In 2001, the National Household Survey on Drug Abuse estimated that 15.9 million (7.1%) Americans of age 12 years or older were current illicit drug users (1). This represents an increase from 6.3 percent in 1999 and 2000 (Table 58-1). Between 2000 and 2001, statistically significant increases were also noted for the current use of marijuana (4.8%-5.4%), cocaine (0.5%-0.7%), psychotherapeutic drugs (1.7%-2.1%) and hallucinogens (0.4-0.6%). Current heroin use was estimated at 0.1%. Marijuana was the most commonly used illicit drug. Approximately 56% consumed only marijuana, 20% used marijuana and another illicit drug, and the remaining 24% used an illicit drug but not marijuana in the past month. Thus, about 44 percent of current illicit drug users in 2001 (7 million Americans) used illicit drugs other than marijuana and hashish, with or without using marijuana as well.

The rate of drug use substantially varied by age. Among youths 12 to 17 years of age, 10.8% were current illicit drug users which tended to increase with age and peaked at age 18 to 20 years (22.4%). By race, the rate of current illicit drug use was 7.4% for blacks, 7.2% for whites (6.1%), and 6.4% for Hispanics. The rate was highest among American Indians/Alaskan natives (9.9%). As in prior years, men continue to have a higher rate of current illicit drug use than women (8.7% vs. 5.5%). Illicit drug use remains highly correlated with educational status and employment. Those who did not complete a high school education had the highest rate of use (7.6%) compared to college graduates (4.3%). Similarly, the rate of illicit drug use was 17.1% among unemployed adults (18 years of older) compared to 6.9% of full time employed adults. Among pregnant women, aged 15 to 44 years, 3.7% reported using illicit drugs. The rate was highest among pregnant women aged 15 to 17 years (15.1%). Rates of illicit drug use among pregnant women aged 18 to 25 and 26 to 44 years were 5.6% and 1.6%, respectively. The rates of current illicit drug use were similar for white (4.0%), black (3.7%), and Hispanic (3.3%) pregnant women. However, the true prevalence of illicit drug use among pregnant women is difficult to determine, as a result of significant underreporting of drug use by these women. One study, based on a survey using maternal history, urine toxicology, or both, of predominantly urban hospitals, gave an estimate of drug use among pregnant women as 0.4% to 27%; cocaine use ranged from 0.2% to 17%. With the use of a more sensitive drug screening method (e.g., meconium drug test), a 44% prevalence of illicit drug use was found among pregnant women in a high risk center in contrast to 11% by maternal self-report and 30% of the infants were positive for cocaine (2). The association of illicit drug use with HIV infection in pregnant women is high. Use of hard drugs was 42% in a cohort of HIV-infected pregnant women and was further associated
with positive maternal HIV culture at delivery and perinatal transmission (3).

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, whereas the synthetic opiates include heroin, methadone, propoxyohene (Darvon), pentazocine (Talwin), meperidine (Demerol), oxycodone (Percodan, Tylox, Vecodine, Percocet), hydromorphone (Dilaudid), and fentanyl (Immovar, Sublimaze). Chronic use of narcotics, even in therapeutic doses, results in addiction, which is characterized by psychological and physical dependence on the drug.

Opium use probably dates back to about 6,000 years. One of the earliest references to opiate complications in the perinatal period was made by Hippocrates, who mentioned “uterine suffocation” as possibly secondary to opium use. By the late nineteenth and early twentieth century, reference to the passively addicted neonate is evident from reports describing the diffusion of morphine through the placenta and transmission through the breast milk (4). The naturally occurring opiates, morphine and codeine, are derived from the seeds of the unripe poppy plant, Papaver somniferum, and were consumed for their narcotic and analgesic properties. Heroin (diacetylmorphine), a semisynthetic opioid, was first introduced in 1874. It became popular because of the rapid onset of its central nervous system (CNS) effects. By 1950, heroin had supplanted morphine as the drug of choice among abusers (5). It is available illicitly in bags containing up to 40 to 50 mg of the active ingredient, cut or diluted variably with quinine, lactose, starch, lidocaine, or even powdered milk. Methadone was first synthesized in 1945. It is longer-acting than heroin, and can be administered orally. These properties render it the drug of choice for replacement therapy of heroin addicts undergoing detoxification. Because Dole and Nyswander (6) advocated the use of methadone in maintenance treatment programs, it has become the most widely used and studied opiate in pregnancy. However, methadone treatment of the opioid dependent pregnant woman has also led to significant withdrawal in the infant (7).

Almost all narcotics 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 morphine, many other important problems are encountered (Table 58-2).

Intrauterine asphyxia is perhaps the single greatest risk to the fetus of a drug-dependent woman based on reports of a high incidence of stillbirths, meconium-stained amniotic fluid, fetal distress, non reactive stress test, low Apgar score, and neonatal aspiration pneumonia (8,9,10,11,12). 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 lead to a hyperactive state that causes a 20% increase in fetal oxygen consumption (13). 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 (14,15). 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 (16). In a lamb model, withdrawal was induced in the morphine-exposed fetal lamb by the administration of naloxone, an opiate antagonist. Manifestations included immediate bradycardia associated with transient increases in systolic and diastolic blood pressure, rapid, continuous deep breathing movements, increased total body movements, eye movements and neck tone, and desynchronization of electrocortical activity (15). A high incidence of preeclampsia, abruptio placentae and placenta previa in the pregnant addict also predispose to placental insufficiency and fetal distress (7).

Meconium-stained amniotic fluid is frequently encountered in the pregnant addict and is a manifestation of fetal distress (7). Aspiration of meconium as a result of fetal distress may account for the increased frequency of meco nium aspiration syndrome and persistent pulmonary hyper- tension of the newborn after birth.

Intrauterine infection is another risk in the fetus of a drug addict. Because of the life-style of the pregnant addict of


trading sex for drugs, she is predisposed to infections, particularly of sexually transmitted diseases such as syphilis, gonorrhea, hepatitis and HIV infection, all of which can be transmitted to her fetus (2,17,18). 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 (7). Opiates may also compromise immune functions in the fetus through its adverse effect on cell-mediated and humoral immune responses (19,20).

Barbiturates have been used in clinical medicine for many years, but its addiction potential has only been recently recognized. In adults, the frequent association of barbiturate use with alcohol may have contributed to the delayed recognition of its addicting potential because of the ability of barbiturates to control the withdrawal from alcohol (89,90).

Barbiturates are classified, based on their duration of their 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 not as common as the abuse of the shorter-acting forms. Phenobarbital, however, is more frequently involved in withdrawal syndrome in the newborn because it is used frequently by the mother for insomnia, for the relief of anxiety, as an anticonvulsant, or for sedation when toxemia of pregnancy occurs.

Passive addiction of the fetus to barbiturates can occur after its prolonged exposure to the drug in utero (49,91). 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 (92). The manifestations of barbiturate withdrawal in the neonate are similar, regardless of the type of barbiturate used by the mother; however, the onset of withdrawal may differ. Withdrawal typically occurs within a day after birth with intermediate-acting barbiturates (93), and from 3 to 7 days after birth with the long-acting barbiturates (91).

Barbiturates are metabolized principally by the liver, although a significant portion may be excreted unchanged by the kidney. In adults, up to 30% of the total dose of phenobarbital ingested is excreted unchanged in the urine (94). The half-life of phenobarbital prenatally administered to infants is almost twice that in the adult, and varies inversely with the extent of the prenatal exposure to the drug (95). 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 (96).

The signs of withdrawal from barbiturates in neonates are similar to those described in adults. The infants 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 (91). A subacute phase of hyperphagia, episodes of prolonged crying, episodic irritability, hyperacusis, and sweating have been described (91). These
manifestations 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 monotherapy alone (97). Cognitive functions in infants exposed to phenobarbital, in utero, did not differ from controls, except for a higher incidence of learning problems (98).

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 long-acting barbiturates should alert the clinician to follow these infants closely during the first 2 weeks of life.

Chlordiazepoxide (Librium) and diazepam (Valium) are widely used for their hypnosedative effects. Abuse and dependence on these drugs have been reported in adults. During pregnancy, benzodiazepines cross the placenta with relative ease, resulting in significant drug levels in the serum and tissues of the fetus (99). Placental transfer of diazepam can occur from the sixth week of gestation and accumulate in the fetal tissues during organogenesis (100). 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 (101).

An acute withdrawal syndrome from chlordiazepoxide or diazepam was observed in the newborn infant (102,103). A presumptive diagnosis of chlordiazepoxide withdrawal was made in a set of twins born to a mother who used chlordiazepoxide (20 mg per day) during the second and third trimesters of her pregnancy (102). 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 (103). The dose of diazepam used by the mother up to the time of birth ranged from 15 to 20 mg per day. 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 (13-25 days). In another report, a mother used narcotics and diazepam during pregnancy. There was an initial good response of the infant to treatment for narcotic withdrawal but the withdrawal manifestations intensified at 7 to 14 days of life. The late withdrawal was attributed to prenatal diazepam exposure (104). Late third trimester use and exposure to diazepam during labor has been associated with the floppy infant syndrome, or marked neonatal withdrawal. 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 (105). High dose, intravenous administration or prolonged duration of diazepam therapy in mothers has also caused significant depression in the newborn with poor muscle tone (101,106). In one report, infants prenatally exposed to diazepam had lower birth weight compared to controls, but eventually showed catch up growth by eight months of age (107). Congenital malformations are uncommon with antenatal diazepam exposure although a case has been reported of an omphalocoele-exstrophy-imperforate anus-spina bifida complex occurring in a infant whose mother took 30 mg of diazepam daily for affective disorder during the entire pregnancy (108). Offspring of rats who were treated with chlordiazepoxide during the critical period of neural development showed significant deficits in learning acquisition and retention (109). 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 (105).

Hypnosedatives, which used to be popular in the past, have been associated with adverse effects in the newborn infants. These include chloral hydrate (110), bromide (111,112 and 113), ethchlorvynol (114,115,116,117,118 and 119), and gluthetimide (120). A withdrawal syndrome and growth retardation have been reported in newborn infants after the use of bromides by the mother during pregnancy (111,112). Studies on rat pups whose dams were given sodium bromide, ad libitum, showed significant delay in postnatal development, permanent deficits in body weight, brain weight and protein content of brain tissue but with an increased size of the olfactory glomeruli (113). Ethchlorvynol (Placidyl) was introduced in 1955 as a nonbarbiturate, non addicting hypnotic for the treatment of insomnia (114,118). However, subsequent reports of addiction to ethchlorvynol have been reported (115,116 and 117). An abstinence syndrome from ethchlorvynol was observed in a newborn infant, which consisted of extreme jitteriness, irritability, and hyperphagia (119). The drug that was taken by the mother was within the recommended therapeutic dose. The onset of withdrawal in the infant occurred during the second day of life. No convulsions were noted because the infant received phenobarbital treatment early in the course of the abstinence syndrome. Glutethimide (Doriden) was first intro duced in 1954 as a nonbarbiturate hypnosedative, allegedly free of addicting properties. As in the case of most nonbarbiturate hypnosedatives, this led to its widespread use, particularly as a substitute drug for the treatment of alcohol addiction (120). Since then, numerous reports of acute and sometimes fatal intoxication with the drug in adults and the occurrence of physical dependence have been reported (120,121 and 122). Glutethimide is structurally related to phenobarbital.

A possible case of neonatal withdrawal to glutethimide was reported in a pregnant heroin addict who supplemented her habit with 2 to 3 g of glutethimide three or
four times a week to get a desired euphoric effect (123). Within 8 hours of birth, the infant exhibited signs of withdrawal from narcotics that were readily controlled with chlorpromazine. However, on the tenth day of life, while on a tapering dose of chlorpromazine, the infant suddenly manifested diarrhea, fever, tachypnea, irritability, hypertonicity, and diaphoresis. It was presumed that the unusual recurrence of withdrawal on the tenth day of life may have been secondary to withdrawal from glutethimide.

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 examination, and cultures should be performed as indicated by the clinical circumstances.

Infants whose mothers were on tricyclic antidepressants and lithium during pregnancy for psychiatric conditions may manifest toxicity similar to withdrawal, such as irritability, tachycardia, respiratory distress, sweating, and convulsions (124,125,126,127 and 128). Likewise, 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 (129,130). The prenatal history and the identification of the corresponding drug in the infant’s serum or urine are necessary to establish the diagnosis.

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 (296,297). 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 (298,299). Excellent reviews on this topic have been written (300,301 and 302).