that of a control group that received saline. However, a cocaine dose of 60 mg/kg led to significant reductions in maternal and fetal weights. The majority of the fetuses (79 of 94) appeared normal, though 13 had edema, one had a cleft palate, one had a hypertrophic left ventricle, and one had undergone severe autolysis. After receiving 75 mg/kg of cocaine, all maternal animals died on or before day 14 of gestation. The authors suggested that exposure to all but the highest dose of cocaine did not appear to be teratogenic, though it did lead to growth retardation and fetal edema.

In an experimental setting, Church et al (57) documented the occurrence of common defects in rats and the effects of drug dose on the occurrence of such defects. They examined maternal and infant rats given cocaine subcutaneously and found that doses ranging from 40 to 90 mg/kg produced dose-related decreases in maternal food and water consumption and consequently, lower maternal weight gain. Fetal weight was affected only at the 90 mg/kg dose, however. Abruptio placentae, cephalic hemorrhage, and edema were identified in some fetuses.

VI. Cocaine Use and Infant Neurodevelopmental Effects

In addition to effects on physical development, neurologic and behavioral abnormalities observed in cocaine-exposed human infants have included poor performance on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS), (58) tremulousness, and muscle rigidity (4 59). Schneider and Chasnoff (60) reported motor disabilities, such as hypertonicity, tremulousness, and retained primitive reflexes, at 4 months of age in infants exposed to cocaine in utero. Madden et al (4) and LeBlanc et al (24) noted similar neurobehavioral abnormalities in a clinical study of eight infants whose mothers' urine tested positive for cocaine. These infants exhibited no physical symptoms, teratogenicity, or symptoms of neonatal drug withdrawal. Cocaine exposure has also been associated with brain stem auditory defects, (52) perinatal cerebral infarction, (13 61) and transient abnormalities on EEG obtained during the first week of life (62). Because few data are available regarding the persistence of behavioral and developmental effects in infants exposed prenatally to cocaine, little is known of the potential long-term adverse effects. Therefore, long-term assessments of learning and behavior are needed to provide unequivocal evidence of cocaine's effects on the development of central nervous system.

Preliminary clinical observations suggest that in utero exposure to cocaine can lead to significant impairment in neurobehavioral capabilities whether cocaine use was discontinued during the first trimester or continued throughout pregnancy (50). Long-term development may be related to structural abnormalities of the brain induced during the perinatal or neonatal period, but proper development is highly dependent on postnatal environmental influence. The often chaotic environment of the addicted mother combined with a lack of appropriate stimulation and an inappropriate developmental model may cause substantial impairment of intellectual capability as well as social-ethical behavior (63).

Several experimental animal studies have focused on the occurrence of neurobehavioral and developmental abnormalities after exposure to cocaine in utero. Using rodents, Spear et al (64) examined the effects of cocaine exposure in utero and found that fetal rats exposed to repeated subcutaneous injections showed decreased learning and memory performance, decreased wall- climbing, and increased locomotor activity after mild foot-shock.

Dow-Edwards and colleagues (65-67) studied cocaine's effects on the synaptic development of the brain in rats and reported that cocaine had potent and relatively permanent effects on the functioning of the forebrain. They also observed an interesting sex-related difference in metabolic response to cocaine. Sokoloff et al (68) found that cocaine-treated female rats exhibited a pattern of cerebral glucose metabolism significantly different from that of male rats. Their findings suggest that there are sex-related differences in response to cocaine, with female rats showing a greater sensitivity to the drug's effects, and that the resulting behavioral effects may be relatively permanent. Other studies support this phenomenon; Glick and colleagues (69) reported increased prevalence and longer duration of behavioral sensitization to cocaine in female rats.

Although many of cocaine's effects may be transitory, Schneider and Chasnoff (60) suggested that the neurobehavioral effects may be more enduring than previously suspected. If the subtle abnormalities in neurobehavioral functioning are, in fact, more persistent, the true impact of cocaine's effects on a fetus and neonate may well be underestimated. Indeed, Dow-Edwards (65) suggested that prenatal exposure to cocaine may place an infant at risk for the development of minimal brain dysfunction and learning disabilities.

Many cocaine-exposed human neonates show evidence of physical and/or behavioral abnormalities that may be due, at least in part, to cocaine exposure. However, other factors that affect physical and behavioral development are seen frequently in cocaine-abusing mothers, and the potentially confounding effects of these variables cannot be ignored. For example, in a study of patients at Grady Memorial Hospital in Atlanta, 50% of cocaine-abusing mothers also abused alcohol (43). Fetal alcohol syndrome (FAS) is a known cause of morphologic as well as central nervous system abnormalities in human and nonhuman infants. Similarly, there is an increased incidence of low birth weight and prematurity among babies of mothers who use cocaine. These factors have been shown to be associated with an increased incidence of developmental delay in the infant. Any discussion of the clinical effects of cocaine must therefore recognize the influence of other confounding variables.

Of course, many of the abnormalities attributed to cocaine occasionally are observed in premature infants independently of any drug involvement (70). Therefore, when infants are born preterm, the appropriateness of attributing abnormalities in the infants to maternal cocaine use can be questioned. An unequivocal relationship between maternal cocaine use and the occurrence of physical and/or behavioral abnormalities in neonates can be revealed only through well-controlled experiments. Only through studies that allow control of additional extraneous factors contributing to prematurity (e.g., inadequate maternal weight gain due to poor nutrition, tobacco use, failure to seek proper prenatal care, etc.) can cocaine's antecedent role in the occurrence of such abnormalities be documented and established.

VII. Conclusions

This review describes the progress that has been made toward understanding the effects of prenatal exposure to cocaine, and it identifies the need for more controlled, prospective studies to investigate and characterize systematically those variables that might influence prenatal effects. There is a pressing need to test and to substantiate the findings from human clinical studies in an appropriate, well-controlled animal model.

Most of the studies conducted with humans have been clinical or retrospective case studies in which the experimental control needed to disentangle the effects of complex interactions of drug use (e.g., drug dosage, frequency and pattern of use, polydrug use), life-style, and subject histories is difficult to achieve. Moreover, clinical investigations typically have not included long-term follow-up studies of cocaine-exposed infants, particularly with respect to neurobehavioral assessments, an important consideration for achieving a thorough understanding of cocaine's effects.

Since the number of infants born to cocaine-using mothers is increasing at an alarming rate, and the effects of prenatal exposure to cocaine are still largely unknown, studies based on an appropriate animal model using rigorous experimental control are timely. A more adequate understanding of cocaine's effects on the developing fetus and neonate can be provided only by prospective controlled studies of in utero cocaine exposure and the careful evaluation of potentially confounding influences.

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