In recent years, an epidemic of cocaine abuse has swept across the United States. An increase in cocaine use by intravenous injection and by inhalation of the free alkaloid base "crack* has given rise to increased crime rates and many serious toxic reactions to both users and their offspring. With the attendant publicity of the plight of coca ine -addicted mothers and their babies, the public, government agencies, and the medical profession have a heightened awareness of the potential dangers of substance abuse during pregnancy.
SUBSTANCES OF ABUSE
The addictive properties of psychoactive drugs lead individuals to increase usage, both frequency and dose, which leads to varying degrees of toxicity to themselves and, if pregnant, their offspring. These psychoactive drugs represent both legal substances, which include caffeine, nicotine, and alcohol, and illegally procured street drugs. The latter substances of abuse include benzodiazepines and barbiturates, which fit into the alcohol category because these agents show cross tolerance to each other and may function at a γ-aminobutyric acid receptor site. Also included are cannabis (marijuana and hashish), hallucinogens (lysergic acid diethylamide [LSD] and phencyclidine hydrochloride [PCP]), opiates, and finally cocaine and similar-acting amphetamines (eg, methamphetamine).
The reproductive toxicity of the class of psychoactive agents runs the gamut from most of these agents, producing various degrees of reproductive toxicity, including intrauterine growth retardation, fetal death and postnatal morbidity, and unproven birth defects (teratogenesis). One striking exception is alcohol, which is responsible for fetal alcohol syndrome (FAS), representing the largest identified cause of teratogenesis by drugs or environmental agents at the present time.1 This article focuses primarily on how cocaine fits into this picture.
It is difficult to assess the effect of street drugs in producing congenital malformations because the drugs vary in potency and purity, the life-styles of abusers are chaotic (leading them to neglect proper nutrition and prenatal medical care), and the incidence of infections such as venereal disease and acquired immunodeficiency syndrome is high. Because drug abusers in the United States number in the millions, isolated case reports of birth defects associated with substance abuse may not be statistically significant to infer cause and effect. Finally, drug abusers usually take more than one drug, which confounds the determination of whether the street drug in question (eg, cocaine) is the teratogen or interacts with other substances (eg, alcohol or opiates).
Therefore, to assess the teratogenic potential of a substance of abuse at least some of the following criteria would have to be met:
* human epidemiological studies indicate an association with a unique group of malformations,
* human epidemiological studies consistently indicate that the exposed population has a higher incidence of malformations than an unexposed control population,
* an animal model has been developed for the malformations observed using exposures in the therapeutic range,
* teratogenic and embryotoxic effects have a doseresponse relationship in the therapeutic range, and
* the mechanism of teratogenesis is understood and the results make biologic sense.2
The general increase in cocaine use in the past decade has produced a dramatic rise in the use of cocaine by pregnant women and women of reproductive age. It has been estimated that 10 million Americans have used cocaine and that 5 million use cocaine regularly.3 A second, smaller survey of more than 50 000 people in 16 states and the District of Columbia indicates that women aged 18 to 34 constitute 15% of all regular users of recreational cocaine.4 Various surveys have documented cocaine use by pregnant women to range between 3.4% and 10%,5'6 which could equate into 126 000 to 370 000 prenatal exposures based on 3.7 million births in 1984.1 However, because many studies are based on hospital-based populations in urban areas with largely poor populations, the studies should produce overestimates. On the other hand, many women may have taken cocaine during their pregnancy but would not test positive for cocaine and its metabolites due to complete excretion at the time of drug assay, thus underestimating prenatal exposure. Finally, recent surveys indicate that casual cocaine use by more affluent suburban populations may be decreasing, while that of hard-core abusers in central cities may not be changing.
Pharmacology of Cocaine
A number of reproductive toxic and teratogenic effects have been reported to be associated with cocaine abuse. To help determine whether these effects are due to cocaine itself or to the chaotic life-style of the abuser, the pharmacology of cocaine was compared with the observed toxic effects on the newborn to infer a causal effect of cocaine. Pharmacologie actions of cocaine include:
* Inhibiting active uptake of catecholamines (norepinepkrine, epinephrine, and dopamine) and serotonin. Cocaine binds to a nonspecific, high-affinity biogenic amine transporter, blocking active uptake and subsequent metabolism of catecholamines and serotonin into nerve endings. Increased levels of norepinephrine and dopamine at nerve endings and circulating plasma lead to a stimulation of the central and peripheral nervous systems. Increased dopamine levels and stimulation by dopamine in specific brain areas have been associated with the reinforcing activity of cocaine, the consequence of which is severe dependence.
* Eliciting cardiovascular responses by blockade of reuptake of neural norepinephrine and release of adrenal epinephrine and norepinephrine causing tachycardia and vasoconstriction. Cocaine can produce severe toxicity by this route including hypertension, cardiac arrhythmias, myocardial ischemia or infarction, congestive heart failure, and cerebrovascular spasm with transient neural ischemia or infarct in the brain. These cardiovascular toxicities, especially heart failure, are probably responsible for cocaine- induced death.
* Blocking nerve conduction by preventing the transient inflow of sodium ions. Cocaine was originally used as a local anesthetic until its addictive properties were recognized and procaine was substituted. The block in nerve conduction in the myocardium may lead to arrhythmia, and in concert with tachycardia, it may lead to heart failure.7
Reproductive Toxicity of Cocaine in Humans
Clinical Studies With Cocaine
Prematurity, spontaneous abortion, stillbirth, and intrauterine growth retardation have been reported in newborn infants of mothers who have taken cocaine during their pregnancy (Table 1). This spectrum of reproductive toxicity is not dissimilar to that of other substances of abuse. TTiat cocaine may be more damaging than other street drugs is its apparent specific effect to induce microcephaly. Because malnutrition produces intrauterine growth retardation in which inhibition of brain growth is relatively spared, the effect of cocaine may be specific. This inhibition of brain growth rivals that of alcohol and may portend subsequent mental retardation and other behavioral sequelae.8
The ability of cocaine to induce spontaneous abortion has led some abusers to attempt termination of their pregnancy with the drug. One of the early striking findings in newborn infants of cocaineabusing mothers was the presence of abruptio placentae contributing to stillbirth in these infants, with the abruption being attributed to the vasoconstrictive actions of cocaine. Cerebral infarctions, which also can be attributed to the vasoactive effects of cocaine, have been reponed in a number of instances. An increase in sudden infant death syndrome has been reported to be associated with prenatal exposure to cocaine. Cocaine may alter the behavior of newborn infants, eliciting increased degrees of irritability and tremors. In addition, startle response that has been ascribed to a direct effect on sensorineural processing is enhanced, which may place these infants at risk for cognitive or neurological sequelae.8 The long-term effects of prenatal cocaine on childhood behavior is of intense interest.
Whether cocaine is teratogenic and produces birth defects in newborn infants of cocaine-abusing mothers is unclear and of considerable controversy. First, although many case reports have indicated that cocaine use is associated with birth defects, others do not show an association even though many of the reproductive toxic effects described above have been observed. These contradictory results may indicate that cocaine is a weak teratogenic agent such that too few cocaine-abusing mothers are present in a particular study to be able to observe any congenital anomalies. The most common morphological defects reported are those of the genitourinary tract, which have been associated with cocaine abuse in the first trimester.9 These studies have been supported by a recent case control study in which a statistically significant association of reported cocaine use was observed with an increased risk for urinary tract defects (odds ratio: 4-39). Genital organ defects were observed with an odds ratio of 2.26, although this increase was not statistically significant, possibly because the sample size was limited.10
Birth Defects Associated With Cocaine Use in Humans
In addition, other defects such as prune belly syndrome, limb and cardiac anomalies, and brain lesions (including cerebral infarcts) have been observed in epidemiologie studies (Table 2). In a recent study of 10 children of cocaine-abusing mothers, nine had congenital limb reduction defects, intestinal atresia, or infarction.1 ' Taken together, these studies suggest that cocaine could produce many types of congenital malformations through a mechanism of fetal vascular disruption, by either vasoconstriction or hemorrhage.9'11
Animal Studies With Cocaine
Support for the notion that a drug is teratogenic comes from experimental animal studies in which a profile of congenital defects is similar to those observed in newborn infants of drug-abusing mothers. The results of such studies on cocaine are mixed. Some of these studies have found low frequencies of congenital malformations when cocaine is administered to pregnant mice and rats throughout the total period of organogénesis, when cocaine is administered over the course of about 3 days, and when cocaine is administered on single days of development. Other studies have elicited reproductive toxicity such as increased resorptions and decreased body weight but no change in malformation rates.
Malformations observed in the positive studies are similar to those associated in human studies, including genitourinary, cardiovascular, and limb reduction defects. However, these are of a general nature and do not quite fit the criteria of a characteristic profile of malformations. Secondly, characteristic doseresponse curves of increasing doses that produce an increase in the frequency of malformations are not uniformly seen. In addition, production of defects appears to occur in a random fashion over development and not at specific times that are characteristic of most teratogens.
Finally, malformations may be produced by cocaine that is at toxic or near toxic doses to the pregnant dams. This latter result usually argues that a drug or environmental toxin is not teratogenic. However, because it is not uncommon that cocaine abusers suffer fatal heart attacks, this relative lack of an effect on the fetus compared to the mother cannot preclude classification as a teratogen. The judgment could be that cocaine is a relatively weak teratogen that produces toxicity to both mother and offspring in a very low frequency to a very large population. If this were the case, it would still constitute a marked public health problem.
Proposed Mechanism of Reproductive Toxicity
It has been shown that if cocaine is administered to the pregnant rat in late development (after the time of limb organogénesis) a high frequency of limb reduction defects are observed. Marked hemorrhages in the limb are seen and apparently are responsible for the defect. This study constitutes strong evidence that cocaine is teratogenic by causing vasoconstriction and local hemorrhage.12
Vasoconstriction usually can produce anoxia, which could be responsible for growth retardation, perturbed development, or an ischemie response leading to hemorrhage. In fact, it has been shown in pregnant sheep in late development that cocaine causes a significant decrease in uterine blood flow, which may in turn cause fetal hypoxia and infarction of developing organs.13 However, fetal hypoxia is extremely short-lived, and the fetus is relatively resistant to hypoxia. In early development, when rat embryos are cultured with cocaine under hypoxic conditions, the hypoxia exacerbates the embryotoxic effect of cocaine. This result and that of cocaine- inhibiting mitochondnal electron transport activity have suggested that decreased energy supplies produced by cocaine form the basis of the developmental toxicity of cocaine.14
Both clinical and animal studies suggest that the effect of cocaine on reproductive toxicity, including possible teratogen icity, is due to a vasoactive mechanism, which mimics its normal pharmacologie activity. However, it is unclear what mechanisms underlie the vasoconstriction that occurs in the uterine and possibly the embryonic/fetal circulation. Local hemorrhages leading to infarcts are frequently observed. Are they directly responsible for embryotoxicity, or are they associative phenomena? Is the subsequent anoxia-producing inhibition of growth and differentiation in the developing embryo a direct result of vasocontriction or due to local hemorrhage?
Anoxia, embryonic hemorrhage, and limb reduction defects can result from maternal uterine clamping in late gestational rats15 that is comparable to the administration of cocaine to late gestational rats.12 These results suggest that anoxia would lead to hemorrhage and subsequent malformation. However, in an interesting study by Millicovsky and DeSesso,16 the hemorrhage observed in rabbit embryos by maternal uterine clamping was prevented by additional clamping of umbilical cords to each embryo. This result indicates that anoxia per se is not the causative effect to embryonic hemorrhage since in the dualclamped procedure uterine and umbilical) adequate oxygenation is further prevented. Release of unknown substances from the uterus could cause the embryonic hemorrhage. With regard to cocaine- induced hemorrhage and embryotoxicity, it is unknown whether cocaine or released catecholamines are the direct causative agent.
This amphetamine has recently undergone a resurgence as a substance of abuse and has been reported to be endemic in Hawaii and Southern California- The compound that is being abused is a pure form of ( + ) methamphetamine hydrochloride, termed "ice." This new form of methamphetamine can be smoked, which allows rapid absorption into the bloodstream from where the drug moves rapidly into the brain. Smoking methamphetamine produces a response similar to that resulting from the intravenous route, without the hazards associated with syringe needles.
The substance produces a stimulation of the central nervous system similar to that of cocaine, but because of its long half-life of 12 hours, its "high" persists for many hours, whereas the high from cocaine lasts only a few minutes. Although methamphetamine shows similar sympathomimetic actions to cocaine, its mechanism differs in that it is a potent indirect dopaminergic agonist that induces release of dopamine, and to a lesser extent, serotonin, from presynaptic terminals in the brain. The drug also inhibits the storage of dopamine by vesicles and its degradation by monoamine oxidase, thereby increasing cytoplasmic levels of neurotransmitter and its subsequent release to synaptic clefts. The circulating dopamine stimulates the central nervous system, which constitutes its major effect. In addition, the release of norepinephrine by a similar mechanism in the periphery causes increased heart rate, cardiac output, and blood pressure.17 As with cocaine, marked vasoconstriction, hypertension, and ischemie infarcts have been observed with methamphetamine use. Repeated administration of methamphetamine is neurotoxic to animals.
The effects of methamphetamine during pregnancy have not been as widely reported as with cocaine. Nevertheless, it has been observed that neonates whose mothers abused methamphetamine during pregnancy were born with significant decreases in body weight, length, and head circumference, similar to that of cocaine. However, Little et al found no significant increase in congenital anomalies in this group.18 In another study, echoencephalography was used to determine central nervous system injury in neonates.19 TTie results indicate that methamphetamine and cocaine were both associated with intraventricular hemorrhage, in ranges similar to infants at risk for hypoxic- ischemie injury, but at significantly greater risk than normal infants. A limited number of teratology studies in pregnant mice, rats, and rabbits indicate that methamphetamine can produce exencephaly, cleft palate, and eye anomalies including anophthalmia, microphthalmia, and cyclops.20,21 Thus, it appears that methamphetamine abuse can lead to reproductive toxicity and possible birth defects.
Substances of abuse include those that are legal (such as alcohol) and those that are illegal (street drugs). Many of these agents produce reproductive toxicity including intrauterine growth retardation. Teratogenesis is unproven with most of these agents. Alcohol is an exception, producing the fetal alcohol syndrome. Cocaine causes marked reproductive toxicity including decreased growth and morbidity. A number of birth defects have been associated with cocaine use including genitourinary, cardiac, and limb anomalies. The reproductive toxic and putative tera' togenic effects of cocaine are probably associated with its well-known pharmacologie action causing vasoconstriction. From preliminary studies, it would appear that methamphetamine also produces reproductive toxic effects similar to those of cocaine.
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Reproductive Toxicity of Cocaine in Humans
Birth Defects Associated With Cocaine Use in Humans