Since the earliest days of recorded history, mood-altering drugs have been used for pleasurable purposes. While the effects of the use of one of these agents (alcohol) on the developing fetus during pregnancy was observed in antiquity, it has only been in the past 10 to 15 years that the full scope of the problem of abuse of psychoactive drugs during pregnancy has been recognized.
Narcotics, alcohol, barbiturates, tranquilizers, analgesics, nicotine, cocaine, amphetamines, marijuana, and psychedelic drugs (such as LSD) are used extensively during pregnancy, either alone or in combination (Table 1). All of these drugs freely cross the placenta and may affect both the developing fetus and the newborn infant. Since multipledrug abuse is extremely common, it is often difficult, if not impossible, to associate a specific drug with either signs of neonatal withdrawal or teratogenic effects in any particular infant. In addition, non-drug-related factors, such as intrauterine infection and genetic disorders, may lead to congenital malformations.
While much attention in recent years has been focused on the problems associated with narcotic abuse, use of nonnarcotic agents during pregnancy is far more widespread and poses an increasingly serious problem.
PSYCHOACTIVE DRUGS COMMONLY USED DURING PREGNANCY
Since the effects of smoking on the fetus and newborn infant were discussed in the March, 1978, issue of Pediatrics Annals,1 this article will review abuse of drugs other than tobacco during pregnancy.
Until about 1970, heroin (diacetylmorphine) was the most common narcotic agent used during pregnancy. By this time, the problem had reached epidemic proportions in many urban areas in the United States, with at least 2,000 to 3,000 pregnant addicts delivering infants each year in New York City alone. Methadone, a synthetic narcotic agent that blocks the euphoric effects of heroin and lessens the craving for this drug in addicted subjects,2 began to gain acceptance as a therapeutic agent for the treatment of heroin dependence at about this time. It has been used with increasing frequency in management of narcotic addiction during pregnancy, so that at present methadone has become the most commonly used opiate during pregnancy.3"6 It is used either as a single agent by wellcontrolled women enrolled in methadone maintenance programs or in combination with heroin or other drugs of abuse, such as alcohol, marijuana, or cocaine.
Both heroin and methadone have profound effects on the fetus and newborn infant (Table 2). If drug intake is suddenly stopped or if there is a substantial decrease in dosage, fetal withdrawal may occur. Fetal growth and development may be affected. Following delivery, a neonatal abstinence syndrome may be observed. In addition, the psychosocial aspects of maternal use of narcotics may have a great influence on long-term development of the infant.
Heroin. Heroin dependence develops in the majority of fetuses of women who are addicted to this drug during pregnancy.8 Some fetuses do not become addicted. This may be due to both the relatively small quantity of heroin actually present in the glassine envelopes (which sell on the streets for up to $75.00 each) and the casual rather than steady use of the agent by many women. Fetal narcotic withdrawal is manifested clinically by hyperactivity. Hypoxia, accompanied by passage of meconium, and fetal death may occur.
Intrauterine exposure to heroin is associated with both intrauterine growth retardation and prematurity, with about 50 percent of these infants weighing less than 2,500 gm. at birth. The impaired rate of intrauterine growth appears to be due to a direct action of the drug on the fetus rather than to poor maternal nutrition; however, several factors may be operative. The increased incidence of prematurity may be associated wirh a high rate of intrauterine infection in this group of women.9
Most infants of narcotic users are vigorous at birth and have Apgar scores of 7 to 10. Respiratory depression secondary to exposure to a very high dose of heroin just before delivery is not common. However, if the neonate is depressed, naloxone, in a dose of 0.01 mg./ kg., may be administered parenterally.10 If a rapid response to this drug is not observed, it is probable that the respiratory depression is secondary to hypoxia, and resuscitative measures should be started.
EFFECTS OF NARCOTICS ON THE FETUS
An abstinence syndrome usually develops within the first 24 hours after delivery but may occasionally first be observed on the second or third day of life11"13 (Table 3). If withdrawal has begun in utero,8 clinical manifestations may be observed in the delivery room. The two major signs of the neonatal abstinence syndrome are a unique type of coarse, flapping tremor and irritability. Hyperactivity is almost always noted, and muscular rigidity is commonly observed. Other manifestations include a shrill, high-pitched cry, vomiting, diarrhea, excessive sweating, sleep disturbances, sneezing, yawning, poor feeding and weight gain, and rapid respiration in the absence of pulmonary pathology. The hyperventilation is often associated with a primary respiratory alkalosis.14 The respiratory distress syndrome is infrequently observed,15 even in infants of very low gestational age. This is thought to be due to an in utero maturational effect of heroin on pulmonary surfactant production. Mortality is rare, and when it does occur it is usually secondary to extreme prematurity, infection or intrauterine asphyxia. There is no present evidence that intrauterine exposure to narcotics has a teratogenic effect. However, this possibility has not been completely eliminated.
SIGNS OF NEONATAL NARCOTIC WITHDRAWAL
Treatment (Table 4) should be instituted as early in pregnancy as possible. Unfortunately, many pregnant addicts either seek no antenatal care or are seen for the first time late in pregnancy. Substitution of methadone for heroin, in the lowest possible dosage necessary to prevent a craving for the latter drug (usually about 30 mg./day, taken orally), appears to be the optimal therapeutic approach.3"6 This is done through methadone maintenance programs, in which the patient also receives strong psychologic and social support. Attempting to achieve a drug-free state during pregnancy may lead to intrauterine hypoxia and further use of drugs later on in pregnancy.
TREATMENT OF NEONATAL NARCOTIC WITHDRAWAL
In order to successfully treat the neonatal withdrawal syndrome, it is important to know if the mother had been concurrently using nonnarcotic drugs. Such agents as barbiturates, tranquilizers, and nonnarcotic analgesics may produce clinical signs similar to those seen in narcotic withdrawal. Since the maternal history may not be completely accurate, chromatographic examination of the urine of mother or infant will identify metabolites of both narcotic and nonnarcotic drugs.
The postnatal treatment of heroin withdrawal consists of specific therapy, aimed at alleviating major neurologic signs, and supportive therapy, such as treatment of infection; provision of adequate fluid, electrolytes, and calories; and correction of such metabolic defects as hypoglycemia and hypocalcemia.
Several pharmacologic agents are currently being used to treat neonatal narcotic withdrawal.16 Paregoric (camphorated tincture of opium), containing 0.4 mg. of morphine per ml., has been used successfully for many years. The usual dose is 1 to 3 drops/kg. administered every four hours, before feeding. The full dosage is usually required for one to two weeks, with tapering of the dosage carried out over the next several weeks.
Chlorpromazine and phénobarbital have been used in many nurseries, with about equal efficacy.17 Both of these agents appear to sedate the infant to a greater degree than paregoric, and this may not be ideal. Chlorpromazine is usually administered orally in a dose of 2 to 3 mg./kg./day, in four divided doses. If the infant is vomiting, the drug may be given intramuscularly. A full dosage is usually required for about one week, with tapering over the next one to two weeks. Phénobarbital, in a dose of 8 to 10 mg./kg./ day, in two or three divided doses, usually controls clinical signs. Like chlorpromazine, it may be administered either orally or intramuscularly. The full dose is generally maintained for about one week and is tapered over the next two to three weeks.
The vast majority of these infants respond well to medical management and are asymptomatic within a few weeks. However, the long-term outlook may be complicated by the less than optimal life style of the addicted parents. Strong social and psychologic support of the family, along with enrollment of the parents in a rehabilitation program, is necessary to bring about some stabilization of the home situation. Not infrequently, these parents are found by child-welfare agencies to be incapable of providing proper care for their infants, and placement either in a foster home or with relatives may be necessary.
Methadone. Unlike heroin, exposure to methadone in utero is not associated with an increased incidence of intrauterine growth retardation or prematurity. If the mother is under careful control, the pregnancy usually proceeds smoothly, with few antenatal problems encountered. With the high doses of methadone (up to 120 mg./day) used to maintain the pregnant addict during the early 1970s, a relatively severe and prolonged neonatal withdrawal syndrome was encountered.28 Seizures, rarely encountered among infants exposed to heroin in utero, occur in about 8 percent of these infants.
However, with the low doses currently being used, signs of neonatal withdrawal from this synthetic narcotic tend to be relatively mild.20 In general, signs of withdrawal occur at a somewhat later time after birth than is observed with heroin withdrawal, often the second or third day of life. Occasionally, initial signs of methadone withdrawal may be observed after the first week.21 Treatment is essentially the same as that for heroin withdrawal.
Two late complications of neonatal methadone withdrawal that have recently been described are an increased incidence of the sudden- infant-death syndrome22 and markedly elevated platelet levels.23
Long-term developmental studies of infants exposed to methadone in utero are currently in progress.
Alcohol. While the adverse effects of maternal alcohol intake were noted over 2,000 years ago in Mediterranean civilizations and well recognized in Great Britain during the 19th century, our present understanding of effects of alcohol on the fetus and neonate is based on recent clinical and experimental observations.24"26 Alcohol readily crosses the placenta and enters the fetal circulation. With heavy, persistent maternal intake (Ouellette et al.25 consider this to be an average daily intake of more than 45 ml. of absolute alcohol), there is very high risk of perinatal mortality, damage to the central nervous system, with subsequent psychomotor retardation, a decreased rate of fetal and postnatal growth, and a high incidence of congenital anomalies.26 Some of the adverse effects of exposure to alcohol may be related to the extremely low levels of the enzyme alcohol dehydrogenase present in the fetal liver. In addition, a neonatal withdrawal syndrome secondary to intrauterine exposure to alcohol has been described.27
In the Collaborative Perinatal Project of the National Institute of Neurologic Disease and Stroke, 23 infants of chronic alcoholic mothers had a perinatal mortality of 17 per cent, with a 44 per cent incidence of mental retardation among survivors.28 Hanson et al. have described a set of findings that are commonly observed among infants born to mothers who are heavy users of alcohol.24 Among these (Table 5) are a marked decrease in antenatal and postnatal linear growth, microcephaly, craniofacial abnormalities - including short palpebral fissures, microphthalmia, maxillary hypoplasia, epicanthic folds, and cleft palate - abnormal palmar creases, and congenital malformations of the brain, skeletal system, heart, genitourinary tract, and joints. These findings have led to the common usage of the term "fetal alcohol syndrome" to describe the appearance of many infants born to alcoholic mothers. However, in one series,25 while the incidence of growth retardation and congenital anomalies was markedly increased in infants of women with heavy alcohol intake during pregnancy, the specific pattern of anomalies commonly associated with the fetal alcohol syndrome was not observed. The larger the volume of ethanol consumed during pregnancy, the more likely it is that "fetal alcohol syndrome" will develop. A crude "dose response" can be established.25
Moderate consumption of alcohol, both before pregnancy and during late pregnancy, may be associated with decreased birth weight in the absence of congenital anomalies. 29,3° The concurrent use of tobacco and alcohol during pregnancy may have an adverse synergistic effect on neonatal learning processes.31
Following delivery, the infant may appear depressed and lethargic, with a low Apgar score. This is due to the soporific effects of maternal ingestion of a large quantity of alcohol just before or during delivery.32 The odor of alcohol may be apparent in the infant's breath as well as in the mother's. (The therapeutic administration of an excessive amount of alcohol in an attempt to halt premature labor may produce similar findings.) Gastritis, emesis, and hypoglycemia may be present in these infants.
CLINICAL FEATURES OF THE FETAL ALCOHOL SYNDROME
The tremulo usness, hyperactivity, irritability, and occasional frank convulsions observed in infants undergoing withdrawal symptoms following intrauterine exposure to alcohol are similar to what is observed following narcotic withdrawal.27 Short-term treatment with chlorpromazine or phenobarbital, in doses similar to those used for narcotic withdrawal, appears to relieve symptoms.
The long-term outlook for many of these infants is poor. In addition to retarded linear growth and weight gain, there may be motor dysfunction and development delay. The extremely high incidence of mental retardation may be secondary to structural malformations of the brain stemming from errors in migration of neuronal and glial elements,32 as well as generally impaired brain growth.
While it is now evident that moderate or large intake of alcohol during pregnancy is deleterious to fetal growth and development, the effects of casual use of alcohol are not currently known. Since alcohol is a known teratogen, its avoidance, at least during the first trimester of pregnancy, would appear prudent.
Barbiturates and tranquilizers. While barbiturates are prescribed therapeutically in pregnancy as anticonvulsants and sedatives, they are frequently used in a nontherapeutic manner for their mood-altering effects. Prolonged intrauterine exposure may lead to physical dependence on these agents, and postnatal withdrawal may lead to symptoms similar to those observed following narcotic withdrawal.34,35 Although there is uncertainty as to the relationship of maternal intake to physical dependence in the fetus, neonatal withdrawal has been observed following a maternal daily dose of phenobarbital of 60 mg./ day.35
The clinical picture observed in these infants is similar to that seen with narcotic withdrawal, with a relatively high incidence of seizures. With short-acting barbiturates, such as pentobarbital and secobarbital, withdrawal may be observed soon after delivery. However, with a long-acting agent, such as phenobarbital, which has a prolonged half life in the neonate, signs of withdrawal may not be evident until a week after birth, by which time the infant may have been discharged from the nursery.
Treatment consists of the administration of phenobarbital in a dose similar to that used in narcotic withdrawal. The course of treatment is usually 10 days to two weeks, followed by tapering of the dose over the next week. While no long-term neurologic sequelae have been described, these infants may remain irritable for several months.
There is no current evidence of an increased incidence of congenital anomalies in infants whose mothers have used barbiturates during pregnancy (in contrast to diphenylhydantoin, whose use during pregnancy is associated with an increased incidence of cleft palate and harelip).
Tranquilizers, sedatives, and analgesics. A neonatal abstinence syndrome has been described following maternal use of diazepam,36 chlordiazepoxide,37 hydroxyzine,38 glutethimide,39 and ethchlorvynol.40 This picture is comparable to that seen in narcotic withdrawal. In view of the large-scale use of these agents during pregnancy and the very few case reports describing a neonatal withdrawal syndrome, the risk of fetal dependence following intrauterine exposure to these agents appears to be slight. Nonetheless, these drugs should be used with extreme caution during pregnancy.
The analgesic agents propoxyphene and pentazocine are structurally similar to narcotic agents. Neonatal withdrawal, similar to that occurring following maternal use of narcotics, has been described following intrauterine exposure to these agents.41,42
Cocaine and amphetamines. Cocaine and amphetamines are sympathomimetic drugs whose systemic effects include decreased fatigue and a sense of euphoria. While no neonatal withdrawal syndrome or neurologic sequelae have been described following maternal use of these drugs, there is experimental evidence that amphetamines are teratogenic and may cause behavior disturbances in experimental animals following intrauterine exposure.43
Marijuana. Despite its widespread use during pregnancy, there is no evidence that marijuana affects the human fetus.43 Although there are a few case reports of congenital anomalies in infants born to these mothers, the concurrent use of other drugs in these cases casts some doubt on the teratogenic potential of marijuana.44,45 Since immunologic defects have been reported following the use of marijuana, 46 it is possible that intrauterine exposure to marijuana interferes with fetal immunologic competence.
Lysergic acid diethylamide (LSD). LSD is teratogenic in experimental animals and may cause chromosomal breakage in adult humans.47 While congenital anomalies have been reported in infants of mothers using LSD together with other illicit drugs,44,45 there is no clear-cut evidence that this agent is teratogenic in humans. However, an increased incidence of spontaneous abortion has been observed in these women.43
The vast majority of pharmacologic agents cross the placenta and enter the fetal circulation. In the administration of any drug during pregnancy (for either therapeutic or pleasurable reasons) benefits must be weighed against potential risk to the fetus. Since mood-altering drugs have minimal, if any, therapeutic benefit and an extremely high risk of adverse effects on the fetus, their widespread use during pregnancy must be viewed as a great cause for concern in this country.
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2. Dole, V. P., and Niswander, M. E. A medical treatment for diacetylmorphine (heroin) addiction J. A. M. A. 193 (1965), 646.
3. Harper, R. G., et al. The effect of a methadone treatment program upon pregnant heroin addicts and their newborn infants. Pediatrics 54 (1974), 300.
4. Strauss, M. E., et al. Methadone maintenance during pregnancy. Pregnancy, birth, and neonate characteristics. Am. J. Obstet. Gynecol. 120 (1974), 895.
5. Stimmet, B., and Adamsons, K. Narcotic dependency in pregnancy. Methadone maintenance compared to street drugs. J.A.M.A. 235 (1976), 1121.
6. Finnegan, L. P., et al. Methadone maintenance and detoxification programs for the opiate-dependent woman during pregnancy A comparison. In Rementeria, J. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C. V. Mosby Company, 1977, p. 40.
7. Glass, L., and Evans, H. E. Physiological effects of intrauterine exposure to narcotics. In Rementeria, ]. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C. V. Mosby Company, 1977, p. 108.
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9. Naeye, R. L., et al. Fetal complications of maternal heroin addiction: abnormal growth, infections, episodes of stress. J. Pediatr. 83 (1973), 1055.
10. Gerhardt, T., et al. Use of naloxone to reverse narcotic respiratory depression in the newborn infant. J. Pediatr. 90 (1977), 1009.
11. Zelson, C, Lee, S. ]., and Casaline M. Neonatal narcotic addiction. N. Engl. J. Med. 289 (1973), 1216.
12. Glass, L. The neonate in withdrawal - identification, diagnosis, and treatment. Pediatr. Ann. 4 (1975), 384.
13. Pierog, S. H. The infant in narcotic withdrawal: Clinical picture. In Rementeria, J. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C V. Mosby Company, 1977, p. 95.
14. Glass, L., et al. Effect of heroin withdrawal on respiratory rate and acid base status in the newborn. N. Engl. ]. Med. 286 (1972), 746.
15. Glass, L., Rajegowda, B. K., and Evans, H. E. Absence of respiratory distress syndrome in premature infants of heroin addicted mothers. Lancet 1 (1971), 685.
16. Harper, R. G., and Edwards, G. B. Management of the neonatal narcotic withdrawal syndrome. In Rementeria, J. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C V. Mosby Company, 1977, p. 103.
17. Kahn, E. J., Neumann, L., and Polk, G. The course of the heroin withdrawal syndrome in newborn infants treated with phenobarbital or chlorpromazine. J. Pediatr. 75 (1969), 495.
18. Rajegowda, B. K., et al. Methadone withdrawal in newborn infants. J. Pediatr. 81 (1972), 532.
19. Herzlinger, R. A., Kandall, S. R., and Vaughan, H. F., Jr. Neonatal seizures associated with narcotic withdrawal. J. Pediatr. 91 (1977), 638.
20. Harper, R. G., et al. Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome. Am. J. Obstet. Gynecol. 129 (1977), 417.
21. Kandall, S. R., and Gartner, L. M. Late presentation of drug withdrawal symptoms in newborns. Am. J. Dis. Child. 127 (1974), 58.
22. Rajegowda, B. K., Kandall, S. R., and Falciglia, H. Sudden infant death (SIDS) in infants of narcotic addicted mothers. Pediatr. Res. W (1976), 334.
23. Burstein, Y., et al. Prolonged isolated thrombocytosis in infants of polydrug abusers. Pediatr. Res. 12 (1978), 461.
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25. Ouellette, E. M., et al. Adverse effects on offspring of maternal alcohol use during pregnancy. N. Engl. ]. Med. 297 (1977), 528.
26. Jones, K. L. Fetal alcohol syndrome. In Rementeria, J. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C V. Mosby Company, 1977, p. 157.
27. Pierog, S-, Chandavasu, O., and Wexler, I. Withdrawal symptoms in infants with fetal alcohol syndrome. J. Pediatr. 90 (1977), 630.
28. Jones, K. L., et al. Outcome in offspring of chronic alcoholic mothers. Lancet 1 (1974), 1076.
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30. Little, R. E. Moderate alcohol use during pregnancy and decreased infant birth weight. Am. J. Pub. Health 67 (1977), 1154.
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33. darren, S. K., et al. Brain malformations related to prenatal exposure to ethanol. J. Pediatr. 92 (1978), 64.
34. Bleger, W., and Marshall, R. C Barbiturate withdrawal syndrome in a passively addicted infant. J.A.M.A. 221 (1972), 185.
35. Desmond, M. M., et al. Maternal barbiturate utilization and neonatal withdrawal symptomatology. J. Pediatr. 80 (1962), 190.
36. Rementeria, J. L., and Bhatt, K. Withdrawal symptoms in neonates from intrauterine exposure to diazepam. J. Pediatr. 90 (1977), 123.
37. Athinarayanan, P., et al. Chlordiazepoxide withdrawal in the neonate. Am. J. Obstet. Gynecol. 124 (1976), 212.
38. Prenner, B. M. Neonatal withdrawal syndrome associated with hydroxyzine hydrochloride. Am. J. Dis. Child. 131 (1977), 529.
39. Reveri, M., Pyati, S. P., and Pildes, R. S. Neonatal withdrawal symptoms associated with glutethimide (Doriden) addiction in the mother during pregnancy. Clin. Pediatr. 16 (1977), 424.
40. Rumack, B. H., and Walravens, P. A. Neonatal withdrawal following maternal ingestion of ethchlorvynol (Placidyl). Pediatrics 52 (1973), 714.
41. Klein, R. B., Blatman, S-, and Little, G. A. Probable neonatal propoxyphene withdrawal: a case report. Pediatrics 55 (1975), 882.
42. Goetz, R. L., and Bain, R. V. Neonatal withdrawal symptoms associated with maternal use of pentazocine. J. Pediatr. 84 (1974), 88.
43. Evans, M. A., and Harbison, R. D. Cocaine, marijuana, LSD. Pharmacologic effects in the fetus and newborn. In Rementeria, J. L. (ed.). Drug Abuse in Pregnancy and Neonatal Effects. Saint Louis: C V. Mosby Company, 1977, p. 195.
44. Hecht, F., et al. Lysergic acid diethylamide and cannabis as possible teratogens in man. Lancet 2 (1968), 1087.
45. Carakushansky, G., New, R. L., and Gardner, L. I. Lysergide and cannabis as possible teratogens in man. Lancet 1 (196), 150.
46. Nahas, G. G., et al. Inhibition of cellular mediated immunity in marijuana smokers. Sdence 183 (1974), 419.
47. Dishotsky, N. I., et al. LSD and genetic damage. Science 172 (1971), 431.
PSYCHOACTIVE DRUGS COMMONLY USED DURING PREGNANCY
EFFECTS OF NARCOTICS ON THE FETUS
SIGNS OF NEONATAL NARCOTIC WITHDRAWAL
TREATMENT OF NEONATAL NARCOTIC WITHDRAWAL
CLINICAL FEATURES OF THE FETAL ALCOHOL SYNDROME