Substance abuse has become one of the major public health problems of the decade. As many as 20 to 30 million Americans abuse illicit substances and approximately 5 million are regular users. Current estimates are that about 225 000 US women of childbearing age are using intravenous drugs and about 9000 narcotic-exposed infants are bom each year (2 to 3 per 1000 live births). The estimates for the use of cocaine and crack are as high as 10% of all live births (375000 infants). While other substances used by the mother (eg, alcohol, cigarettes, and sedatives) may affect fetal outcome, this article focus on these two primary illicit drugs of abuse. The specific effects of these drugs on neonatal and postneonatal development are summarized, areas where there is insufficient knowledge to determine specific effects are defined, and a model for thinking about drug effects in the context of interrelated multiple adverse health and social conditions is described.
The effect of prenatal drug exposure on the new-born infant depends on many factors including the type of drug, the timing of the drug exposure during gestation, the frequency of exposure, and specific direct and indirect actions of the drug either on placental blood flow or on fetal tissues or cells after crossing the placenta.
Interpretation of outcome studies of drug use in pregnancy is complicated by the presence of many confounding variables associated with the drug-using life style, which may have an independent effect on infant outcome (eg, failure to obtain adequate prenatal care, cigarette smoking, alcohol use, low prepregnancy weight and low weight gain during pregnancy, acquisition of sexually transmitted diseases during pregnancy, and poly-drug use). Outcome studies are also marred by the difficulty in obtaining appropriate control groups that do not contain differences in demography, socioeconomic status, incidence of maternal psychiatric disorders, parenting abnormalities, and parity. Such differences between a drug-using and drug-free control group might be expected to account for much of the variance reported. Long-term developmental and behavioral effects are even harder to determine because the difficulty in controlling for prenatal variables is compounded by the contributions of the often adverse postnatal environment.
The concept of environmental injury added to biologic insult has been well-described in follow-up studies of premature infants. Premature infants with similar biologic insults have different outcomes depending on the quality of the caregiving environment. Hunt et al reported on the outcome of 108 low birthweight children (≤1500 g) bom between 1965 and 1978 and followed through 1 1 years of age.1 Both indices of neonatal illness and parental education were predictive of outcome. However, neonatal illness more strongly predicted whether the infant would have an abnormal outcome, whereas parental education better predicted the level of disability. A similar mechanism may be at work in the infants of mothers who use illicit substances during pregnancy -the drug exposure may render the child more vulnerable to the effects of poor caretaking. It is important to consider the effects of illicit drug use in the context of a multifoctorial developmental model.
Opiates are a group of opium-derived alkaloids obtained by drying the milky white sap of the unripe seed of the poppy plant (Papaver somniferum), which is indigenous to Asia Minor. At least 20 alkaloids are found in opium powder including the naturally occurring opiates (ie, morphine, codeine, and opium), which have been in use for millennia. Semisynthetic narcotics, made by simple biochemical modifications of morphine include heroin (diacety !morphine), hydromorphine (Dilaudid, Knoll Pharmaceuticals, Whippany, NJ), and oxycodone (present in Percocet and Percodan IDu Pont Pharmaceuticals, Wilmington, Delaware], Tylox [McNeil Pharmaceutical, Spring House, Pennsylvania], and Vicodin [Knoll Pharmaceuticals, Whippany, NJ]). Heroin was first manufactured in the last quarter of the 19th century. Totally synthetic narcotics, whose chemical structure is unrelated to morphine, include methadone, fentanyl, meperidine (Demerol, Winthrop Pharmaceuticals, New York, New York), and propoxyphene (Darvon, Eli Lilly and Co, Indianapolis, Indiana). Methadone, which has identical physiological effects to those seen with morphine, was first manufactured in Germany in the 1940s.
Most drug-abusing women have not yet discovered or acknowledged their pregnancy during the first trimester when teratogenic effects might occur. Some animal studies have shown the occurrence of teratogenic effects but only at extremely large doses. Many of these studies were not controlled for the effects of anorexia and decreased caloric intake seen in most animals given narcotics.2 Studies that use smaller doses more closely approximating human usage and take into account nutritional intake have not demonstrated an increased rate of malformations.
Studies of the teratogenicity of methadone in animals have been criticized because the rate of methadone metabolism in most animal models is faster than in humans. Because the half-life may be as short as 3 to 5 hours in the pregnant rat, once-a-day dosing leads to a daily cycle of drug treatment followed by many hours of withdrawal prior to administration of the next dose. Therefore, it is possible that many of the effects reported may be secondary to the cardiovascular alterations due to narcotic withdrawal rather than a direct effect of methadone. Moreover, no consistent pattern of anomalies has been described in human infants, and the rate of malformations has not been increased compared to the general population.3'6 Thus, there is no convincing evidence of narcotics exerting a morphologic teratogenic effect.
Numerous studies have documented low birthweight for gestational age in infants exposed to narcotics in utero.7'10 Length and head circumference also are decreased in narcotic-exposed infants.9'10 However, these findings are unlikely to be the sole result of prenatal narcotic exposure. Drug-addicted mothers are more likely to be poorly nourished and have inadequate nutritional intake and distribution of calories. They are also much more likely to smoke cigarettes, drink alcohol, use other illicit drugs, fail to get prenatal care, and have multiple infections during pregnancy than nondrug-using women.9'11 While participation in a methadone maintenance program in pregnancy improves infant birth weight, drugexposed infants are still more growth retarded compared to drug-free controls.9'12
Lifcchitz and colleagues prospectively followed infants who were heroin-exposed, methadone-exposed, and drug-free and controlled for biologic, demographic, and health differences among the mothers in the three groups.8 The mean birthweight, length, and head circumference were significantly lower in infants of both the heroin-using and methadone-using mothers. More heroin-exposed infants were small for gestational age methadone-exposed infants. When group means were adjusted for sex, race, prenatal care, weight gain during pregnancy, prenatal risk score, maternal education, and maternal smoking, there were no longer significant differences between the drug-exposed (heroin or methadone) and drug-free groups. Follow-up of these infants at 3 years of age showed that the growth of the drug-exposed infants was no more impaired than the control group of similar socioeconomic status. All three group means fell below the 50th percentile for height, weight, and head circumference. The authors concluded that the multiple risk factors present in the life-style of the drug-abusing pregnant women were major factors in the growth retardation reported both prenatally and postnatally for this group of infants.
There is growing evidence that in utero exposure to narcotic drugs may result in abnormal structural organization of the fetal brain.13'15 Hammer et al recently published an elegant series of animal studies on the effects of morphine on neuroanatomical development in the rat.16 The abnormalities reported affect primarily the hypothalamus and dendritic arborization. These studies suggest that the neurobehavioral abnormalities seen in narcotic-exposed infants, particularly those in the area of behavior and synaptic integration, may in fact be caused by an underlying structural change in brain development.
Alteration of neurochemical pathways may result in neurologic dysfunction such as seizures and EEG abnormalities or in behavioral dysfunction such as passivity or hyperalertness. Hertzlinger and colleagues reported an incidence of seizures of 1.2% of heroinexposed infants and 7-8% of methadone-exposed infants.17 A 1-year follow-up study of infants with abstinence-related seizures showed that most early EEG and neurologic abnormalities associated with abstinence-related seizures were transient.18 By 8 to 16 months of age, neurologic exams were normal, no infants had a seizure disorder, EEGs were normal, and no abnormalities were noted on the Bayley Scales of Infant Development. In contrast to other causes for neonatal seizures, the authors proposed that the pathogenesis of abstinence-related seizures may relate to the depletion of neurotransmitters. Perhaps the infants restore neurotransmitter concentration thereby improving synaptic function resulting in normal neurologic function.
Neonatal Abstinence Syndrome Scoring Criteria25
The most immediate neurologic complication seen in narcotic-exposed infants is the presence of a neonatal abstinence syndrome (NAS), including signs of irritability, tremulousness, sweating, stuffy nose, difficulty feeding due to an uncoordinated and inefficient suck, diarrhea, and vomiting. Finnegan19 developed a now commonly used scoring system to quantify the severity of withdrawal signs (Table 1 ). Infants are scored at 4 hourly intervals over the first several days of life. Three consecutive scores greater than 8 or two scores greater than 12 are an indication for pharmacologie treatment. The NAS score also can be used to guide therapy and drug detoxification.
The time of onset of withdrawal symptoms depends on the type of narcotic. Heroin has a short half-life (4 hours) so that clinical signs are apparent on the first day of life. Methadone, on the other hand, has a very long half-life (32 hours in the newborn), and therefore, clinical signs seldom occur before 24 to 48 hours of life or later. Methadone is excreted in the infant's urine over the first week of life, which may account for the very prolonged withdrawal period seen with methadone-exposed infants. In addition, a subacute withdrawal syndrome characterized by restlessness, agitation, tremors, and sleep disturbance may last as long as 3 to 6 months after birth and may be a reflection of the prolonged metabolism and excretion of methadone.
Cognitive Function in Narcotic-Exposed Infants and Children
The severity of withdrawal is related to the maternal methadone dose. Mothers maintained on a dose of less than 20 mg/day seldom give birth to infants who require pharmacotherapy.20,21 About 60% of infants (heroin 40% to 50% and methadone 70% to 90%) will exhibit sufficiently severe withdrawal that pharmacotherapy is indicated. The remainder of infants are treated with the "tender loving care" approach including swaddling, use of a pacifier, demand feeding with a hypercaloric formula, and decreased environmental stimuli (ie, low light and noise level, and touching and handling minimal).
Narcotics (paregoric or denatured tincture of opium [DTO]), phénobarbital, diazepam, and chlorpromazine have all been used to treat NAS. Chlorpromazine has multiple untoward side effects, including cerebellar dysfunction, decreased seizure threshold, and hématologie problems, that make it an undesirable drug for use in the newborn, although it is quite effective in managing NAS symptoms. Diazepam has been shown in many studies to lack efficacy when used as a single drug therapy and is thus not the first drug of choice.
Paregoric or DTO are the drugs of choice for infants of women using narcotics alone. Finnegan19 has demonstrated that 93% of such infants will respond well to single-drug therapy with paregoric, which will control all the central nervous system and gastrointestinal symptoms and will allow the newborn to maintain normal sucking activity so feeding ability is improved. The disadvantages of paregoric are longer duration of therapy and a possible continued suppression of catecholamine synthesis.
Phenobarbital controls the central nervous system signs extremely well but is not effective in controlling diarrhea. It has a longer duration of time between treatment initiation and clinical control but results in a shorter total duration of treatment. It is the drug of choice in nonnarcotic-related NAS and for narcotic withdrawal in infants exposed to narcotics plus sedatives or stimulants. Once a maintenance dose has been established for either drug, the dose is decreased approximately 10% per day so that the mean duration of therapy ranges between 2 and 3 weeks.
Behavioral dysfunction, including increased irritability, tremors, and muscle tone, has been described using the Brazelton Newborn Behavioral Assessment Scale. Infants have decreased consolability and are less responsive to visual stimuli.20,22,23 While motor abnormalities respond to therapy, neurobehavioral abnormalities persist.24 This suggests that the neurologic and neurobehavioral dysfunction may be produced through different mechanisms.
There is considerable controversy as to whether the neurobehavioral effects seen from birth to 6 months of age are transient or represent permanent changes in brain structure or biochemical function. Much of the discussion centers around the issue of confounding variables in the social/psycholeptic makeup of the infant's environment that might contribute to any adverse outcome.7 Controlled long-term follow-up studies of this population are extremely difficult to do both in terms of attrition and of control group definition.
There is no convincing evidence that exposure to narcotics in utero results in abnormal cognitive outcome when exposed infants are compared to appropriate controls of similar socioeconomic status. Major long-term studies7'10,22'25'28 are reviewed in Table 2. Only one study showed any significant differences in cognitive function between narcoticexposed and control infants.27 The one available study of school performance, however, shows a different picture. As many as 41% will require special education classes and 28% will need to repeat one or more grades.25 Behavioral dysfunction in the classroom was reported by teachers of 66% of the schoolaged children. Teachers reported inattention and poor self-discipline in half the students.
The discrepancy between early cognitive measures and later school performance may be explained by environmental factors. Methadone-exposed children at the lowest socioeconomic level, although they had comparable cognitive function, fared worse than control infants at the same low socioeconomic level. This finding suggests that in utero methadone exposure may produce injury to which is added the insult of being raised in a disadvantaged social environment. This would provide support for the concept of early prevention and intervention strategies to improve the quality of home care for this group of infants.
Cocaine is a tropane alkaloid derived from the leaves of the erthroxylon coca plant found on the mountain slopes of Central and South America. It is a stimulant and is similar to amphetamines in structure and function. Crack cocaine is a freebased form (ie, inhalable) produced by alkalinization of the HCl salt of cocaine (white powder) followed by extraction with a solvent such as ether. The inhalable form is preferred by users for its very rapid onset of psychotropic activity (4 to 6 seconds).
Cocaine readily crosses both the placenta and the blood-brain barrier as it is soluble in both water and lipid. In the chronically catheterized fetal sheep model,29 fetal blood concentrations are half those of the mother with a significant rise in fetal heart rate and blood pressure in response to maternal cocaine administration. In adults, brain concentrations of cocaine are four times higher than peak plasma concentrations. The drug is metabolized in liver and plasma by cholinesterases. Activity of cholinesterase is low in the fetus and in many but not all pregnant women so that clearance of the dmg is delayed for several days. In adults, the urine wilt be clear of drug within I to 2 days after drug use, while in newboms, the urine may be positive for the drug for 5 to 7 days.
Cocaine is thought to exert its primary effects by blocking the reuptake of neurotransmitters at the presynaptic nerve terminals. This results in an excess of dopamine at the postsynaptic membrane that would result in an exaggerated signal. By blocking the presynaptic reuptake of dopamine in the central nervous system, increasing dopamine synthesis, and upregulating dopamine receptors on the postsynaptic nerve, cocaine produces a neurochemical magnification of the pleasure response creating a heightened sense of power, euphoria, and sexual excitement. This augmented pleasure response initiates such persistent drug-seeking behavior that rats press levers to obtain cocaine until they die of overdose.30
With chronic use, cocaine is thought to deplete dopamine stores in presynaptic neurons. This results in an inability to experience pleasure during periods of nonuse. Cocaine also blocks reuptake of norepinephrine at the presynaptic terminal, increases norepinephrine synthesis, and upregulates norepinephrine receptors on the postsynaptic nerve ending resulting in an accumulation of norepinephrine in the nerve synapse and propagation of the norepinephrinemediated signals. This may account for the increased heart rate and myocardial contractility, increased blood pressure, hyperalert behavioral state, and peripheral muscle contractility seen in patients using cocaine.
No consistent syndrome of congenital anomalies has been described for cocaine-exposed infants. Animal studies have implicated maternal cocaine use in the etiology of anomalies consistent with fetal vascular accidents presumably secondary to cocaineinduced vasoconstriction.31 Reports of defects in human infants are compatible with the vascular disruption hypothesis.32 These include cerebral infarction,33 urogenital tract anomalies,34,35 limb reduction defects,32,3"* echodensities or echolucencies on cranial ultrasound,36 congenital heart disease,37 and an ischemie enteropathy31 similar to necrotizing enterocolitis seen in preterm infants. All these studies were either case reports or were based on small samples of infants. Other studies do not show such associations.12 One recent large-scale study involving 18056 infants failed to find an association between cocaine exposure and renal defects.38 The ability of cocaine to induce structural damage to the development of germinal tissue and early vascular compromise will be determined only a large-scale study with sufficient power to control for the many confounding variables involved.
Numerous studies have shown an association between cocaine use during pregnancy and a decrease in birthweight and head circumference.12'39'44 However; this effect on growth is probably compounded by maternal undernutrition and poly-drug abuse.12,45 Only one of these studies controlled for potentially confounding variables.12 Although infants in this study whose mothers had a positive urine assay for cocaine during pregnancy had birthweights that were 407 g below that seen for infants of mothers who were drug-free, multivariate statistical analysis controlling for confounding variables revealed that only 25% of the weight decrement could be attributed directly to cocaine. The remainder was attributable to the effects of cigarettes, marijuana, other drugs, and poor nutrition. Moreover the effect was only significant for those mothers and infants who had a positive urine toxicology screen for cocaine. Mothers with negative urine toxicology, but who reported cocaine use during pregnancy, did not give birth to infants who had decreased birthweight. Chasnoff reported that cessation of cocaine use by the end of the first trimester resulted in improved birthweight and no increase in preterm birth compared to continued use throughout pregnancy.39 This finding reinforces the importance of entry into drug treatment as early as possible in pregnancy.
Cocaine-exposed infants do not have significant withdrawal symptoms as measured by the neonatal abstinence scale OT clinical checklist.43,44 It is likely, however, that these measures are not sensitive measures of infant behavior and may have missed subtle dysfunctions.
Neurobehavioral abnormalities, especially in state regulation and interaction ability, measured by the Neonatal Behavioral Assessment Scale (NBAS) have been reported in some but not all studies.26,39,42'46 Whether alterations in behavior are caused by withdrawal or by a direct effect of cocaine on the brain's neurotransmitters are unknown. A role for neurotransmitter changes was suggested by a pilot study47 showing that blood levels of the norepinephrine precursor dihydroxyphenalanine were higher in cocaineexposed newboms than in unexposed newborns.
Two neurobehavioral profiles have been described for cocaine-exposed infants studied with computeraided cry technology. One profile, characterized as "excitable," is hypothesized to be related to a direct effect of cocaine exposure; the second profile, characterized as "depressed," is thought to be secondary to effects of intrauterine growth retardation.48 The results of most studies of infant behavior associated with cocaine exposure are difficult to interpret because the mothers in these studies tended to abuse more than one drug, so it was unclear whether these neurobehavioral findings were due solely to cocaine. Other factors such as poor prenatal nutrition also contribute to neonatal neurobehavioral dysfunction.
Although some studies deal with infants exposed to both cocaine and opiates, there are currently no published peer-reviewed studies of the development and behavior of children exposed prenatally to cocaine alone. Findings from the newborn period (discussed earlier) raise important concerns regarding long-term effects.
By altering neurotransmitter activity in the developing nervous system, chronic prenatal exposure to cocaine may adversely aeffect autonomie function, state regulation, and response to sensory stimuli, potentially leading to impulsivity and instability of mood as children get older. Echodensities and echolucencies in the frontal lobe and basal ganglia may result in morphologic alterations that affect specific functions such as affect or information processing.2,32 Therefore, global outcome measures such as developmental quotients and behavior problem scales may not identify the specific impact of prenatal drug exposure or suggest specific intervention plans.
In one study, drug-exposed (cocaine, opiates, and other drugs) toddlers had significantly greater difficulty than nonexposed toddlers in unstructured tasks (ie, tasks that required the child's initiation, goal setting, and follow through).49 This finding suggests a behavioral disorganization that may not be identified in the structured settings of traditional developmental assessment tests. However, the newborn brain may be able to adapt and to compensate for at least some of these biological changes. If behavior and developmental problems are identified, how much of these problems will be the result of caretaker dysfunction and how much will be the result of biologic vulnerability created by prenatal cocaine exposure will need to be determined.
SUDDEN INFANT DEATH SYNDROME
Although early studies based on small sample sizes raised concerns that cocaine-exposed infants were at extraordinarily high risk for sudden infant death syndrome (SIDS), more recent studies have shown either no increased risk50 or slightly elevated risk. The largest sample reported is of 1.2 million live births in New York City from 1979 to 1989.51 There were 1729 SIDS cases (1.43/1000), which is the expected population incidence. The rate for infants of mothers who used heroin was 6.97/1000 live births; for methadone, 9.07/1000; for cocaine, 4.18/1000; for all white infants, 0.57/1000; and for all black infants, 2.4/1000. The data were not analyzed after controlling for confounding variables such as cigarette smoking, which is more common in drug-using than nondrugusing women. Thus, if an increased risk exists for cocaine-using women, it is not very large.
NEED FOR COMPREHENSIVE DRUG TREATMENT PROGRAMS
Prenatal narcotic and cocaine exposure increases the risks for adverse effects to the newborn. The type and extent of problems is more clearly delineated for narcotics than for cocaine. Early entry into drug treatment programs for pregnant substance-abusing women can improve outcomes. Unfortunately, few drug treatment programs accept pregnant women. After delivery, women are faced with the additional need to separate from their children to obtain treatment because only a few treatment programs have facilities to care for mothers and infants together.
Traditional drug treatment programs are maleoriented in approach and do not address issues of special importance to women. The majority of women in drug treatment are (or have been) physically or sexually abused.52 Women have lower self-esteem and are more socially isolated than men entering treatment programs. They are more likely to be single parents and therefore have a difficult time entering residential treatment programs. Pregnant women seeking drug treatment present with complex problems including medical problems unrelated to pregnancy; problems of homelessness; battering; lack of literacy, job, and social skills; and being without health insurance.53
The adverse impact of drug abuse on the outcome of pregnancy could be considerably lessened if a comprehensive approach including drug treatment, prenatal, medical, nutritional, and social service interventions was readily available. The National Commission on Infant Mortality recently issued a report advocating a "one stop shopping" approach to prenatal care in order to break down some of the barriers to care that are so prevalent for high-risk women. Such family-oriented drug treatment approaches have been successful in reducing pregnancy-related complications for narcotic-addicted pregnant women to a level comparable with that seen in nondrug-using women from similar socioeconomic backgrounds.21 Failure to provide adequate treatment programs will impair the future for a generation of children. We cannot afford to let this situation continue.
The authors thank Nancy Coyne and Jeanne McCarthy for their help in preparing the manuscript.
1. Hunt JV, Cooper BAB, Tooley WH. Very low birth weight infants at 8 and 11 years of age: role of neonatal illness and family status, Pediatrics. 1988;82: 596-603.
2. Hutchings DE, Dow-Edwards D. Animal model« of opiate, cocaine and cannabis use. Ctoiftrmewl. 1991;18:l-22.
3. Gstrea EM, Qiavez C]. Perinatal problems (excluding neonatal withdrawal) in mattmal drug addictions a study erf 830 cases. J Pedina. 1979:94:292-296.
4. Naeye RL, Blanc W, Leblanc W, Khatamee MA. Fetal complications of maternal heroin addiction: abnormal growth, infections and episodes of stress. J Pedina. 1973;83:1055.
5. Stimmel B, Adamsons IC. Narcotic dependency in pregnancy: methadone maintenance compared to use of street drugs. JAMA. 1976;235:1121.
6. Kandall SR, Albin S, Gärtner LM, Lee KS, Eidelman A, Lowinson J The narcotic dependent mother: fetal and neonatal consequences. Early Hum Dev. 1977; 1/2; 159.
7. Hans SL. Developmental consequences of prenatal exposure to methadone. In: Prenatal abuse of licit and illicit drugs. Arm NY Acad Sri. 1 989 ;5 62: 195-207.
8. Llfechic MH, Wilson GS, Smith EO, Desmond MM. Factors affecting head growth and intellectual function in children of drug addicts. Pediatrics. 1985;75:269-274.
9. Wilson GS, Desmond MM, Wait RB. Follow up of melhadone-treated and untreated narcotic-dependent women and their infants; health, developmental, and social implications. J Pedían. 1981;98:7t6-722.
10. Kaltenbach KA, Finnegan LP. Prenatal narcotic exposure: perinatal and developmental effects. Neurotoxicology. 1989; 10: 567 -604.
11. Zuckerman B, Rank D, Hingson R, et al. Effects of matemal marijuana and cocaine use on fetal growth. N Engl J Med. 1989:320:762-768.
12. Kandall SR, Albin S, Lowinson J, Berle B, Eidelman Al, Gatner LM. Differential effects of maternal heroin and methadone use on birthweight. Pediatric. 1976;58:681-685.
13. Smith AA, Hui FW, Crofford H]. Inhibition of growth in young mice created with dj-methadone. EurJ Pharmacd. 19? 7 i43:307-309.
14. Zagon IS, McLaughlin PJ. Naltrexone regulares body and brain development in rats: a role for endogenous opioids in growth. Life Sci. 1984^5:2057-2064.
15. Sakellaridis N, Mangoura D, Veradakis A. Effects of opiates on the growth of neuron-enriched cultures from chick embryonic brain. ImJ Dev Neuroso. 1986;4:293-302.
16. Hammer RP, Ricalde AA, Seatriz JV. F-ffects of opiates on brain development. Netaotoxicology. 1989:10:475-484.
17. Hertzlinger RA, Kendall SR. Vaughan HG. Neonatal seizures associated with narcotic withdrawal. J Pediatr. 1977:91:638.
18. Doberczak TM, Shaniier S, Cutler R. Senie RT. Loucoupoubs JA, Kandall SR. One-year follw-up of infants with abstinence-associated seizures. Arch Neural. 1988:45:649-653.
19. Finnegan LR Neonatal abstinence. In: Nelson NM, ed. CUTTCTK Therapy in Neonatal-Perinatal Medicine. Philadelphia, Pa: BC Decker Ine; 1990:314-320.
20. Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. J Pediatr. 1976;88;642-645.
21. Connaughton iP, Reeser D, Shut J, Finnegan LP. Perinatal addiction: outcome and management. AmJ ObsKt GynectA. 1977;! 29:679-686.
22. Strauss ME, Starr RH, CWreaEM, Chavez CJ, StrykerJC. Behavioral concomitants of prenatal addiction to narcotics. J Pediatr. 1976;89:842-846.
23. Chasnoff IJ, Schnoll SH, Bums WJ, Bums K. Maternal nonnarcotic substance abuse during pregnancy: effects on infant development. Neurobehav ToactA Teratol. 1984:6:277-280.
24. Brown ER, Cole J, Parker S, Coulter D, Corwin M, Aboigyne K. Treatment of newborn narcotic abstinence faik to normalize intani behavior- Patiatr Res. 1989:25:1 2A.
25. Wilson GS. Clinical studies of infants and children exposed prenatally Io heroin. AroiNYAcfldSci. 1989-62:183-194.
26. Chasnoff IJ, Burns KA, Bums WJ, Schnoll SH. Prenatal drug exposure: effects on neonatal and infant grcnfh and development. NeurabehavToxicolTeraial. 1986:8:357-362.
27. Rosen TS, Johnson HL. Children of methadone-maintained mothers: follow-up to 18 months of age. JFfafcin-. 1982; 101: 192- 196.
28. Strauss ME, Lessen-Firesrone JK, Chavez C], Stryker JC. Children of methadonetteaied women at 5 years of age. Pharm Biochem BeW. 1979;ll(suppl):3-6.
29. Woods JR Jr, Plessinger MA, Clark KE Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA. 1987 ;25 7:957-961.
30. Geary N. Cocaine animal research studies. In: Spitz Hl, Rosecan JS, eds. Cocaine Abuse: New Détections in Treatment and Reiearch. New York, NY: Brunner/Mazel; 1987:19-47.
31. Hoyme HE, Jones KL, Dixon SD, et al. Prenatal cocaine exposure and fetal vascular disruption, Marries. 1990:85:743.
32. Chasnoff IJ, Bussey ME, Savich R, Stack C. Perinatal cerebral infarction and maternal cocaine use. J ftdiarr. 1986; 108:4 56.
33. Chasnoff IJ, Chisum GM, Kaplan WE, et al. Maternal cocaine use and genitourinary tract malformations. Teratology. 1988:201:1988.
34. Chavez GF, Mulinare J1 Cordero JE Maternal cocaine use during early pregnancy as a risk better for congenital urogenital anomalies. JAMA. 1989;262:795-798.
35. Hoyme HE, Jones 10-, Van Alien M!, Saunders BJ, Betiitsch KE Vascular pathogenesis of transverse limb reduction detects. J Pediacr. 1982;101:839.
36. Dixon SD, Bejar R. Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: incidence and clinical correlates. J Pediacr. 1989;115:7709.
37. Lipshulz SE, Frassica JJ, Orav J. Cardiovascular abnormalities in infants prenatally exposed to cocaine. J Prdiatr. 1991;118:44-51.
38. Rajegowda B, Lala R, Nagaraj A, et al. Does cocaine increase congenital urogenital abnormalities in newbomsiftdiarr Rej. 1991;29;71A.
39. Chasnoff IJ, Griffith DR, MacGregor S, Dirkes K, Burns KA. Temporal patterns of cocaine use in pregnancy. JAMA. 1989;261:1 741-1744.
40. Cherukuri R, Minkoff H, Feldman J, Pavekh A, Glass L. A cohort study of alkaloidal cocaine ('crack') in pregnancy. ObsKi Gynecd. 1988;72:147-151.
41. Chouteau M, Namerow PB, Leppert R The effect of cocaine abuse on birth weight and gestational age. Obstet Gynecol. 1988:72:351-354.
42. Fulroth R, Phillips B, Durand DJ. Perinatal outcome of infants exposed to cocaine and/or heroin in ulero. Am J Dis CWd. 1989; 143:905 -9 10.
43. Hadeed AJ, Siegel SR. Maternal coca ine use during pregnancy: effect on the newborn infant. Marries. 1989;84:205-210.
44. Ryan L, Ehrlich S, Finnegan L. Cocaine abuse in pregnancy: effects on the fetus and newborn. Neiaotoncol Teratol . 1987:9:295-299.
45. Frank D, Zuckerman B, Reece H, et al. Cocaine use during pregnancy: prevalence and correlates. Marries. 1988;8 2:888-895.
46. Chasnoff IJ, Burns WJ, Schnoll SH, Bums KAa. Cocaine use in pregnancy. N Engl. iMed. 1985-13:666-669.
47. Mirochnick M, Meyer J, Cole J, Herren T, Zuckemian B. Circulating catecholamine in cocaine-exposed neonates: a pilot study: Pediatrics. In press.
48. Lester BM, Corwin MJ, Sepkoski C, et al. Neurobehavioral syndromes in cocaine exposed newborn infants. Child Den. In press.
49. Rodnlng C, Beckwith L, Howard J. Characteristics of attachment organization and play organiiation in prenatally drug-exposed toddlers. Dec Piycfiopaiho!. 1990:277-289.
50. Bauchner H, Zuckerman B, McOain M, Frank D, Fried LE Kayne H. Risk of sudden infant death syndrome among infants with in utero exposure to cocaine. J Pediatr. 1988;113:831-834.
51. Kandall SR, Damns K, Gaines JJ, Habel L. Maternal substance use and sudden infant death syndrome in offspring. Pediacr Res. 1991;29:92A.
52. Eldren CA, Washington MN. Female heroin addicts in a city treatment program: the forgotten minority. Psychiatry. 1975J8:75-85.
53. Brown ER. Program and Staff Characteristics m Successful Treatment. NlDA Research Monograph Series. In press.
Neonatal Abstinence Syndrome Scoring Criteria25
Cognitive Function in Narcotic-Exposed Infants and Children