The Infant of the Drug-Dependent Mother
Enrique M. Ostrea Jr
J. Edgar Winston Cruz Posecion
Ma. Esterlita Villanueva Uy
Josef M. Cortez
The problem of drug abuse has reached epidemic proportions during the past two decades, with increases not only in the number of drug users but also in the types of drugs abused. Equally alarming is the increase in the proportion of drug users among women of childbearing age or who are pregnant, because the effects of drugs on the pregnancy and fetus can be far reaching (Table 54.1).
▪ EPIDEMIOLOGY
In 2012, an estimated 23.9 million Americans aged 12 years or older were current (past month) illicit drug users, meaning they had used an illicit drug during the month prior to the survey interview (1). This estimate represents 9.2% of the population aged 12 years or older. Illicit drugs include marijuana/hashish, cocaine (including crack), heroin, hallucinogens, inhalants, or prescription-type psychotherapeutics (pain relievers, tranquilizers, stimulants, and sedatives) used nonmedically. Marijuana was the most commonly used illicit drug. Among pregnant women aged 15 to 44 years, 5.9% were current illicit drug users based on data averaged across 2011 and 2012. It should be noted that these statistics were obtained exclusively from maternal interviews and, therefore, are highly underestimated due to significant underreporting of drug use by these women. In one study, an estimate of drug use among pregnant women varied from 0.4% to 27% when drug use was detected by maternal history, urine toxicology, or both (2). When a more sensitive method for drug testing (meconium drug testing) was employed, a prevalence rate of 44% of illicit drug use was found in a study population, in contrast to 11% by maternal self-report (2).
▪ NARCOTICS
The term “opiate” or “narcotic” refers to any natural or synthetic drug that has morphine-like pharmacologic actions. The natural opiates include morphine and codeine; the synthetic opiates include heroin, methadone, propoxyphene (Darvon), pentazocine (Talwin), meperidine (Demerol), oxycodone (Percodan, Tylox, Vicodin, Percocet), hydromorphone (Dilaudid), buprenorphine, and fentanyl (Immovar, Sublimaze). Chronic use of narcotics by the mother, even in therapeutic doses, results in addiction, which is characterized by psychological and physical dependence on the drug.
Most drugs, when taken by the pregnant woman, cross the placenta and enter the fetal circulation. Thus, the fetus is chronically exposed to these drugs and can develop problems in utero and after birth. Although the development of passive addiction is the most commonly known fetal complication of narcotic use in the pregnant woman, many other important problems are encountered (Table 54.1).
Antenatal Problems
Intrauterine asphyxia is perhaps the single greatest risk to the fetus of the narcotic-dependent woman based on reports of a high incidence of stillbirths, meconium-stained amniotic fluid, fetal distress, nonreactive stress test, low Apgar score, and neonatal aspiration pneumonia (3). The predisposition of the fetus to asphyxia underscores the need for repeated evaluation of fetal well-being during the course of the pregnancy of the drug-dependent woman. Fetal asphyxia may be secondary to a number of factors. Studies using methadone in a fetal lamb model suggest that opiates affect both quiet and rapid eye movement (REM) sleep, which leads to a hyperactive state and a 20% increase in fetal oxygen consumption (4). Sleep disturbances, consisting of more REM and less quiet sleep, have been observed in newborn infants chronically exposed in utero to low doses of methadone with or without concomitant heroin usage (5,6). Another possible cause of fetal asphyxia is fetal withdrawal, which usually coincides with the mother’s withdrawal. Fetal withdrawal leads to fetal hyperactivity, increase in catecholamine release, increase in oxygen consumption and, if not adequately compensated for, fetal asphyxia (6,7). A high incidence of preeclampsia, abruptio placentae, and placenta previa in the pregnant addict also predisposes to placental insufficiency and fetal distress (3,8).
Meconium-stained amniotic fluid is frequently encountered in the pregnant addict and is a manifestation of fetal distress (3,8). Aspiration of meconium accounts for the increased frequency of meconium aspiration syndrome and (at least in part) persistent pulmonary hypertension (PPHN) of the newborn.
Intrauterine infection is another risk in the fetus of the narcoticaddicted pregnant woman. Because of the lifestyle of the pregnant addict of trading sex for drugs, she is predisposed to infections, particularly of sexually transmitted diseases such as syphilis, chlamydia, gonorrhea, hepatitis, and human immunodeficiency virus (HIV) infection, all of which can be transmitted to her fetus (9). During delivery or before labor, the increased incidence of premature membrane rupture in the pregnant addict further exposes the fetus to the risk of nonspecific infections (8). Opiates may also compromise immune functions in the fetus through an adverse effect on cell-mediated and humoral immune responses (10).
Neonatal Problems
Prematurity and Low Birth Weight
Infants born to mothers on heroin have a higher incidence of prematurity and low birth weight (LBW) for gestational age than do drug-free control subjects (3). One mechanism for the fetal growth restriction in narcotic addiction may be the effect of opiates stimulating opiate kappa receptors, which inhibit acetylcholine release in the placenta. Acetylcholine is responsible for increasing placental blood flow through vasodilatation and facilitating the transport of amino acids across the placenta (11).
On the other hand, infants whose mothers were on methadone have varied from being higher or lower in birth weight than the infants of untreated pregnant addicts, or not significantly different from the general newborn population (3,12). Higher birth weights probably reflect the good prenatal care that the woman receives in a methadone program. On the other hand, studies on pregnant rats exposed to methadone have shown their offspring to have significantly lower body weight, length, head diameter, and organ weight and impaired brain development and thermoregulation (13) compared to non-methadone-exposed pups. A meta-analysis of opiate use and birth weight showed a mean reduction of 489 g associated with heroin use, 279 g with methadone use, and 557 g with combined heroin and methadone use. These findings suggest that concurrent use of heroin although on methadone treatment counteracts the birth weight advantage gained from methadone alone (14).
Low Apgar Score
There is a high incidence of low Apgar score in infants of narcoticdependent mothers. This may be related to intrauterine asphyxia (see “Antenatal Problems”) or to the effects of narcotics that the mother received before delivery. Caution must be exercised with
the use of narcotic antagonists to reverse the respiratory depression in drug-dependent infants, because the narcotic antagonists can precipitate an acute withdrawal in the infant.
the use of narcotic antagonists to reverse the respiratory depression in drug-dependent infants, because the narcotic antagonists can precipitate an acute withdrawal in the infant.
TABLE 54.1 Complications Associated with Maternal Abuse of Drugs during Pregnancy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Others
In addition to withdrawal, other problems are seen with increased frequency in the infant of a narcotic-dependent mother: jaundice, aspiration pneumonia, meconium aspiration, PPHN of the newborn, transient tachypnea, hyaline membrane disease, and infections (3). These problems are the major causes of death in these infants.
Aspiration pneumonia, hyaline membrane disease, and transient tachypnea are the leading pulmonary problems in the infant of the drug-dependent mother. About 30% of aspiration pneumonia is as a result of meconium aspiration. Transient tachypnea may be secondary to the inhibitory effects of narcotics on the reflex clearing of fluid by the lungs. The high incidence of hyaline membrane disease among infants of drug-dependent mothers is likely a result of prematurity. What has been reported as a protection among premature, drug-dependent infants from hyaline membrane disease may be due primarily to the increased incidence of small for gestational age (SGA) infants in this group (8,15). Meconium aspiration, PPHN of the newborn, and hyaline membrane disease account for more than 50% of the deaths among infants of drug-dependent mothers (8).
In general, opiates are not teratogenic to the fetus. Most reports do not show an increase in the frequency of congenital anomalies (3), and in one study, although an increased frequency of malformations was found (3), the malformations were minor (e.g., skin tag) and no consistent pattern of malformation was observed. Animal studies, however, have shown a dose-related teratogenic effect of narcotics on the central nervous system (CNS) of the developing hamster, which can be blocked by narcotic antagonists (16). In vitro studies have also shown opiates to impair deoxyribonucleic acid (DNA) repair and cause chromosome aberration with hyperdiploidy (17).
There is an altered sleep pattern in infants of drug-dependent mothers, characterized by more REM-associated sleep than quiet sleep (18). In term infants exposed to opiates, abnormal auditory brainstem-evoked response shows decreased conductance time for waves I to III (19). Abnormal heart rate and breathing patterns have also been observed (20). The respiratory rates are higher, with low end-tidal volume PCO2 and a shift to the left in their breathing response to CO2. These abnormalities have been suggested to increase their predisposition to the sudden infant death syndrome (SIDS) (see “Long-Term Outcome”).
There is an increased incidence of jaundice in the infants of drugdependent mothers, which is likely related to the high incidence of prematurity in this group (3). Although induction of liver enzymes by morphine has been demonstrated in experimental animals (21), the dose of morphine used was exceedingly high (250 mg/kg), a situation unlikely to be paralleled in a clinical setting. A significant thrombocytosis, occasionally exceeding 1,000,000 platelets/mm3, was reported in infants of mothers receiving maintenance doses of 40 to 90 mg of methadone per day. Onset was by the 2nd week of life, with counts remaining high for over 16 weeks. The thrombocytosis, and associated increased circulating platelet aggregates, may play a role in the development of the focal cerebral infarctions and germinal matrix and subarachnoid hemorrhages, which have been encountered in some postmortem examinations of these infants (22). The incidence of intraventricular hemorrhage (IVH) in the opiate-exposed infant is not increased (23). Cranial ultrasound has shown slit-like ventricles and small intracranial diameter.
Along with the high incidence of infection in the pregnant addict is a correspondingly high incidence of infection in her infant. Although some of the neonatal infections are nonspecific, many are related to the lifestyle of the mother and include hepatitis and venereal diseases, for example, syphilis, chlamydia, gonorrhea, herpes simplex, group B streptococcal, and HIV infections (3).
Neonatal Narcotic Withdrawal or Abstinence Syndrome
As tolerance and addiction to drugs develop in the pregnant woman, passive dependence on the drug also develops in her fetus. Two major theories about the etiology of narcotic withdrawal have been postulated. The theory of disuse hypersensitivity postulates that a drug may depress certain neural systems and render their targets hypersensitive to their usual stimuli with an increase in binding sites for the drugs. When the depressant drug is removed, the withdrawal syndrome occurs, due to rebound hypersensitivity of the affected targets. Chronic morphine exposure results in an increase in the number of brainstem adrenergic binding sites. When morphine is withdrawn, the abstinence syndrome occurs as a consequence of adrenergic hypersensitivity (24). The theory of alternate pathways states that a drug may depress a primary neural pathway, and as a result, alternate pathways, normally of minor activity, become prominent in an attempt to compensate. When the drug is removed, both the primary and alternate pathways are operative in an additive fashion and cause the withdrawal syndrome (25). The onset of narcotic withdrawal usually occurs within the first 72 hours after birth. In a few instances, the onset may appear soon after birth, particularly if the mother has begun to experience withdrawal before delivery. Reports of withdrawal occurring after the 1st or 2nd week may be secondary to withdrawal from methadone or other drugs, for example, phenobarbital (25,26). Many factors, such as amount of narcotics used by the mother, timing of the last dose before delivery, character of the labor, type and amount of anesthesia or analgesia given to the mother, and the maturity of the infant, influence the onset of withdrawal (3,8).
The use of methadone in pregnant women for the treatment of opiate addiction is associated with an abstinence syndrome in their infants at birth, and its severity is related to the maternal dose (27), cord blood level of methadone, and concomitant use of heroin or benzodiazepines. Buprenorphine has been used as a substitute treatment for maternal heroin addiction and can also induce a neonatal withdrawal syndrome, although less severe and less prolonged in comparison to methadone (28).
There has been increasing use of opiates and hypnosedatives in infants in the intensive care unit, due to increased awareness of the adverse effects of pain in the infants. The drugs that are commonly used include fentanyl, morphine sulfate, and midazolam. Due to the continuous and chronic use of these medications, withdrawal has been observed in these infants when the drugs are abruptly discontinued consisting of shorter sleeping time and increased muscle tone (29). In one report, severe midazolam and opioid withdrawal resulted in transient myocardial ischemia in the infant, which resolved once fentanyl and midazolam were reinstituted (30).
Narcotic withdrawal in the infant usually peaks by about the 3rd day of postnatal life and decreases in intensity by the 5th to 7th day. The duration of withdrawal is related to its severity. When drugs are used to treat the withdrawal, relapse may occur if treatment is discontinued abruptly. The withdrawal manifestations, although they may improve within a week, do not completely disappear until about 8 to 16 weeks of age (see “Long-Term Outcome”).
The severity of the withdrawal is influenced by several factors. It is less severe in the preterm infants as a result of their neurologic immaturity or reduced total exposure to narcotics (31). Withdrawal is significantly related to the amount of narcotics that the mother used during pregnancy. With methadone, a high maintenance maternal methadone dose during pregnancy or at the last methadone intake is associated with more intense withdrawal (8,32). Buprenorphine, a potentially safer, opioid, maintenance drug than methadone, has been associated with a lower incidence of abstinence syndrome in both the mother and infant and lower mean weight reduction in the infant (33). Manipulation of the environment, such as reduction in the amount of light or noise in the nursery, does not ameliorate the severity of withdrawal in the infants (8).
Neonatal narcotic withdrawal is associated with noradrenergic hyperactivity, and the manifestations involve the CNS, the respiratory, gastrointestinal, vasomotor, and cutaneous systems (Table 54.2).
Central Nervous System Signs
Neurologic signs predominate and appear early. The findings are those of CNS excitability, such as hyperactivity, irritability, tremors, sneezing, and hypertonicity. Occasionally, fever may accompany these increased neuromuscular activities.
Hyperactivity manifests as almost incessant movements of the extremities. When the infant is supine and unrestrained, the movements assume a jerky, purposeless, en masse nature, apparently perpetuated by unchecked, proprioceptive stimuli. When placed in the prone position, the motor behavior becomes more organized. There are crawling movements, which can lead to the infant’s displacement from the crib, and other motions such as chin lifting, head movement from side to side, chest elevation, and hand-to-mouth facility. The latter usually soothes the infant, indicating the usefulness of pacifiers during withdrawal. Hyperirritability manifests as almost incessant crying with shrill, high-pitched outcries. The infant’s muscle tone is exaggerated, and sometimes, an opisthotonic position is assumed. Tremors and myoclonic jerks are frequent and are sometimes sustained. To distinguish tremors from seizures, the former can be abolished by gentle restraint of
the tremulous extremities. The reflexes of the infant (e.g., Moro, traction response, weight bearing, placing, stepping, crawling, and Landau) are all exaggerated. The infant’s responses to stimuli, such as sound and light, are also increased disproportionately. In premature infants, the neural hyperexcitability is more episodic; these infants appear restless and overactive for short periods and then lapse into periods of lethargy and inactivity. Sustained tremors usually are not seen in premature infants until they mature to a point when sufficient tone is present in the upper and lower extremities. Electroencephalographic (EEG) tracings on the addicted neonate may be abnormal, showing high-frequency dyssynchronous activity suggestive of CNS irritability.
the tremulous extremities. The reflexes of the infant (e.g., Moro, traction response, weight bearing, placing, stepping, crawling, and Landau) are all exaggerated. The infant’s responses to stimuli, such as sound and light, are also increased disproportionately. In premature infants, the neural hyperexcitability is more episodic; these infants appear restless and overactive for short periods and then lapse into periods of lethargy and inactivity. Sustained tremors usually are not seen in premature infants until they mature to a point when sufficient tone is present in the upper and lower extremities. Electroencephalographic (EEG) tracings on the addicted neonate may be abnormal, showing high-frequency dyssynchronous activity suggestive of CNS irritability.
TABLE 54.2 Manifestations of Neonatal Narcotic Withdrawal | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Respiratory Signs
Infants in withdrawal may be tachypneic, with irregular respirations. Alkalosis may result from hyperventilation. Fluid loss may also be increased.
Gastrointestinal Signs
The suck of the withdrawing infant is disorganized, reduced in rate and sucking pressure (34), and poorly coordinated with swallowing. Consequently, milk frequently drools around the corner of the infant’s mouth. The infant appears incessantly hungry, which, when unfulfilled, leads to mounting agitation, persistent crying, hyperactivity, and exhaustion. Proper positioning of the infant to enhance hand-to-mouth facility may be soothing. Vomiting and diarrhea are often observed. This may lead to dehydration, electrolyte imbalance, and excoriations in the buttocks.
Vasomotor Signs
Significant vasomotor instability manifests as stuffy nose, flushing, mottling, sweating, and episodes of sudden, circumoral pallor.
Cutaneous Signs
Because of hyperactivity, facial scratches and abrasions on pressure points may be observed on the infant’s skin.
Mortality
The mortality rate among infants born to narcotic-dependent mothers used to be as high as 50%. With early recognition and treatment of the infant’s withdrawal syndrome and prevention of its complications, the mortality from neonatal withdrawal is almost negligible. Nonetheless, overall mortality among infants of drug-dependent mothers remains high. In one report, mortality rate was 27 per 1,000 live births compared to 12 per 1,000 live births in the general population (12). The causes of death were related to immaturity, prematurity, hyaline membrane disease, meconium aspiration, and PPHN of the newborn.
Neonatal Neurobehavioral Abnormalities
By the Brazelton Neonatal Assessment Scale, hypertonicity, hyperirritability, hyperactivity, and increased hand-to-mouth facility can be demonstrated. Some other fine behavioral abnormalities are also found that could affect early infant-caregiver interaction (35). For instance, congenital narcotic addiction seems to affect those behavior systems that are associated with arousal and early development of mother-infant bonding. The addicted infant is less easy to cuddle because of increased tone, less readily maintained in an alert state through handling and less responsive to visual stimuli, although auditory-evoked responses are better integrated. Because cuddliness, alertness, and visual regard are the primary means by which the infant initiates and maintains interaction with its mother, the impairment of these behavior patterns may have a profound effect on the early infant-mother bonding.
Long-Term Outcome
Persistence of Withdrawal
Withdrawal in infants from narcotics may persist for 8 to 16 weeks and is more prolonged in those who had severe withdrawal and were treated with drugs for withdrawal (36). Thus, although drug treatment may ameliorate the manifestations of withdrawal, it does not shorten its total duration. The mother should be made aware that the infant’s withdrawal, albeit manageable, can persist at home after the infant’s discharge. She should be instructed on how to reduce the infant’s discomfort by swaddling and cuddling the infant. Additionally, she should be reassured that the infant’s withdrawal will eventually subside without the use of medications. In most instances, the mother who is well informed can cope with the situation successfully.
Child Abuse and Neglect and Sudden Infant Death Syndrome
The high incidence of child abuse and neglect constitutes one of the serious problems in infants of drug-addicted mothers once they are discharged from the nursery (37). Thermal burns, usually from cigarettes, traumatic ecchymoses, and hematoma, have been observed in 8% of infants during the first 8 months of life. About 8.3% of the infants have to be placed in alternative care environment because of maternal neglect, abandonment, or maternal death. Many factors contribute to the risk of child abuse. The persistence of withdrawal for some weeks, feeding problems, abnormal sleep patterns, and periods of restlessness in the infant can generate tension in the mother, whose tolerance for frustration is already low. Thus, the mother, unable to cope with the situation, may simply withdraw from her infant and avoid any contact or may abandon or injure the infant.
There is a four- to fivefold increase in the incidence of sudden death syndrome in infants of opiate-dependent mothers (38). The cause is not clear, although its occurrence is significantly higher in those infants who had moderate-to-severe than in those who had mild withdrawal after birth. Abnormal breathing patterns, control of breathing, and exposure of the infant to maternal smoking have been implicated as contributory causes to the SIDS (39).
Growth and Psychomotor Development
In general, the physical growth of the congenitally narcoticaddicted infant has been shown to catch up when adjusted for sex, race, maternal education, and smoking. At 12 months of age, the weight, head circumference, and length of the infants have been observed to fall within the 10th to the 90th percentile on the growth chart. Similarly, the percentage of addicted infants whose growth parameters were below the 10th percentile did not differ significantly from the nonaddict group (40). However, some studies have reported retardation in the weight, length, and head circumference at age 3 to 6 years (41,42,43). A high incidence of transient or minor motor deficits, poor motor coordination, and abnormal eye findings, such as nystagmus and strabismus, have also been observed in these infants in the 1st year of life (43).
The mental and cognitive performance of the opiate-exposed infants have been shown to be comparable to the control, non-drugexposed group (44,45). Within the 1st year, infants of narcotic addicts have been shown to manifest some difficulty in regulating their behavior but otherwise had normal developmental scores except in early language development (40,41,42,43). However, at preschool age, compared to controls, that is, children at similar environmental risk and sociodemographic background, the addicted children performed less well in terms of perception, short-term memory, and organization but did just as well on objective tests of activity and attention (42).
Behavioral problems have been observed among the opiateexposed infants and have persisted even in late childhood. These consisted of hyperactivity, aggressiveness, inattention, impulsiveness, short attention span, and lack of concentration and inhibition (46,47,48), which lead to learning problems in school, truancy, and suspension. However, these problems are probably more as the result of environmental and emotional deprivation of the child rather than due to the effects of in utero drug exposure. These deprivations include significant psychopathology in the mother (or parents) with or without comorbid alcohol abuse and negative parenting behavior, which contribute to poor infant rearing. The problems are further compounded by arrest or incarceration of the mother and her treatment for emotional disorders (49). The mother is also more socially isolated and less likely to pursue vocational or educational attainment. Thus, the addicted mother needs assistance in parenting. Someone should be available to help her in the care of her child (often the maternal grandmother), and a visiting or public health nurse and a social and protective service worker should actively participate in the follow-up of the mother and her infant (50). The alternative measure of placement of the child into a more favorable home environment has sometimes resulted in improvement in behavioral functioning of the child (48,51).
▪ NONNARCOTIC HYPNOSEDATIVES
Nonnarcotic Abstinence Syndrome
Infants born to women who have used nonnarcotic hypnosedatives during pregnancy (Table 54.3) can become addicted to the drugs and manifest withdrawal, which are similar to narcotic withdrawal (52). However, some differences exist between addiction to narcotic and nonnarcotic hypnosedatives (52). In adults, the rate of developing physical dependence to the nonnarcotic hypnosedatives does not increase with the drug dose, as it does with narcotics. Rather, prolonged and continuous administration of large and partially incapacitating doses are necessary, over months or years, to produce addiction to nonnarcotics, especially if the drugs are taken orally. The situation is different in the newborn infant. Passive addiction in the fetus and infant has been observed even with the use of therapeutic doses of nonnarcotic hypnosedatives by the mother during pregnancy. For instance, a pregnant woman who is treated with phenobarbital for epilepsy can induce serious addiction in her fetus, although she herself may not be addicted to the drug (52).
TABLE 54.3 Nonnarcotic Hypnosedatives | ||||||||||||||||||
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The manifestations of the nonnarcotic abstinence syndrome are more frequently intense and life threatening compared to narcotic withdrawal. The occurrence of convulsion is also more frequent. Most of the withdrawal from narcotics is seen within the first 3 days of postnatal life, as a result of the short half-life of narcotics. In contrast, withdrawal from the nonnarcotics, for example, phenobarbital, diazepam, or chlordiazepoxide, may occur 7 to 21 days after birth, due to the slow clearance of the drug in the infant (53,54). Unlike the narcotics, neonatal addiction to many of the nonnarcotic hypnosedatives is not infrequently induced by physicians who prescribe the drug to the mother, totally unaware of its addicting potential on the fetus (55).
Barbiturates
Barbiturates are classified, based on their duration of action, as ultrashort, intermediate, and long acting. The intermediate-acting barbiturates are most frequently abused (e.g., secobarbital [Seconal], pentobarbital [Nembutal], amobarbital [Amytal], butabarbital [Butisol]). The abuse of the long-acting barbiturates (e.g., phenobarbital) is uncommon, although phenobarbital is more frequently involved in withdrawal syndrome in the newborn because it is taken by the mother for insomnia, relief of anxiety, or as an anticonvulsant or sedation during toxemia of pregnancy.
Barbiturates cross the placenta readily and establish high levels in both the maternal and cord blood. Relatively, high levels of barbiturates have been found in the fetal brain, liver, and adrenal glands (56). Barbiturates are metabolized principally by the liver, although a significant portion may be excreted unchanged by the kidney (57). The half-life of phenobarbital in infants is almost twice that in the adult. Phenobarbital levels in the arterial cord blood have ranged from 77% to 100% of maternal levels depending on the duration of maternal treatment, gestational age, and cord pH in the infant (58).
The infants withdrawing from barbiturates are overactive and restless, with excessive crying, twitching, hyperactive reflexes, and hypertonicity. They also manifest diarrhea, vomiting, and poor sucking ability. When tonic-clonic convulsions occur, the EEG patterns show diffuse, paroxysmal, high-voltage, slow-wave bursts, similar to those seen in adults (59). A subacute phase of hyperphagia, episodes of prolonged crying, episodic irritability, hyperacusis, and sweating have been described (59), which may last from 2 to 6 months. A combination of phenobarbital-phenytoin treatment of the mother has also been observed to predispose to smaller occipitofrontal circumference in the infants compared to phenobarbital alone (60). Cognitive functions in infants exposed to phenobarbital in utero did not differ from controls, except for a higher incidence of learning problems (61).
Recognition of the abstinence syndrome from phenobarbital is essential for the proper management of the infant. An awareness of late-onset withdrawal in infants exposed in utero to longacting barbiturates should alert the clinician to follow these infants closely during the first 2 weeks of life.
Chlordiazepoxide and Diazepam
Benzodiazepines are frequently prescribed to women of reproductive age and to pregnant women for reducing anxiety and managing toxemia of pregnancy (62). The most commonly used benzodiazepines in the United States are diazepam, chlordiazepoxide, clonazepam, lorazepam, and alprazolam. Benzodiazepines cross the placenta with relative ease, resulting in significant drug levels in the serum and tissues of the fetus. Placental transfer of diazepam can occur from the 6th week of gestation, with accumulation in the fetal tissues during organogenesis (63). Mean levels of diazepam were found to be markedly higher in the umbilical cord serum than in the maternal serum after a single intravenous injection of 10 mg of diazepam (64). There are many possible effects to the fetus whenever anxiolytic medications are prescribed to pregnant women, which include abortion, malformation, and intrauterine growth restriction. If benzodiazepines are administered at or near term, they may cause fetal dependence and eventual neonatal abstinence syndrome (65).
Major neonatal withdrawal syndromes are observed among infants exposed to maternal parenteral diazepam for long periods or to dosages exceeding 30 to 40 mg/d, especially if given intravenously or intramuscularly during pregnancy and labor. In case reports of neonatal withdrawal from diazepam, withdrawal signs consisted of tremors, irritability, hypertonicity vigorous sucking, vomiting, and diarrhea (65). Phenobarbital was effective in controlling the withdrawal although the drug had to be administered for a prolonged period. The withdrawal from diazepam can last up to several months, and the syndrome is best minimized by gradually tapering diazepam before delivery. Late third-trimester use and exposure to diazepam during labor have been associated with the “floppy infant syndrome.” The manifestations of this syndrome are hypothermia, lethargy, apnea, cyanosis, and reluctance to suck. All these infants appeared to recover without long-lasting sequelae (66).
Chlordiazepoxide is a long-acting benzodiazepine frequently used in the management of anxiety disorders, withdrawal symptoms from alcoholism, and preoperative anxiety. It has very low toxicity and is safe for preanesthetic use during labor. There are well-documented case reports of neonatal withdrawal syndrome among infants who were either chronically exposed to chlordiazepoxide in utero or exposed to small amounts intrapartum (67).
The withdrawal occurred on day 21 of life and consisted of severe irritability and coarse tremors. However, in three reports of neonatal withdrawal from diazepam, the onset of withdrawal occurred within 2.5 to 6 hours after birth and consisted of tremors, irritability, hypertonicity, vigorous sucking, vomiting, and diarrhea. In all three cases, phenobarbital was effective in controlling the withdrawal in the infant, although the drug had to be administered for a prolonged period (13 to 25 days). Late third-trimester use and exposure to diazepam during labor have been associated with the floppy infant syndrome. The manifestations varied from mild sedation, hypotonia and reluctance to suck to apneic spells, cyanosis, and impaired metabolic responses to cold stress. These signs may persist from a few hours to months after birth (66). High-dose intravenous administration or prolonged duration of diazepam therapy in mothers has also caused significant depression in the newborn, with poor muscle tone (68,69). Congenital malformations are uncommon with antenatal diazepam exposure, except for one report of an omphalocele-exstrophy-imperforate anus-spina bifida complex occurring in an infant whose mother took 30 mg of diazepam daily for affective disorder during the entire pregnancy (70). In general, most studies involving first-trimester use of benzodiazepines have shown the majority of infants to be normal at birth and have normal postnatal development (71).
Lorazepam, which is a treatment for pregnancy-induced hypertension, has also been used frequently during labor due to its prolonged amnestic action. Lorazepam and its metabolite do not cross the placenta as easily as other benzodiazepines. However, its elimination from the newborn is slow and may take up to 8 days in term babies and even longer in premature infants. Full-term infants whose mothers had received oral lorazepam were noted to have no complication apart from a slight delay in establishing feeding. In contrast, intravenous use of lorazepam for severe hypertension was associated with neonatal withdrawal and significantly low Apgar scores, hypothermia, poor suck, and depressed respiration that required ventilation. Preterm babies whose mothers had been given lorazepam by oral or IV routes had a high incidence of low Apgar scores, need for ventilation, hypothermia, and poor suckling (72).
Other Hypnosedatives
Hypnosedatives, which used to be popular in the past, have been associated with adverse effects in the newborn infants. These include chloral hydrate, bromide (73), ethchlorvynol (74,75), and glutethimide, which is structurally related to phenobarbital (76). There has been less occurrence of neonatal withdrawal to these drugs due to their infrequent use compared to newer hypnosedatives.
Differential Diagnosis
Withdrawal from the narcotic and nonnarcotic hypnosedatives should be distinguished from hypoglycemia, hypocalcemia, hypomagnesemia, sepsis, meningitis, subarachnoid hemorrhage, infectious diarrhea, and intestinal obstruction. Blood chemistry, white cell count and differential, cerebrospinal fluid examination, radiographic imaging, and cultures should be performed as indicated.
Maternal intake of phenothiazines (e.g., chlorpromazine) may induce extrapyramidal dysfunctions in the newborn infant, such as tremors, facial grimacing, increased muscle tone, cogwheel rigidity, increased reflexes, and torticollis, all of which can resemble the withdrawal syndrome (77,78). The prenatal history and the identification of the corresponding drug in the infant’s serum or urine are necessary to establish the diagnosis.
▪ ANTIDEPRESSANTS: SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI)
Since the introduction of SSRIs in 1988, they have become the drug of choice in the treatment of depression and other mood and behavioral disorders. The use of SSRI during pregnancy has also become more common. The existence of withdrawal syndrome with antidepressants, both the classic tricyclic antidepressants (TCAs) and the newer SSRI, is well documented in adults. Infants whose mothers are on TCAs or lithium may exhibit manifestations such as irritability, tachycardia, respiratory distress, sweating, and convulsions (79,80). Withdrawal or “discontinuation” syndrome has been described in newborn infants following third-trimester fluoxetine, paroxetine, sertraline, and venlafaxine exposure (81,82,83). The withdrawal signs include acrocyanosis, tachypnea, temperature instability, irritability, and elevated drug levels among infants with prenatal fluoxetine exposure and respiratory distress, hypoglycemia, and jaundice with paroxetine exposure.
A total of 93 cases of SSRI use associated with either of the neonatal withdrawal syndromes described above. Additional signs included convulsions, abnormal crying, and tremors (79). The withdrawal syndrome associated with SSRI use could be attributed to the cholinergic overdrive or redefined in terms of dependence on the serotonin system. Nearly two-thirds of reported cases of suspected SSRI-induced neonatal withdrawal were associated with paroxetine. Paroxetine is a more potent inhibitor of norepinephrine reuptake than sertraline or citalopram. Paroxetine also has a distinctive effect on muscarinic receptors compared with fluoxetine
and other SSRIs. These aspects of paroxetine’s mechanism are more suggestive of a cholinergic withdrawal syndrome that is also described in adults (82). Thus, paroxetine should not be used in pregnancy or, if used, should be given at the lowest effective dose. In another report, among a cohort of 64 infants with late-gestation fluoxetine exposure, there was a greater frequency of poor neonatal adaptation, for example, presence of jitteriness, tachypnea, hypoglycemia, hypothermia, poor tone, and a weak or absent cry. These signs were observed within the 1st hour of life and typically had resolved by 48 hours of life (83).
and other SSRIs. These aspects of paroxetine’s mechanism are more suggestive of a cholinergic withdrawal syndrome that is also described in adults (82). Thus, paroxetine should not be used in pregnancy or, if used, should be given at the lowest effective dose. In another report, among a cohort of 64 infants with late-gestation fluoxetine exposure, there was a greater frequency of poor neonatal adaptation, for example, presence of jitteriness, tachypnea, hypoglycemia, hypothermia, poor tone, and a weak or absent cry. These signs were observed within the 1st hour of life and typically had resolved by 48 hours of life (83).
▪ COCAINE
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 (86,87,88).
Cocaine is an alkaloid that is extracted from the leaves of the Erythroxylon coca bush. Its chemical name is methylbenzoylecgonine and is the only known, naturally occurring local anesthetic. Cocaine hydrochloride (HCl) is the most commonly available form of cocaine. In its acid state, cocaine HCl is a white powder that is soluble in water and can be snorted or injected. Cocaine HCl is commonly adulterated with starch, glucose, phencyclidine (PCP), heroin, or amphetamines, and its purity ranges from 20% to 80%. An alkaloidal base of cocaine can be obtained from cocaine HCl (“freebasing”) by alkalinizing the aqueous solution of cocaine HCl and then extracting the cocaine alkaloid base using volatile organic solvents, such as ether. The gummy cocaine residue, called “rock,” has a lower melting point than cocaine HCl and can be smoked. Crack cocaine is the most popular abused form of the drug and is produced when cocaine HCl is mixed with ammonia, water, and baking soda and then heated. The resulting paste, once dried, forms a hard, rock-like substance that can be smoked. The term “crack” is derived from the crackling sound that is produced when crack cocaine is being prepared or smoked.
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 (93,94,95,96).
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 (99,100). 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 (92,93,103). 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 (99,101,103,104,105).
Unlike in animal studies, cocaine use during human pregnancy has not been associated with an increased incidence of congenital
malformations (106,107,108,109). 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).
malformations (106,107,108,109). 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 | ||||||||||||||||||||||||||||||||||||||||||||
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Maternal cocaine use during pregnancy has been associated with a number of multiorgan dysfunctions in the infant (Table 54.4) (111). 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 (118,119). 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 (128,129). 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.
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 (128,129). 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.
Adverse Effects of Cocaine Exposure in Childhood and Adolescence: Long-Term Outcome
Long-term effects associated with prenatal cocaine exposure include impaired growth, behavior, language, cognition/executive functioning, and achievement, and increased predisposition to drug use (130,131). The effect of prenatal cocaine exposure on growth throughout childhood has been equivocal. In a longitudinal analysis of the effects of prenatal cocaine exposure on growth, from 1 to 10 years of age, the study showed that those who were prenatally exposed to cocaine grew at a slower rate than those who were not exposed, suggesting that prenatal cocaine exposure has a lasting effect on growth and development (132). A cross-sectional analysis revealed that at 10 years of age, children with prenatal cocaine exposure had lower weight, length, and head circumference than those who were not exposed. In contrast, others have reported that at 6 years of age, children with prenatal cocaine exposure were similar in weight to nonexposed children, but being SGA at birth had a detrimental effect on childhood growth (133). Earlier studies showed catch-up growth in weight and length among those exposed to cocaine, but head circumference continued to be smaller than those who were not exposed. Among children aged 10 to 14 years, those with prenatal cocaine exposure had lower cortical gray matter and total parenchymal volumes on MRI as well as smaller head circumference than those without cocaine exposure.
The effects of prenatal cocaine exposure on growth and development may predispose to cardiometabolic diseases later in life. In the Maternal Lifestyle Study, children with prenatal cocaine exposure were four times more likely to be obese (OR 4.11, CI: 2.04 to 9.76) than children not exposed at 9-year follow-up (134). Prenatal cocaine exposure was also associated with increased body mass index (BMI) and hypertension; possibly, cocaine exposure has an indirect effect on systolic and diastolic blood pressures that is mediated through its effect on BMI.
Language delays from childhood to early adolescence have been associated with prenatal cocaine exposure (135). In a study of preschool children with and without cocaine exposure, the more heavily exposed infants had lower auditory comprehension and delayed total language scores, suggesting that receptive language was compromised with prenatal cocaine exposure with a dose-dependent relationship. Further, longitudinal analysis of children from childhood to early adolescence revealed that prenatal cocaine exposure was associated with lower functioning in expressive and total language scores after adjusting for covariates compared to nonexposed children. These results suggest that cocaine exposure has a stable enduring negative effect on children’s language abilities (136).
Prenatal cocaine exposure has been associated with subtle cognitive impairment but with serious public health implications in terms of productivity and academic success of these children. Children with prenatal cocaine exposure invariably have deficits in executive functioning such as visual-motor ability, attention, organization, and working memory (131,132). As in language, the effects of prenatal cocaine exposure on cognition and learning are evident early, as shown by the Maternal Lifestyle Study, which reported that infants with prenatal cocaine and opiate exposure had the greatest autonomic response to visual attention task at 1 month of age, possibly increasing the risk for problems associated with physiologic and behavioral regulation, which in turn could adversely affect early learning (122). Further, prenatal cocaine exposure alone and in combination with other drugs was associated with subtle microstructural CNS changes detected by diffusion tensor imaging, an advanced MRI technique for white matter tracts, suggesting less mature development of frontal white matter pathways (137). Nonetheless, many studies report that prenatal cocaine exposure was not as strong a predictor of IQ or school readiness among children (138,139,140) as previously reported (141). An adequate home environment for rearing may be a stronger determinant of children’s outcome than prenatal cocaine exposure per se (140). Singer et al. (139) reported that the quality of the caregiving environment was the strongest independent predictor of cognitive outcomes and an adequate home environment resulted in similar IQ scores between exposed and nonexposed children. Prenatal cocaine exposure also increased the likelihood of receiving an individualized education plan and support services, which also favors improved cognitive outcome (142). However, Morrow et al. reported a 2.8-fold higher risk of learning disabilities among children with prenatal cocaine exposure compared to those without exposure (143). Other studies report either no adverse effects of prenatal cocaine exposure to school achievement or attenuation of adverse effects of prior cocaine by environmental variables, primary of which is a suitable living condition (141). Similarly, prenatal cocaine exposure significantly increased the risk of less favorable adolescent functioning including behavior, cognition/school performance, brain structure/function, and physiologic responses, as shown in a systematic analysis (143). However, the increased risk of adverse outcome in adolescents is modified by the caregiving environment and violence exposure.
Abnormal behavior, which includes impairment in the areas of self-regulation, excitability/hyperactivity, attention, affect, externalizing/internalizing behavior, and adaptability, has been associated with prenatal cocaine as early as the first year of life, persisting into adolescence (144,145,146). However, others have reported that behavioral problems among preschool-aged and school-aged children were not related to cocaine exposure alone but in combination with other risk factors (147). Prenatal cocaine exposure has been associated with psychological disorders such as depression, anxiety, attention deficit hyperactivity, and oppositional defiant disorder, including an increased frequency of suicidal ideations. The vulnerability of the developing brain at the time of cocaine exposure may be a risk factor in the development of these conditions. Magnetic resonance brain imaging data and volumetric analysis among adolescents between 13 and 15 years of age showed that cortical thickness was smaller in those with prenatal cocaine exposure than controls and was associated with increased impulsivity, which predisposes to increased risk-taking behaviors (148). In the Maternal Lifestyle Study, delinquent behavior, substance use, and sexual activity among adolescents were higher in those with prenatal cocaine exposure than those without (149). Moreover, prenatal cocaine exposure predisposed to postnatal adolescent cocaine use (150). Initiation of substance use among adolescents may be mediated by neurobehavioral disinhibition, which is higher in adolescents with prenatal cocaine exposure than those without. In contrast, Warner et al. (151) reported no direct relationship between prenatal cocaine exposure and adolescent cocaine use, but those with prenatal exposure displayed more externalizing and social problems including experimentation with other substances.
Many of the adverse long-term outcomes in the infants are not exclusively the effects of prenatal cocaine exposure alone but the influence of other important factors such as aberrant parental behavior and interaction with the child, poor home environment, poor caregiving skills, abnormal maternal psychological functions, and low socioeconomic status. Maternal cocaine use adversely affects infant development by disrupting parental behavior including altered maternal sensitivity to infant cries, dissociation, inappropriate reaction to infant cues, and increased aggression (152).
Prenatal cocaine exposure has been associated variably with SIDS (153). However, in a large cohort of infants, prenatal drug exposure was not associated with an overall increase in mortality
rate or SIDS during the first 2 years of life, except for a subset of LBW infants wherein mortality was higher in those who were positive for both cocaine and opiate than those who were nonexposed (154). After controlling for concurrent use of other drugs, a metaanalysis did not attribute SIDS to prenatal cocaine exposure alone (155). In addition, a higher degree of child neglect is reported in those with prenatal cocaine exposure, but more importantly, it was increased in those with ongoing active substance abuse.
rate or SIDS during the first 2 years of life, except for a subset of LBW infants wherein mortality was higher in those who were positive for both cocaine and opiate than those who were nonexposed (154). After controlling for concurrent use of other drugs, a metaanalysis did not attribute SIDS to prenatal cocaine exposure alone (155). In addition, a higher degree of child neglect is reported in those with prenatal cocaine exposure, but more importantly, it was increased in those with ongoing active substance abuse.
The exposure of the infant to cocaine can be ongoing after birth through breastfeeding, intentional administration of the drug by caregivers, accidental ingestion of cocaine or cocaine-contaminated household dust via normal hand-to-mouth activity, or passive inhalation of cocaine smoke during freebasing activities of adults (156). Cocaine and benzoylecgonine have been found in the hair, saliva, skin, and urine of these children. Morbidities from postnatal cocaine exposure have included seizures, drowsiness, unsteady gait, diarrhea, shock, and death (157). Neurologic manifestations were observed with cocaine intoxication among children presenting at an urban emergency room that included seizures (focal or generalized), obtundation, delirium, dizziness, drooling, and ataxia (158). Passive ingestion/inhalation is the most common route of exposure when children are in the presence of caregivers actively using cocaine.
▪ ALCOHOL
The use or abuse of alcohol during pregnancy has serious effects on the fetus and newborn. The adverse effects of alcohol on the offspring have been observed for centuries, although the fetal alcohol syndrome (FAS) was not defined as a medical entity until 1973. Infants born to alcoholic parents may have dysmorphic features and are subsequently observed to have a higher than expected incidence of delayed growth and development and of neurologic disorders (159). Excellent reviews on this topic have been written (160,161).
Epidemiology
More than half of Americans aged 12 years or older (52.1%) reported being current drinkers of alcohol in a recent report from the National Household Survey on Drug Abuse (162). Among pregnant women aged 15 to 44 years in 2011 and 2012, a yearly average of 8.5% reported current use of alcohol, 2.7% reported binge drinking, and 0.3% were heavy drinkers (162). A variety of programs have been developed to prevent drinking during pregnancy, such as public service announcements and beverage warning labels, which strive to increase public knowledge about how alcohol effects the fetus. Selective prevention approaches to women of reproductive age involve screening all pregnant women for alcohol consumption and counseling for those who drink (163). It has been shown that pregnant adolescents with knowledge about drinking, especially those with specific knowledge of FAS, drank less before pregnancy. Among drinkers, general knowledge was significantly related to a decrease in drinking between prepregnancy and first trimester and between first trimester and third trimester (163).
Attempts to standardize terms such as “light,” “moderate,” and “heavy” alcohol consumption resulted in the following operational definitions: “light” drinking as 1.2 drinks per day, “moderate” as 2.2 drinks per day, and heavy drinking as 3.5 drinks per day (164). Alcohol use may also be defined in three ways: current (past month) use—at least one drink in the last 30 days; binge use—four or more drinks for females and five or more drinks for males on one occasion on at least 1 day in the last 30 days; and heavy use— five or more drinks on the same occasion on each of 5 or more days in the last 30 days. Although most of the women who report alcohol use are light drinkers, those who drink heavily are more likely young, white, single, to have higher education and income, and to be employed outside the home. However, women who drink during pregnancy, and particularly those who are binge drinking or continue to drink through the third trimester or have children with FAS, are older (14.3% are aged 35 to 44), unemployed, single, and more likely black and have higher rates of illicit drug use, less education, and lower social status (165). These women also tend to have no prenatal care and have more live born children. About 9% to 29% have another child with suspected alcohol effects. When compared to other mothers, they are more likely to be on public assistance at the time of delivery, to have had treatment for alcohol abuse, or to have been confirmed to have alcoholism. They are more likely to have used marijuana or cocaine during pregnancy, are more likely to have had induced abortion, and are more likely to drink heavily or be involved in binge drinking during pregnancy (166). They also have higher levels of psychopathology such as depression, psychopathic deviance, schizophrenia, and social introversion. In one survey, almost half (45%) of all pregnant women drank alcohol during the first 3 months before finding out they were pregnant (167).
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