Cocaine

 Risk Factor: CM*
 Class: AUTONOMICS / Sympathomimetics (Adrenergics)

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Cocaine, a naturally occurring alkaloid, is legally available in the United States as a topical anesthetic, but its illegal use as a central nervous system stimulant far exceeds any medicinal market for the drug. Cocaine is a sympathomimetic, producing hypertension and vasoconstriction as a result of its direct cardiovascular activity. The increasing popularity of cocaine is due to its potent ability to produce euphoria, an effect that is counterbalanced by the strong addictive properties of the drug (1). As of 1985, an estimated 30 million Americans had used cocaine and 5 million were believed to be using it regularly (1). Although the exact figures are unknown, current usage probably exceeds these estimates. Preliminary results of a study conducted between July 1984 and June 1987 in the Boston area indicated that 117 (17%) of 679 urban women used cocaine at least once during pregnancy as determined by prenatal and postpartum interviews and urine assays for cocaine metabolites (2). Final results from this study, now involving a total of 1,226 mothers, found that 216 (18%) used cocaine during pregnancy, but that only 165 (76%) of these women would have been detected by history alone (3). Fifty-one women who had denied use of cocaine had positive urine assays for cocaine metabolites. Other investigators have reported similar findings (4). Of 138 women who had positive urine screens for cocaine at delivery, only 59 (43%) would have been identified by drug history alone. In this same study, the increasing prevalence of maternal cocaine abuse was demonstrated (4). Over a 24-month period (September 1986August 1988), the incidence of positive urine screens for cocaine in women at delivery rose steadily, starting at 4% in the first 6-month quarter and increasing to 12% in the final quarter. The total number of women (1,776) was approximately equally divided among the four quarters.

Illicitly obtained cocaine varies greatly in purity, and it is commonly adulterated with such substances as lactose, mannitol, lidocaine, and procaine (5). Cocaine is detoxified by liver and plasma cholinesterases (1,5). Activity of the latter enzyme system is much lower in the fetus and in infants and is decreased in pregnant women, resulting in slower metabolism and elimination of the drug (1,5). Moreover, most studies have found a correlation between cocaine use and the use of other abuse drugs such as heroin, methadone, methamphetamine, marijuana, tobacco, and alcohol. Compared to drug-free women, this correlation was highly significant (p<0.0001) and, further, users were significantly more likely to be heavy abusers of these substances (p<0.0001) (2).

Research on the effects of maternal and fetal cocaine exposure has focused on several different areas and reflects the wide-ranging concerns for fetal safety this drug has produced: Placental transfer of cocaine Pregnancy complications Placental receptor function Duration of gestation Premature labor and delivery Spontaneous abortions Premature rupture of membranes Placenta previa Pregnancy-induced hypertension Abruptio placentae Rupture of ectopic pregnancy Maternal mortality Fetal complications Growth retardation Fetal distress Meconium staining Bradycardia/tachycardia Apgar scores Cerebrovascular accidents Congenital anomalies Neonatal neurobehavior Although the placental transfer of cocaine has not been quantified in humans, cocaine metabolites are frequently found in the urine of in utero-exposed newborns. Because cocaine has high water and lipid solubility, low molecular weight (approximately 340), and low ionization at physiologic pH, it should freely cross to the fetus (5). In pregnant sheep given intravenous cocaine, 0.5 mg/kg, to produce plasma levels similar to those observed in humans, fetal plasma levels at 5 minutes were 46.8 ng/mL compared to simultaneous maternal levels of 405 ng/ml (fetus 12% of mother) (6). At 30 minutes, the levels for fetal and maternal plasma had decreased to 11.8 and 83 ng/ml, respectively (fetus 14% of mother). Uterine blood flow was decreased in a dose-dependent manner by 36% after the above dose (6). Decreases in uterine blood flow of similar magnitude have also been observed in other studies with pregnant sheep (7,8). In one report, the reduction was accompanied by fetal hypoxemia, hypertension, and tachycardia, which were more severe than when cocaine was administered directly to the fetus (8).

In a study examining the effects of prenatal cocaine exposure on human placental tissue, significant decreases, as compared to nonexposed controls, were found for the total number of b-adrenergic receptor-binding sites (202 vs. 313 fmol/mg,p<0.01), -opiate receptor-binding sites (77 vs. 105 fmol/mg,p<0.05), and g-opiate receptor-binding sites (77 vs. 119 fmol/mg,p<0.01) (9). These effects were interpreted as a true down-regulation of the receptor population and may be associated with increased levels of adrenergic compounds (9,10). The authors speculated that if a similar down-regulation of the fetal adrenergic receptor-binding sites also occurred, it could result in disruption of synaptic development of the fetal nervous system. However, the clinical significance of these findings has not yet been determined (9).

The effect of maternal cocaine use on the duration of gestation has been included in several research papers (3,4,11,12,13,14,15,16,17,18,19,20,21,22,23,24 and 25). When compared with non-drug-using controls, in utero cocaine exposure invariably resulted in significantly shortened mean gestational periods ranging up to 2 weeks. A statistically significant mean shorter (1.9 weeks) gestational period was also observed when cocaine-polydrug users (20% used heroin) were compared with noncocaine-polydrug users (26% used heroin) (13). Two other studies, comparing cocaine/amphetamine (18) or cocaine/methadone (17) consumption with noncocaine heroin/methadone-abusing women, found nonsignificantly shorter gestational lengths, 37.9 vs. 38.3 weeks and 37.2 vs. 38.1 weeks, respectively. A third study classified some of their subjects into two subgroups: cocaine only (N=24) and cocaine plus polyabuse drugs (N=46) (20). No statistical differences were measured for gestational age at delivery (36.6 vs. 37.4 weeks) or for the incidence of preterm (<37 weeks) delivery (25.0% vs. 23.9%). When included as part of the research format, the incidence of premature labor and delivery was significantly increased in comparison to that in drug-free women (4,11,18,19,20,21,22,23,24 and 25,). When comparisons were made with noncocaine opiate abusers, the incidences were higher but not significant. One investigation also found that cocaine use significantly increased the incidence of precipitous labor (11). Although objective data were not provided, a 1985 report mentioned that several cocaine-exposed women had noted uterine contractions and increased fetal activity within minutes of using cocaine (26). This same group reported in 1989 that infants who had been exposed to cocaine throughout pregnancy (N=52) (average maternal dose/use = 0.5 g) had a significantly shorter mean gestational age than infants of drug-free women (N=40), 38.0 weeks vs. 39.8 weeks (p<0.001), respectively (24). The gestational period of those who used cocaine only during the 1st trimester was a mean 38.9 weeks, which was not significantly different from that of either of the other two groups. The incidence of preterm delivery (defined as <38 weeks) in the three groups was 17% (4 of 23; 1st trimester use only), 31% (16 of 52; cocaine use throughout pregnancy), and 3% (1 of 40; drug-free controls) (24). Only the difference between the latter two groups was statistically significant (p<0.003). In another 1989 study, bivariate comparisons of 114 cocaine users (as determined by positive urine assays) with 1,010 nonusers (as determined by interview and negative urine assays) indicated the difference in gestational length to be statistically significant (38.8 weeks vs. 39.3 weeks, p<0.05) (3). However, multivariate analyses to control the effect of other substances and maternal characteristics known to affect pregnancy outcome adversely resulted in a loss of significance, thus demonstrating that, in this population, cocaine exposure alone did not affect the duration of gestation (3).

A 1985 report found an increased rate of spontaneous abortions in previous pregnancies of women using cocaine either alone or with narcotics compared to women using only narcotics and women not abusing drugs (26). These data were based on patient recall, so the authors were unable to determine whether a causal relationship existed. In a subsequent report on this patient population, the incidence of previous abortions (not differentiated between elective and spontaneous) was significantly greater in women who predominantly used cocaine either alone or with opiates when compared to those who used only opiates or to non-drug-using controls (25). A statistically significant (p<0.05) higher incidence of one or more spontaneous abortions was found in 117 users (30%) compared to 562 nonusers (21%) (2). Other studies, examining cocaine consumption in current pregnancies, found no correlation between the drug and spontaneous abortions (5,15,16 and 17,22).

Premature rupture of the membranes (PROM) was observed in 2% of 46 women using cocaine and/or methamphetamine vs. 10% of 49 women using narcotics vs. 4.4% of 45 drug-free controls (differences not significant) (18). Similarly, no difference in PROM rates were noted between two groups of women admitted in labor without previous prenatal care (cocaine group N=124, noncocaine group N=218) (23). However, a 1989 report found a statistically significant increase in the incidence of PROM in women with a positive urine screen for cocaine (29 of 138, 21%) in comparison to non-cocaine-using controls (3 of 88, 3%) (p<0.0005) (4). Although not statistically significant, the risk of PROM was higher in women who predominantly used cocaine either alone (10%, 6 of 63) or with opiates (14%, 4 of 28) than in drug-free controls (2%, 3 of 123) (26). The incidence of placenta previa was also not increased by cocaine use in this study (22). In contrast, 33% of 50 crack (alkaloidal cocaine that is smoked) users had PROM compared to 18% of non-drug-using controls (p=0.05) (21). Drug abuse patterns in both groups were determined by interview, which may have introduced classification error into the results, but the authors reasoned that any error would have underestimated the actual effect of the cocaine exposure (21).

Two studies have measured the incidence of pregnancy-induced hypertension in their patients (22,23). In one, the rate of this complication in cocaine-exposed and nonexposed women was too low to report (22). In the second, 25% (13 of 53) of cocaine-exposed women vs. 4% (4 of 100) of nonexposed controls had the disorder (p<0.05) (23). Such other factors as maternal age, race, use of multiple abuse drugs, small numbers, and self-reported cocaine exposure may have accounted for this difference.

Two cases of abruptio placentae after IV and intranasal cocaine use were reported in 1983 (27). Since this initial observation, a number of similar cases of this complication have been described (1,4,5,11,14,18,19,21,24,25 and 26,28,29 and 30), although some investigators either did not observe any cases (31) or the number of cases in the studied patients was too low to report (22). The findings of one study indicated that abruptio placentae-induced stillbirths in cocaine users (N=50), multiple drug users (some of whom used cocaine) (N=110), and drug-free controls (N=340) were 8%, 4.5%, and 0.8%, respectively (5). The difference between the cocaine-only group and the controls was significant (p<0.001). The four mothers in the cocaine group suffered placental abruption after IV and intranasal administration (one each) and smoking (two cases). Two of the five mothers in the multiple drug use group suffered the complication after injection of a speed ball (heroin plus cocaine) (5). Thus, 6 of the 12 cases were associated with cocaine use. Onset of labor with abruptio placentae was observed in 4 of 23 women after the use of IV cocaine (25). Additional information was provided by these investigators in a series of papers extending into 1989 (11,14,20,24,25). The latest data indicated that in women who had used cocaine during pregnancy (N=75, 23 of whom used cocaine only during the 1st trimester), 10 (13.3%) had suffered abruptio placentae compared to none of the 40 drug-free controls (p<0.05) (24). Retroplacental hemorrhages, including placental abruption, were significantly increased in a cocaine and/or methamphetamine group (13% of 46) in comparison to either opiate users (2% of 49) or drug-free controls (2.2% of 45) (p<0.05) (18). Two cases of abruptio placentae were observed in 55 women using crack (none in 55 drug-free controls) (21) and one case in a woman using cocaine in 102 consecutive deliveries at a Texas hospital (28). Three additional cases of sonographically diagnosed abruption probably related to cocaine use were described in a 1988 report (29). While the exact mechanism of cocaine-induced abruptio placentae is still unknown, the pharmacologic effects of the drug offer a reasonable explanation. Cocaine prevents norepinephrine reuptake at nerve terminals, producing peripheral and placental vasoconstriction, reflex tachycardia with acute hypertension, and uterine contractions. The net effect of these actions in some cases may be abruptio placentae (1,5,11,18,24,26,27,32).

Two cases of rupture of ectopic pregnancies were reported in 1989 (33). In both incidences, the women described severe abdominal pain immediately after consuming cocaine (smoking in one, nasally in the other). While the authors of this report could not totally exclude spontaneous rupture of the tubal pregnancies, they concluded that the short time interval between cocaine ingestion and the onset of symptoms made the association appear likely (33).

Fatalities following adult cocaine use have been reported frequently, but only two cases have been located that involve pregnant women (34,35). A 24-year-old woman, who smoked crack daily, presented at 34 weeks' gestation with acute onset of severe headache and photophobia (34). Her symptoms were determined to be due to subarachnoid hemorrhage resulting from a ruptured aneurysm. Following surgery to relieve intracranial pressure and an unsuccessful attempt to isolate the aneurysm, the patient gave birth to a normal 2400-g male infant. Her condition subsequently worsened on postpartum day 21 and she expired 4 days later from recurrent intracranial hemorrhage. The second case involved a 21-year-old in approximately her 16th week of pregnancy (35). She was admitted to the hospital in a comatose condition after about 1.5 g of cocaine had been placed in her vagina. She was maintained on life support systems and eventually delivered, by cesarean section, a female infant at 33 weeks' gestation with severe brain abnormalities. The infant died at 10 days of age, and the mother expired approximately 4 months later.

Fetal complications reported after exposure to cocaine include growth retardation, fetal distress, cerebrovascular accidents, and congenital anomalies. A large number of studies have examined the effect of in utero cocaine exposure on fetal growth parameters (birth weight, length, and head circumference) (2,3,4 and 5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25 and 26,36,37,38 and 39). The majority of these studies found, after correcting for confounding variables, that cocaine exposure, when compared to non-drug-abuse populations, was associated with reduced fetal growth. This reduction was comparable, in most cases, to that observed in fetuses exposed to opiates, such as heroin or methadone. A survey of 117 users compared to 562 nonusers discovered that 14% of the former had given birth to a low-birth-weight infant vs. 8% of the nonexposed women (p<0.05) (2). In one investigation, when maternal drug use included both cocaine (or amphetamines) and narcotics, the infants (N=9) had a significant reduction in birth weight, length, and head circumference compared to either stimulant or narcotic use alone (18). In an earlier report, no significant differences were observed in fetal growth parameters between groups of women consuming cocaine (N=12), cocaine plus methadone (N=11), methadone (N=15), and noncocaine/nonmethadone controls (N=15) (26). However, in a subsequent publication from these researchers, women who used cocaine throughout gestation (as opposed to those who only used it during the 1st trimester) were significantly more likely than drug-free controls to deliver low-birth-weight infants; 25% (13 of 52) vs. 5% (2 of 40) (p<0.003), respectively (24). Fetal growth parameters (birth weight, length, and head circumference) were also significantly (p<0.001) depressed compared to those of controls if the woman used cocaine throughout pregnancy (24). Exposure during the 1st trimester only resulted in reduced growth but the difference was not significant. Some investigators have suggested that the decrease in fetal growth in two studies may have been due to poor nutrition or to alcohol intake (40, 41). In both instances, however, women abusing alcohol either had been excluded or their exclusion would not have changed the findings (42,43). In one study that found no statistical difference in birth weights between infants of cocaine users and noncocaine users, only 10 cocaine-exposed newborns were involved (28) . The cocaine group had been identified from obstetric records of 102 consecutively delivered women. However, the sample size is very small and the character of cocaine use (e.g., dose, frequency, etc.) could not always be determined. In addition, recent research has shown that self-reporting of cocaine use probably underestimates actual usage (3,4).

A single case of oligohydramnios at 17 weeks' gestation with two increased seruma-fetoprotein levels (125 g/L and 168 g/L) has been described, but any relationship between these events and the mother's history of cocaine abuse is unknown (44). Intrauterine growth retardation was diagnosed at 26 weeks' gestation followed shortly thereafter by fetal death in utero. Analysis of fetal whole blood showed a cocaine level of 1 g/mL, within the range associated with fatalities in adults (44).

In a prospective 1989 study involving 1,226 mothers, 18% used cocaine as determined by interview or urine assay (3). After controlling for potentially confounding variables and other substance abuse, infants of women with positive urine assay for cocaine, compared to infants of nonusers, had lower birth weights (93 g less, p=0.07), lengths (0.7 cm less, p=0.01), and head circumferences (0.43 cm less, p=0.01). The effect of cocaine on birth weight was even greater if prepregnancy weight and pregnancy weight gain were not considered. The mean reduction in infant birth weight was now 137 g vs. 93 g when these factors were considered (p<0.01). In those cases where the history of cocaine use was positive but the urine assay was negative, no significant differences were found by multivariate analyses. The authors concluded that cocaine impaired fetal growth but also that urine assays (or another biologic marker) were important to show the association (3).

Multiple ultrasound examinations (two to four) were used to evaluate fetal growth in a series of 43 women with primary addiction to cocaine (45). An additional 24 women were studied, but their ultrasound examinations were incomplete in one aspect or another and they were not included in the analysis. Careful attention was given to establishing gestational age. Complete ultrasonic parameters included biparietal diameter, femur length, and head and abdominal circumferences. The number of addicted infants with birth weight, head circumference, and femur length at the equal to or <50th, equal to or <25th, and equal to or <10th percentile ranks did not differ significantly from expected standard growth charts. However, the number of examinations yielding values for biparietal diameter and abdominal circumference at the equal to or <50th and equal to or <25th percentile ranks was significantly more than expected (p=0.001). Since biparietal diameter and head circumference are not independent parameters, each being an indicator of fetal head size, the authors speculated that the most logical explanation for their findings was late-onset dolichocephalia (45). Based on these findings, the study concluded that maternal cocaine use had adversely affected fetal growth. If only birth weight had been used as a criterion, this effect may have been missed (45).

Several studies have included measurements of fetal distress in their research findings (11,15,16,17,18,19,20 and 21,23,26,31,37,39). In some reports, perinatal distress was significantly (p<0.05) increased in cocaine abusers over women using heroin/methadone (11,12) and drug-free controls (19). Perinatal distress was also noted more frequently in other studies comparing cocaine users to drug-free controls (10% vs. 5.7% and 11.1% vs. 3.7%, respectively), but the differences were not significant (20,21). Compared to nondrug users, higher rates of fetal tachycardia (2% vs. 0%) and bradycardia (17% vs. 6%) have been observed but, again, the differences were not significant (18). One-minute Apgar scores were lower after in utero cocaine exposure in several studies (4,15,16 and 17,20,23,37) but only statistically significant in some (15,16 and 17,23) and no different in another (25). In contrast, only two studies, one a series of three reports on the same group of patients, found a significant lowering of the 5-minute Apgar score (15,16 and 17,25). Other studies observed no difference in this value (4,20,23,26,31,37,39). Significantly more (p <0.05) meconium-stained infants were observed in studies comparing cocaine users to methadone-maintained women (25% vs. 8.2%) (10) and to noncocaine/other drug-exposed subjects (25% vs. 4%) (23). Three other studies observed nonsignificant increased rates of meconium staining or passage (22% vs. 17%, 29% vs. 23%, and 73% vs. 58%) (18,20,25), and a fourth reported a lower incidence (22% vs. 27%), compared to non-drug-using controls (21).

Eight reports have described perinatal or newborn cerebrovascular accidents and resulting brain damage in infants exposed in utero to cocaine (11,14,18,46,47,48,49 and 50). The first report of this condition was published in 1986 (46). A mother who had used an unknown amount of cocaine intranasally during the first 5 weeks of pregnancy and approximately 5 g during the 3 days before delivery, gave birth to a full-term, 3660-g male infant. The last dose of approximately 1 g had been consumed 15 hours before delivery. Fetal monitoring during the 12 hours before delivery showed tachycardia (180200 beats/minute) and multiple variable decelerations. At birth, the infant was limp, he had a heart rate of 80 beats/minute, and thick meconium staining (without aspiration) was noted. Apnea, cyanosis, multiple focal seizures, intermittent tachycardia (up to 180 beats/minute), hypertension (up to 140 mm Hg by palpation), abnormalities in tone (both increased and decreased depending on the body part), and miotic pupils were noted beginning at 16 hours of age. Noncontrast computed tomographic scan at 24 hours of age showed an acute infarction in the distribution of the left middle cerebral artery. Repeat scans showed a persistent left-sided infarct with increased gyral density (age 7 days) and a persistent area of focal encephalomalacia at the site of the infarction (age 2.5 months). One other infant with perinatal cerebral infarction associated with maternal cocaine use in the 4872 hours prior to delivery has been mentioned by these investigators (11,14,24). A separate report described a mother who had used cocaine and multiple other abuse drugs during gestation who delivered a female infant (gestational age not specified) with bilateral cerebrovascular accident and resulting porencephaly (47). The infant expired at 2.5 months of age. In another study of 55 infants exposed to cocaine (with or without opiates), one infant with perinatal asphyxia had a cerebral infarction (18). A severely depressed male infant delivered at 38 weeks' gestation had an electroencephalogram and cranial ultrasound suggestive of hemorrhagic infarction (48). Follow-up during the neonatal period indicated mild to moderate neurodevelopmental abnormalities. Brain lesions were described in 39% (11 of 28) of infants with a positive urine assay for cocaine and in 33% (5 of 15) of newborns with a positive assay for methamphetamine (49). The brain injuries, which were not differentiated by drug type, were hemorrhagic infarction in the deep brain (six cases; three around the internal capsule/basal ganglion), cystic lesions in the deep brain (four cases), large posterior fossa hemorrhage (three cases), absent septum pellucidum with atrophy (one case), diffuse atrophy (one case), and brain edema (one case) (49). In a control group of 20 term infants with severe asphyxia, only one had a similar brain lesion. A second report also described brain lesions in infants exposed in utero to cocaine (50). The 11 infants all had major central nervous system (CNS) anomalies, and 10 of the infants also had craniofacial defects (described later). The CNS defects were hydranencephaly (one case), porencephaly (two cases), hypoplastic corpus callosum with unilateral parietal lobe cleft and heterotopias (one case), intraparenchymal hemorrhage (five cases), unilateral three-vessel hemispheric infarction (one case), and encephalomalacia (one case). In addition, three infants had arthrogryposis multiplex congenita of central origin (50). Four of the infants died, and the other seven had serious neurodevelopmental disabilities (50).

Echoencephalography (ECHO) was performed within 3 days of birth on 74 term (>37 weeks) infants who had tested positive for cocaine or methamphetamine, but who otherwise had uncomplicated perinatal courses (51). The infants had no other known risk factors for cerebral injury. The 74 newborns were classified into three groups: 32 (43%) cocaine exposed, 24 (32%) methamphetamine exposed, and 18 (24%) exposed to cocaine plus heroin or methadone, or both. Two comparison groups were formed: a group of 87 term, drug-free infants studied by ECHO because of clinical concerns for hypoxic-ischemic encephalopathy and a normal group of 19 drug-free term newborns. Both groups of comparison infants were also studied by ECHO within 3 days of birth. Only one structural anomaly, consisting of an absent septum pellucidum, was observed in the infants examined. The affected newborn, exposed to methamphetamine, was also found to have bilateral optic nerve atrophy and diffuse attenuation of the white matter. Twenty-six (35.1%) of the drug-exposed infants had cranial abnormalities detected by ultrasonography, which was similar to the 27.6% (24 of 87) incidence in the comparison group with possible hypoxic-ischemic encephalopathy (p=0.7). The normal controls had an incidence of 5.3% (1 of 19) (p<0.01 in comparison to both of the other groups). The lesions observed in the drug-exposed infants were intraventricular hemorrhage, echodensities known to be associated with necrosis, and cavitary lesions. Lesions were concentrated in the basal ganglion, frontal lobes, and posterior fossa (51). Cerebral infarction was found in two cocaine-exposed infants. The ECHO abnormalities were not predicted by standard neonatal clinical assessment and were believed to be consistent with those observed in adult abusers of cocaine and amphetamines (51).

Maternal cocaine abuse has been associated with numerous other congenital malformations. In a series of publications extending from 19851989, a group of investigators described the onset of ileal atresia (with bowel infarction in one) within the first 24 hours after birth in two infants and genitourinary tract malformations in nine infants (11,13,20,24,26). The abnormalities in the nine infants were prune belly syndrome with urethral obstruction, bilateral cryptorchidism (one also had absence of third and fourth digits on the left hand and a second-degree hypospadias) (two males), female pseudohermaphroditism (one case) (defects included hydronephrosis, ambiguous genitalia with absent uterus and ovaries, anal atresia, absence of third and fourth on the left hand, and clubfoot), secondary hypospadias (two cases), hydronephrosis (three cases), and unilateral hydronephrosis with renal infarction of the opposite kidney (one case). Data from the metropolitan Atlanta Birth Defects Case-Control study, involving 4,929 liveborn and stillborn infants with major defects compared to 3,029 randomly selected controls, showed a statistically significant association between cocaine use and urinary tract malformations (adjusted odds ratio 4.81, 95% CI 1.1520.14) (52,53). The adjusted risk for anomalies of the genitalia was 2.27 (not statistically significant). Cocaine exposure for this analysis was based on self-reported use any time from 1 month before conception through the first 3 months of pregnancy (52,53).

The rates of major congenital malformations in a study involving 50 cocaine-only users, 110 cocaine plus polydrug users, and 340 drug-free controls were 10% (five cases), 4.5% (five cases), and 2% (seven cases), respectively (4). The groups were classified by history and infant urine assays, and chronic alcohol abusers were excluded. The difference between the first and last groups was significant (p<0.01). The incidence of minor abnormalities (e.g., hypertelorism, epicanthal folds, and micrognathia) was similar among the groups (5). Congenital heart defects were observed in all three groups as follows: cocaine-only, transposition of the great arteries (one case) and hypoplastic right heart syndrome (one case); cocaine plus polydrug, ventricular septal defects (three cases); controls, ventricular septal defect (one case), patent ductus arteriosus (one case), and pulmonary stenosis (one case). Skull defects were observed in three infants in the cocaine-only group: exencephaly (stillborn), interparietal encephalocele, and parietal bone defects without herniation of meninges or cerebral tissue. One infant in the cocaine plus polydrug group had microcephalia. Significantly more major and minor malformations were seen in a group of cocaine-exposed infants (N=53) (five major/four minor) than in a matched nonexposed sample (N=100) (two major/four minor) (p<0.05) (23). Congenital heart defects occurred in four of the cocaine-exposed infants: atrial septal defect (one case), ventricular septal defects (two cases), and cardiomegaly (one case). None of the infants born from controls had heart defects (p<0.01). The authors noted, however, that their findings were weakened by the self-reported nature of the drug histories (23).

A 1989 report of 138 women at delivery with positive urine cocaine tests found 10 (7%) infants with congenital anomalies: ventricular septal defect (two), atrial septal defect (one), complete heart block (one), inguinal hernia (two), esophageal atresia (one), hypospadias (one), cleft lip and palate with trisomy 13 (one), and polydactyly (one) (4). Only two (2%) of 88 non-cocaine-using controls had congenital defects, but the difference between the two groups was not significant. When the cocaine group was divided into cocaine only (114 women) and cocaine plus other abuse drugs (24 women), five infants in each group were found to have a malformation. The difference between these subgroups was highly significant (p<0.005).

Necrotizing enterocolitis has been described in two infants after in utero cocaine exposure (48). One of the infants was also exposed to heroin and methamphetamine. The proposed mechanism for the injuries was cocaine-induced ischemia of the fetal bowel followed by invasion of anaerobic bacteria (48). In another report, three newborns (two may have been described immediately above) presented with intestinal defects: one each with midcolonic atresia, ileal atresia, and widespread infarction of the bowel distal to the duodenum (54). Five other infants plus one of those with intestinal disruption had congenital limb reduction defects: unilateral terminal transverse defect (three), Poland sequence (one) (i.e., unilateral defect of pectoralis muscle and syndactyly of hand [55]), bilateral upper limb anomalies including ulnar ray deficiencies (one), and bilateral radial ray defects (two) (54). The defects were thought to be caused by cocaine-induced vascular disruption or hypoperfusion (54).

Facial defects seen in 10 of 11 infants exposed either to cocaine alone (6 of 11) or to cocaine plus other abuse drugs (5 of 11) included blepharophimosis (two), ptosis and facial diplegia (one), unilateral oro-orbital cleft (one), Pierre Robin anomaly (one), cleft palate (one), cleft lip and palate (one), skin tags (two), and cutis aplasia (one) (50). All of the infants had major brain abnormalities, which have been described above.

Ocular defects consisting of persistent hyperplastic primary vitreous in one eye and changes similar to those observed in retinopathy of prematurity in the other eye were described in a case report of an infant exposed throughout gestation to cocaine and multiple other abuse drugs (56). The association of the two defects was thought to be coincidental and not likely due to cocaine (56). Thirteen newborns with cocaine toxicity (each infant with multiple symptoms and positive urine assay) had a complete ophthalmic examination; six were discovered to have marked dilation and tortuosity of the iris vasculature (57). The five infants who were most severely affected were followed for at least 3 months, and all showed a gradual resolution of the defects without apparent visual impairment. The transient iris vasculature defects have also been found in infants of diabetic mothers (both gestational and insulin-dependent) (58) and in non-cocaine-exposed controls (57,59). However, the vascular changes have not yet been observed in infants of mothers abusing methadone, heroin, amphetamines, marijuana, or a combination of these drugs (specific data on the number of infants examined in these categories were not given) (58).

Two mothers who had used cocaine during the 1st trimester produced infants with unusual abnormalities (60,61). Both mothers used other abuse drugs, heroin in one case and marijuana and methaqualone in the other. The anomalies observed were chromosomal aneuploidy 45,X, bilaterally absent fifth toes, and features consistent with Turner's syndrome in one (60) and multiple defects including hypothalamic hamartoblastoma in the other (61). Hydrocephaly was noted in one infant (from a group of 10) exposed in utero to cocaine, marijuana, and amphetamines (28). No major anomalies were seen in 8 infants exposed to cocaine (all had positive urine assays for cocaine) and other abuse drugs, but two infants had minor defects consisting of a sacral exostosis and capillary hemangioma in one and a capillary hemangioma in the other (37). In the latter case, the mother claimed to have used cocaine only during the month preceding delivery. Cocaine was not considered a causative agent in any of these cases (28,37,60,61).

In contrast to the above reports, no congenital abnormalities were observed in several series of cocaine-exposed women totaling 55 (21), 39 (31), 56 (39), and 38 (62) subjects. A prospective 1989 study mentioned previously found cocaine metabolites in the urine assays from 114 (9.3%) of 1,226 women (3). After controlling for the effects of other substances and maternal characteristics known to affect pregnancy outcome adversely, no significant association was found between cocaine and one or more minor anomalies, a constellation of three minor anomalies, or one major anomaly (3). An association with the latter two, however, was suggested by the data (p=0.10) (3). Although animal data cannot be directly extrapolated to humans, administration of cocaine to pregnant rats and mice did not increase the incidence of congenital abnormalities (63).

Newborn infants who have been exposed in utero to cocaine may have significant neurobehavior impairment in the neonatal period. An increased degree of irritability, tremulousness, and muscular rigidity has been observed by a number of researchers (4,11,15,16,17,18 and 19,21,23,26,62,64). Gastrointestinal symptoms (vomiting, diarrhea) have also been observed (4,21). The onset of these symptoms usually occurs 12 days after birth with peak severity of symptoms occurring on days 2 and 3 (19,21,62,64). Seizures, which may have been related to withdrawal, have been observed (14,23). The overall incidence of severe withdrawal symptoms, however, is apparently not increased over that expected in opiate-addicted newborns (15,16 and 17). In one report that identified 138 infants whose mothers tested positive for cocaine, 24 (17%) of the mothers also tested positive for other abuse substances, usually opiates (4). The incidence of withdrawal in infants of the cocaine-only group was 25% (28 of 114) vs. 54% (13 of 24) in infants of the multiple abuse drug group (p<0.005).

The Neonatal Behavior Assessment Scale (NBAS) has been used in several studies to quantify the observed symptoms (11,24,26,64). In a blinded study comparing infants of methadone-maintained women to those of cocaine-exposed women, the latter group had a significantly increased degree of irritability, tremulousness, and state lability (p<0.03) (11). Expansion of this study to include drug-free controls and cluster analysis of the NBAS revealed that the cocaine group had significant impairment in state organization compared to either the opiate group infants or controls (24,26). The NBAS was used to evaluate 16 term newborn infants with cocaine-positive urine assays (65). All demonstrated no to very poor visual attention and tracking, abnormal state regulation, and mild to moderate hypertonicity with decreased spontaneous movement (65). Flash evoked visual potentials were abnormal in 11 of 12 infants studied, and the disturbances remained in six infants studied at 46 months (65).

Ultrasound was used in a study published in 1989 to evaluate the behavior of 20 fetuses exposed to cocaine as a predictor of neonatal outcome (66). All fetuses were exposed to cocaine during the 1st trimester; 4 during the 1st trimester only, 7 during the 1st and 2nd trimesters, and 9 throughout gestation. The investigators were able to document that fetal state organization was predictive of newborn neurobehavioral well-being and state organization. In this study, the most frequent indicators of neurobehavioral well-being were excessive tremulousness of the extremities, unexplained tachypnea, or both (66). Abnormal state organization was shown by hyperresponsiveness and difficulty in arousal (66).

Electroencephalographic (EEG) abnormalities indicative of cerebral irritation have been documented in cocaine-exposed neonates (31,64,65). Normalization of the EEG abnormalities may require up to 12 months (31,64).

Increased perinatal mortality was observed in a study published in 1989, although in comparison to controls, the higher incidence was not significant (4). Seven (5%) of 140 infants (138 mothers, two sets of twins) whose mothers tested positive for cocaine at delivery died compared to none of 88 infants whose mothers did not test positive for cocaine at delivery. The seven cases included three intrauterine fetal deaths and four neonatal deaths.

An increased risk of sudden infant death syndrome (SIDS) has been suggested by three studies (11,17,67). Two infants, from a group of 50 exposed in utero to cocaine and methadone, died of SIDS, one at 1 month of age and the other at 3 months (17). It could not be determined whether a relationship existed between the deaths and maternal cocaine use (17). In one study, 10 of 66 infants (15%) exposed to cocaine in utero died of SIDS over a 9180-day interval (mean 46 days) following birth (11). This incidence was estimated to be approximately 30 times that observed in the general population and almost 4 times that seen in the infants of opiate-abusing women (11). Based on this experience, a prospective study was commenced and the results were reported in 1989 (67). Thirty-two infants of cocaine-using mothers were compared to 18 infants of heroin/methadone-addicted mothers. Eight of the mothers in the cocaine group also used heroin/methadone. The mothers of both groups received similar prenatal care, and they used similar amounts of alcohol, cigarettes, and marijuana. Infants in both groups were delivered at a gestational age of 38 weeks or more, and mean birth weight, length, and head circumference were identical. Cardiorespiratory recordings (pneumograms), conducted in most cases at 814 days of age, were abnormal in 13 infants, 12 cocaine exposed and 1 opiate exposed (p<0.05). Five of the cocaine-exposed infants had an episode of life-threatening apnea of infancy requiring home resuscitation before the pneumograms could be performed. The 13 infants were treated with theophylline until age 6 months, or longer if the pneumogram had not yet normalized. No cases of SIDS were observed in any of the 50 infants. In an earlier study, pneumograms were used to quantify abnormal sleeping ventilatory patterns in infants of substance-abusing mothers (68). Of three cocaine-exposed infants, one had an abnormal pneumogram. Apnea and/or abnormal pneumograms were observed in 20 (14%) of 138 infants whose mothers tested positive for cocaine at delivery (4). None of the 88 control infants whose mothers tested negative for cocaine at delivery had apnea or abnormal pneumograms (p<0.0005). In a large study examining the relationship between SIDS and cocaine exposure, one infant of 175 exposed to cocaine died of SIDS compared to four infants of 821 who were not exposed (36). The risks per 1000 in the two groups were similar, 5.6 and 4.9, respectively, corresponding to a relative risk for SIDS among infants of cocaine-abusing women of 1.17 (95% CI 0.1310.43) (36). Based on these data, the study concluded that the increased rates reported previously probably reflected other risk factors that were independently associated with SIDS (36). However, because the study relied on self-reported cocaine use and urine screens (only detects recent exposure), some of the women may have been misclassified as nonusers (69). Analysis of the hair, where the drug accumulates for months, has been advocated as a technique to ensure accurate assessment of past exposure (69).

Increased neonatal hospitalization in infants whose mothers tested positive for cocaine at delivery has been reported (4). In 137 infants (138 mothers, two sets of twins, three fetal deaths excluded), the mean number of days hospitalized was 19.2 compared to 5.1 for 88 infants of mothers who tested negative for cocaine at delivery (p<0.0001). Moreover, the incidences of neonatal hospitalization for longer than 3 and 10 days were both significantly greater for the cocaine group (80% vs. 24%, respectively, p<0.00001; 35% vs. 10%, respectively, p<0.0005). The implications of these findings on the limited resources available to hospitals are, obviously, very important.

In summary, the widespread abuse of cocaine has resulted in major toxicity in the mother, the fetus, and the newborn. The use of cocaine is often significantly correlated with the heavy use of other abuse drugs. Many of the studies reviewed here were unable completely to separate this usage in their patient populations or were unable to verify self-reported usage of cocaine, thus resulting in the possible misclassification of patients into the various groups. Whether the reported consequences of maternal cocaine exposure are due to these biases, to cocaine itself, to other drugs acting independently or in conjunction with cocaine, to poor lifestyles, or to other maternal characteristics is not presently clear. It is clear, however, that women who use cocaine during pregnancy are at significant risk for shorter gestations, premature delivery, spontaneous abortions, abruptio placentae, and death. The drug decreases uterine blood flow and induces uterine contractions. An increased risk may exist for premature rupture of the membranes but apparently not for placenta previa. The unborn children of these women may be growth retarded or severely distressed, and they are at risk for increased mortality. In utero cerebrovascular accidents with profound morbidity and mortality may occur. Congenital abnormalities involving the genitourinary tract, heart, limbs, and face may occur, and cocaine abuse should be considered teratogenic. Bowel atresias have also been observed in newborn infants, which may be due to intrauterine bowel infarctions. The exact mechanism of cocaine-induced malformations is presently uncertain, but it may be related to the placental vasoconstriction and fetal hypoxia produced by the drug with the resulting intermittent vascular disruptions and ischemia actually causing the fetal damage. Interactions with other drugs, however, may play a role. In addition to the above toxicities, the newborn child exposed to cocaine during gestation is at risk for severe neurobehavior and neurophysiologic abnormalities that may persist for months. An increased incidence of sudden infant death syndrome in the first few months after birth may also be a consequence of maternal cocaine abuse in conjunction with other factors. Long-term studies of cocaine-exposed children need to be completed before a true assessment of the damage caused by this drug can be determined.

[* Risk Factor X if nonmedicinal use.]

Breast Feeding Summary

Milk:plasma ratios of cocaine in human breast milk have not been determined. In one case, the urine of a normal, breast-fed, 6-week-old boy was positive for a cocaine metabolite (70). The mother was using an unspecified amount of cocaine. In another patient, a milk sample 12 hours after the last dose of approximately 0.5 g taken intranasally over 4 hours contained measurable levels (specific data not given) of cocaine and the metabolite, benzoylecgonine, that persisted until 36 hours after the dose (71). The 14-day-old infant was breast-fed five times over the 4-hour period during which the mother ingested the cocaine. Approximately 3 hours after the first dose, the child became markedly irritable with onset of vomiting and diarrhea. Other symptoms observed upon examination were tremulousness, increased startle response, hyperactive Moro reaction, increased symmetrical deep tendon reflexes with bilateral ankle clonus, and marked lability of mood (71). The irritability and tremulousness steadily improved over the next 48 hours. Large amounts of cocaine and the metabolite were found in the infant's urine 12 hours after the mother's last dose, which persisted until 60 hours postdose. On discharge (time not specified), the physical and neurologic examinations were normal. Additional follow-up of the infant was not reported.

In an unusual case report, a mother applied cocaine powder to her nipples to relieve soreness shortly before breast feeding her 11-day-old infant (72). Although a breast shield was used, the unsheathed nipple protruded to allow feeding. Three hours after feeding, the infant was found gasping, choking, and blue. Seizures, which occurred with other symptoms of acute cocaine ingestion, stopped 2 hours after admission to the hospital. The mother's milk was negative for cocaine and metabolites but the infant's urine was positive. Physical and neurologic examinations were normal on discharge 5 days later and again at 6 months. Computed tomography (CT) scan during hospitalization showed a small area of lucency in the left frontal lobe and an EEG at this time was abnormal. A repeat CT scan and EEG were normal at 2 months of age.

Based on the toxicity exhibited in the infant after exposure via the milk, maternal cocaine use during breast feeding should be strongly discouraged and considered contraindicated. Obviously, mothers should also be warned against using the drug topically for nipple soreness. The American Academy of Pediatrics considers cocaine to be contraindicated during breast feeding (73).

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