The rate of illicit drug use among pregnant women aged 15 to 44 years in 2012 was 5.9% (1
). The rate of cocaine use during pregnancy is more difficult to estimate largely due to variability in methods used for detection and partly due to social and legal consequences of its use. In a multicenter study involving 8,527 neonates, meconium analysis was positive for cocaine exposure in 38% of cases in which the mother denied usage (78
). In another study, cocaine use during pregnancy was detected by maternal interview in 50.8%, maternal hair analysis in 78%, and meconium analysis in 67.8% (84
). In contrast, a national survey reported 1.1% of cocaine use among pregnant women (85
). Biologic specimens, in addition to urine and meconium, have been used to detect prenatal cocaine exposure including amniotic fluid, gastric fluid, umbilical cord tissue, and neonatal hair (86
When taken orally, cocaine HCl has a peak effect between 45 and 90 minutes after oral ingestion. Intranasal administration of cocaine (i.e., snorting) has a peak effect in 15 to 30 minutes and lasts from 60 to 90 minutes. Smoking cocaine (“crack” cocaine) provides the most rapid delivery of the drug to the body. Peak effect is within 60 to 90 seconds, but the high lasts only for about 5 to 10 minutes. Cocaine is metabolized by plasma and hepatic esterases into three major water-soluble metabolites, ecgonine methyl ester, benzoylecgonine, and ecgonine, although other minor metabolites are also present. In infants, metabolites can be found for up to 2 weeks after administration. The neuropharmacologic effect of cocaine is due to its effect on three neurotransmitters: norepinephrine, dopamine, and serotonin. Cocaine inhibits the reuptake of norepinephrine and dopamine, which accumulate at the synaptic cleft, leading to prolonged stimulation of their corresponding receptors. Therefore, the effects of norepinephrine stimulation (e.g., tachycardia, hypertension, arrhythmia, diaphoresis, tremors) and dopamine stimulation (e.g., increased alertness, euphoria or enhanced feeling of well-being, sexual excitement, heightened energy) are experienced (88
). Cocaine also decreases the uptake of tryptophan, which affects serotonin biosynthesis (89
). A diminished serotonin level is associated with diminished need for sleep, because serotonin regulates the sleep-wake cycle. The mechanism of cocaine addiction is likely mediated by its effects on the dopaminergic system (90
). The immediate response to cocaine is an increased extracellular concentration of dopamine, and in the brain, the nucleus accumbens appears to be involved in the initial rewarding effects of cocaine.
Adverse Effects of Cocaine in Pregnant Women, Obstetric Effects, and Placental Transfer
A characteristic profile has been observed in pregnant women who abuse cocaine: multigravida, multiparous, and service patient with little to no prenatal care (91
). The pregnant cocaine addict is generally of poor health as a result of poor nutrition and vitamin deficiency (91
). Exchanging drugs for sexual favors, with little attention to personal protection, results in risk of acquiring sexually transmitted diseases.
Maternal use of cocaine has been associated with a number of obstetric complications, which include preterm labor, preterm premature rupture of membranes, precipitous labor, placental abruption, meconium-stained amniotic fluid, abnormal fetal monitor tracings, and fetal death (92
). Acute cocaine toxicity in pregnancy has been associated in the mother with acute thrombocytopenia, hypertension, blurred vision, headache, abdominal pain, and seizures mimicking symptoms of preeclampsia and/or eclampsia, myocardial infarction, and stroke (93
Cocaine-induced vasoconstriction may play a role in the development of obstetric complications. Collectively, the cardiovascular effect of cocaine on the maternofetal circulation is maternal hypertension, increase in uterine vascular resistance, decrease in uterine blood flow, decrease in oxygen transport to the fetus, and fetal hypoxemia (97
). Pregnancy can potentiate the toxic effects of cocaine, because progesterone can increase the sensitivity of adrenergic receptors or delay cocaine metabolism (98
). Further, cocaine enhances umbilical artery vasoconstriction by catecholamines and serotonin, presumably by increasing the sensitivity of the α-adrenergic receptors of arterial smooth muscle.
Breastfeeding following active maternal cocaine use, like other street drugs such as marijuana, opiates, and methamphetamine, is discouraged because the risks outweigh the benefits of human milk (99
). Cocaine and its metabolites have been detected in human milk, which may expose the infant to significant amounts when breastfeeding. Cocaine intoxication and cocaine-induced convulsions have been reported in breastfeeding infants (99
). The American Academy of Pediatrics (AAP) recommends against breastfeeding when there is active maternal use of marijuana, cocaine, opiates, and methamphetamines.
Adverse Effects of Cocaine Exposure in the Fetus and Neonate
Cocaine is highly lipid soluble and has a low molecular weight; thus, it readily crosses the placenta (101
). However, the fetal concentration of cocaine is only one-fourth to one-ninth that of the mother, as the placenta retains large amounts of cocaine serving as depot and offering fetal protection against cocaine toxicity. Nonetheless, animal models have shown extensive fetal exposure to cocaine following administration during pregnancy (102
The cocaine-exposed fetus is at risk for a number of complications: fetal distress, meconium staining of the amniotic fluid, low Apgar score, premature birth, fetal growth restriction, LBW, and small head circumference (92
). The rates of growth restriction are three to four times higher than in non-exposed fetuses. However, caution should be taken in interpreting these complications since concomitant maternal exposure to other substances such as nicotine, alcohol, opiates, and lead also contributes to impaired growth in utero
Unlike in animal studies, cocaine use during human pregnancy has not been associated with an increased incidence of congenital
). In blinded studies, there has also been no characteristic pattern of dysmorphic or anthropometric features of the face, limb, or torso among cocaine-exposed infants, suggestive of a “fetal cocaine syndrome” (110
TABLE 54.4 Reported Complications Involving Specific Organ Systems In Utero Cocaine-Exposed Newborn Infants
Central nervous system
Hypertonicity/hyperreflexia and transient dystonia
Abnormal head ultrasound, for example, echolucencies in basal ganglia, ventricles, periventricular, and germinal matrix cysts
Abnormal sleep pattern
Abnormal brainstem auditory-evoked response
Increased auditory startle response
Retinal hemorrhage and tortuosity and dilatation of iris vessels
Hypertension and diminished stroke volume and cardiac output
Atrial and ventricular arrhythmia
Abnormal breathing pattern, for example, periodic breathing
Maternal cocaine use during pregnancy has been associated with a number of multiorgan dysfunctions in the infant (Table 54.4
). Neurologic abnormalities include seizures with or without perinatal arterial stroke, transient dystonia, hypertonia/hyperreflexia and tremors, and abnormal EEG suggestive of CNS irritability. These neurologic consequences follow a dose-response relationship: neonates with highest prenatal cocaine exposure show higher rates of impairments in fetal head growth and abnormalities of muscle tone, movements, and posture. Problems of low arousal, poor quality of movement, high excitability, poor attention, jitteriness, and nonoptimal reflexes have also been observed. Abnormal sleep patterns have been reported in infants with prenatal cocaine exposure, which include increased wakefulness, more frequent arousals, and a higher proportion of active sleep than quiet sleep.
Abnormal hearing tests have been observed among prenatally cocaine-exposed infants. The auditory brainstem-evoked response shows prolonged interpeak and absolute latencies, suggesting abnormal neural transmission (112
). There is also impaired auditory information processing, with impaired habituation to novel stimulus.
In a small study involving very-low-birth-weight infants with cocaine exposure, there was reported a higher incidence of mild intraventricular hemorrhage (IVH) than in the nonexposed and a higher incidence of cognitive and motor delays on follow-up (113
). However, in a larger study of very-low-birth-weight infants, prenatal cocaine exposure did not increase the incidence (36% in cocaine exposed vs. 35% in nonexposed) or severity of IVH (i.e., grade III or IV IVH, 14% vs. 14%) or periventricular leukomalacia (4% vs. 2% in cocaine exposed and nonexposed, respectively) (114
). Among preterm infants less than 37 weeks of gestation, prenatal cocaine exposure was also not associated with increased incidence of IVH (22% vs. 20% in cocaine exposed vs. nonexposed, respectively).
Cerebral blood flow velocity is increased in infants with prenatal cocaine exposure, consistent with the vasoconstrictive effects of cocaine (115
). However, high-resolution brain imaging (single photon emission computed tomography) to detect neonatal brain perfusion deficits among neonates with confirmed prenatal cocaine exposure failed to show cerebral hypoperfusion in 21 cocaine-exposed neonates (116
). Nonetheless, cocaine-induced vasoconstriction at a critical time of cerebrovascular development has been reported to produce a vascular disruption sequence leading to Möbius syndrome (117
). The vasoconstrictive effect of cocaine on the systemic and cerebral circulation is more prominent in utero
than after birth, because the fetus is more consistently exposed to the drug.
Prenatal cocaine exposure may affect the development of sympathetic and parasympathetic systems that could lead to altered cardiovascular function as well as structural cardiovascular malformations and electrocardiographic abnormalities (118
). Asymptomatic cocaine-exposed infants may have either decreased or increased heart rate variability after birth, which may be related to the effect of cocaine on the autonomic nervous system through either sympathetic stimulation or vagal suppression. A decrease in cardiac output and stroke volume and increase in arterial blood pressure have been reported in cocaine-exposed infants as well as atrial and ventricular arrhythmias and transient ST segment elevation suggestive of myocardial ischemia (120
). A case series of children with prenatal cocaine exposure reported sustained arrhythmias likely resulting from an increased number of potential initiating premature beats, which in some children persisted beyond the period of exposure and were associated with congestive heart failure, cardiopulmonary arrest, and death (121
). In a study to evaluate the autonomic nervous system and neurobehavioral responses among infants with prenatal exposure to cocaine and opiates, those who were exposed had the highest heart rates and lowest levels of respiratory sinus arrhythmia, suggesting that prenatal cocaine exposure is associated with autonomic dysregulation (122
In the respiratory system, abnormal breathing patterns have been observed in the cocaine-exposed infants, for example, high respiratory rate, decreased end-tidal PCO2
and shift to the left of the breathing response curve to CO2
, increased apnea density, and periodic breathing (39
Other findings in the neonate that are attributed to in utero
cocaine exposure include elevation in serum myoglobin and creatine kinase due to excessive tremors (123
) and decreased jaundice because cocaine is a strong inducer of the glutathione-S
-transferase family of enzymes that is closely associated with bilirubin transport (ligandin) in the liver (124
). An increased incidence of early-onset necrotizing enterocolitis and spontaneous intestinal perforation not related to necrotizing enterocolitis have also been observed secondary likely to the vasoconstrictive and ischemic effect of cocaine on the gastrointestinal tract (125
). Retinal hemorrhages as well as dilated and tortuous iris vessels have also been reported. Retinal, vascular, disruptive lesions, which consisted of full-thickness hemorrhages with rounded domed contours suggestive of venous occlusion and retinal ischemia, have been described (126
). These lesions took longer to resolve compared with hemorrhages that result from birth trauma.
Neonatal Neurobehavioral Assessment
By the Neonatal Brazelton Assessment Scale (NBAS), cocaineexposed newborns exhibited significantly depressed performance on the habituation clusters, including lower state regulation and greater depression. During sleep-wake behavior observations, the infants showed difficulty in maintaining alert states and self-regulating their behavior, spent more time in indeterminate sleep and had decreased periods of quiet sleep and increased levels of agitated behavior, including tremulousness, mouthing, multiple limb movements, and clenched fists (127
). There was a dose-response relationship between fetal exposure to cocaine and performance on the NBAS. Two neurobehavioral states have been described in the
infants: an excitable state, which may be as a result of the direct neurotoxic effects of the drug, and a depressed state that may be related to intrauterine growth restriction (128
). However, an abstinence or withdrawal syndrome has not been substantiated. It is likely that the neurobehavioral manifestations are due to cocaine toxicity rather than withdrawal.