Perinatal and Neonatal Issues of Substance Abuse

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SUBSTANCE ABUSE

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PERINATAL AND NEONATAL ISSUES OF SUBSTANCE ABUSE Gary L. Bell, MO, and Keith Lau, MO

In the epidemic of alcohol and substance abuse that has staggered the United States, unborn children have been the unseen victims. In 1992, it was estimated that 36% of the entire population had used an illegal drug in their life, and that 11% had in the past year. 174 Chasnoff and colleagues27 pointed out that in Pinellas County, Florida, there was little difference in the rate of substance abuse among blacks and whites (14.1 % versus 15.4%) and those in public clinics (16.3%) and private offices (13.1%). Substance abuse including alcohol, tobacco, and illegal substances constitutes a major threat to our future children. The impact on the fetus is not necessarily ameliorated by the legality of the substance. In this article, the authors focus on six highly abused substances and try to delineate individual effects of each although this delineation is nearly impossible because confounding variables make the study of each individual substance impure. The use of one drug is often associated with polydrug use. Also, during a pregnancy it is difficult for the clinician to time when and how much of the substance was used. Not only is determination of drug use factors difficult to determine, but biopsychosocial factors such as socioeconomic status, education, biological factors, prenatal care, and nutrition also contribute to fetal and neonatal outcome and vary from individual to individual.

From the Department of Pediatrics, Division of Neonatology, The University of Tennessee College of Medicine at Chattanooga, T. C. Thompson Children's Hospital; the Division of Neonatology, Hutcheson Medical Center, Chattanooga, Tennessee (GLB); and the Department of Pediatrics, Division of Neonatology, University of Alabama at Birmingham, Birmingham, Alabama (KL)

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 42 • NUMBER 2 • APRIL 1995

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MARIJUANA

Marijuana is the most widely abused illicit drug in the United States. 174 The 1992 National Household Survey found that 3.9% of women between the ages of 18 and 25 years had used marijuana at least once a week in the past year. The range of women reported to use marijuana during pregnancy is from 9.5% to 27%.36,81 The active constituent of marijuana is delta-9-tetrahydrocannabinol (THC), which crosses the placenta and accumulates in the fetus. 183 In animal experiments, marijuana was associated with intrauterine growth retardation, teratogenesis, and increased fetal resorption. 88 In humans, however, maternal marijuana use during pregnancy has not been studied extensively. Data from past studies concerning marijuana use during pregnancy have indicated that prenatal marijuana use does not increase the incidence of obstetric complications. 143 The ongoing study of Maternal Health Practice and Child Development Project (MHPCD) found no association of marijuana use with any effect on the incidence of stillbirth or spontaneous abortion. 143 Babies of mothers who used more than five marijuana cigarettes per week had a shortening of gestation by 0.8 week. 66 This finding, however, was not corroborated by other studies. 83 Zuckerman and colleagues185 noticed a significant relationship of a decrement in the body length in the newborn period with marijuana use during early pregnancy and daily use of marijuana has been related to low birth weight.S1, 186 That association disappeared, however, after the influence of the other covariates were controlled in other studies. 64 The Ottawa Prenatal Prospective Study shows no correlation of infant growth parameters and prenatal marijuana exposure. 69 Marijuana has not been definitely shown to have any negative long-term effect on growth. 41 There have been a few isolated case reports implicating marijuana as a human teratogen that may produce a fetal-alcohol-like syndrome.81 O'Connell and Fried126 found no increase, however, in any major physical anomaly in the offspring of mothers who used marijuana during pregnancy. There are also some inconsistent data suggesting that in utero marijuana exposure may delay the maturation of the visual system.171 True ocular hypertelorism and severe epicanthus are occasionally noticed among children of heavy users. Other studies found no consistent effect of marijuana on the morphologic abnormalities in the human fetus.9, 78, 185 The relationship between prenatal marijuana and neurobehavioral changes in infants is difficult to prove. The Canadian study in Ottawa found that marijuana use was associated with abnormal results on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS).63,70 Babies of heavy and moderate marijuana smokers were found to habituate less to light stimulation in the first few days of life and these babies had tremors, exaggerated startle responses, and disturbed sleep patterns. Because the studies were not controlled for other variables, the interpre-

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tation of the findings is very difficult. Prenatal marijuana exposure has also been associated with lower scores for cognitive and language development. 67 These observable effects did not persist after the covariates were controlled. Fried and colleagues68 examined the offspring of heavy marijuana users at the age of 4 years and they found that these children had significantly lower scores in a number of cognitive variables. The negative effects on the memory and verbal component remained statistically significant after the confounding variables were controlled. When the same group of children were investigated again at the age of 6 years, prenatal marijuana exposure was not associated with any statistically significant negative effect on cognition and language developmenUo, 125 In summary, the negative effects on neurobehavior and growth from prenatal marijuana exposure remain unproven.

COCAINE

Although marijuana and alcohol are the more commonly abused drugs, the increase in the use of cocaine has had a dramatic perinatal impact. In 1993, 6.1% of high school seniors had tried it. 175 Many prevalence studies53, 72, 113, 122 have documented a high use rate, from 2.6% in Rhode Island 118 to 17% in Boston. 61 The typical cocaine user is in his or her mid-20s, nonwhite, belongs to a lower socioeconomic class, and is a polydrug abuser. Lack of prenatal care is a hallmark of maternal cocaine abuse. 113 Cocaine and its metabolites readily cross the placenta exposing the fetus. Cocaine blocks the presynaptic catecholamine reuptake that leads to the sympathetic effects of the drug. Cocaine is a powerful vasoconstrictor and hypertensive agent, and many of its adverse outcomes are blamed on these properties. 90 Fetal death (e.g., spontaneous abortion174 and stillbirth58, 90) is a tragic complication of in utero cocaine exposure. There is also an increase in abruptio placentae4 , 12, 22, 58, 87, 93, 131 that leads not only to increased fetal mortality but also to premature births and in utero hypoxia. Rates of prematurity are dramatically increased with in utero cocaine exposure. 33, 58, 107, 108,131 Prematurity with its many complications leads to increased mortality, morbidity, and increased cost of health care. Pregnancy-induced hypertension, premature rupture of membranes,31, 58, 93, 111, 122 precipitate delivery, and meconium-stained fluid 31 , 93, 111 are increased complications of cocaine abuse during pregnancy. Prevalence of sexually transmitted diseases, hepatitis, and AIDS is also increased in cocaine-using expectant mothers.

Teratogenicity of Cocaine

Teratogenetic effects have been recognized in babies born to cocaine- or crack-abusing mothers. A large number of studies do suggest there are congenital defects and fetal vascular accident defects associated

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with the use of cocaine in pregnancy. Vasoconstrictor effects of cocaine were most likely responsible for nonduodenal intestinal atresia or infarction and terminal limb defects in nine patients. 86 The same mechanism has been implicated in cases of necrotizing enterocolitis in cocaineexposed babies. 51 , 139 Skull defects (i.e., exencephaly, interparietal encephalocele, and parietal bone defect) and congenital heart disease, including cardiovascular malformations, electrocardiographic abnormalities, and possibly cardiopulmonary autonomic dysfunction have been demonstrated.9o, 100 Structural cerebral abnormalities associated with in utero cocaine exposure have been reported. In 1986, an infant with a perinatal cerebral infarction was reportedY In 1989, echoencephalographic findings in neonates not predicted by standard clinical assessment were demonstrated,45 These included intraventricular hemorrhage, cavitary lesions, and echodensities known to be associated with necrosis, In 1991, more cerebral anomalies were confirmed, and they included ocular abnormalities such as strabismus, nystagmus, hypoplastic optic discs, or a combination of these,50 An increase in cerebral blood flow velocity reported on the first day of life helps to explain those brains reported with hemorrhage. 176 Multiple other effects have been described, including genitourinary anomalies18, 29,49 and persistent hypertension. 84 Overall, the risk for teratogenicity for the cocaine-exposed fetus is small, but it is still possibly greater than the overall population. One of the more consistent findings in babies exposed to cocaine is that of small head circumference 12, 19, 31, 72, 131, 185 at birth, which often correlates with a small brain. Correlation between poor head growth and poor development has been established. 19 Low birth weight,* decreased length,12, 19, 31, 72, 131, 184 small-for-gestational-age,31, 84, 107, 122 and preterm birtht have all been frequently reported, and they are surely associated with maternal cocaine abuse. Toxic effects of cocaine manifest indirectly and directly. Thus far, the authors have discussed indirect toxic effects such as those manifested by vasoconstrictive effects, premature birth, and low birth weight, which may be preventable to some degree26 ; however, the most deleterious effects of cocaine to the newborn may be direct toxic effects. These effects are like poison to the developing fetal brain, and they have neonatal and persistent neurobehavioral changes. The exact mechanism for these effects is not well-known, but it is known that catecholamines are increased in the in utero cocaine-exposed brainY7, 178 Fifty percent of cocaine-exposed babies had an abnormal electroencephalogram (EEG) in the first week of life that was consistent with cerebral irritability.48 This finding is thought to be the result of changes in neurotransmitter availability and function. By the time the infant is between 3 and 12 months of age, the EEGs in these cocaine-exposed babies had normalized. 48 These babies will most often appear physically normal except for the *References 12, 19, 72, 84, 93, 107, 113, 122, 131, 149, 183. tReferences 22, 31, 33, 72, 84, 93, 107, 111, 113, 122, 131.

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common small-growth parameters. Signs of stress behaviors, however, including tremors, restlessness, irritability, hypertension, abnormal reflex behavior, abnormal moro reflex, excessive mouthing, tachypnea, autonomic instability, and gastrointestinal signs (e.g., vomiting or diarrhea) are common. 54 Abnormal cry acoustics have been shown in cases in which there are fewer cry utterances, more short cries, and less crying in the hyperphonation mode. 39 Abnormal state behavior has been demonstrated in the fetus. 87 This disorganized behavioral state in the fetus was correlated with abnormal newborn behavior. In 1985, Chasnoff and coworkers23 demonstrated that babies born after in utero cocaine exposure had depressed interactive abilities and poor organizational response to environmental stimuli (i.e., state organization). This involves the babies leaving one state (e.g., crying) and entering another (e.g., quiet sleep) in an erratic fashion rather than their normal transition from state to state. In 1989, these same investigators 20 also showed that cocaine-exposed infants had significant impairment in orientation, motor ability, state regulation, and number of abnormal reflexes. Some of the infants were even unable to reach the alert state. There was also an increased rate of seizures in these babies. 2o,53 Inferior performance on the habituation cluster of the Brazelton scale has been demonstrated. 54,112 Habituation is measured by reduced responding over trials to repeated presentation of visual, auditory, and tactile stimuli. Cocaine-exposed babies require more trials to habituation, which, in older drug exposed children, has been related to inferior intellectual ability.54 Chasnoff and colleagues2o demonstrated that these direct toxic effects were present even if the mother had ceased to use drugs early in pregnancy, although the indirect toxic effects may be ameliorated. If the head circumference continued to show poor growth during the first 2 years of life, this factor correlated with poor development. 19 There appears to be no increase in hearing deficit in these babies. Although there have been some mild abnormalities demonstrated in the auditory brain stem response (ABRs),150 most babies exposed to in utero cocaine have normal ABRs.15 There appears to be an increased incidence of sudden infant death syndrome (SIDS) among infants exposed to cocaine. In 1989, Chasnoff and colleagues21 reported a 15% incidence of SIDS in 66 children who had been exposed to cocaine in utero. Although no other study has approached this high incidence, cumulative evidence from several other investigators 28 , 40,52,92 leads to the conclusion that SIDS is increased in in utero cocaine-exposed babies at a rate 5 to 8 times that of the general population (about 8.5/1000).10 Respiratory abnormalities have been confirmed that consist of higher apnea density scores, increased episodes of periodic breathing, and increased respiratory pauses. 30 Despite this, home apnea monitoring is not recommended because this is still a low incidence, and effectiveness of home apnea monitoring remains controversial. The toxic effects of cocaine jeopardize the survival of the baby prenatally and postnatally. After the baby survives, the long-term out-

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look is compromised both through physical anomalies and neurobehavioral alterations, which together manifest a great morbidity from this cocaine abuse.

AMPHETAMINES

Amphetamines are stimulant drugs with effects similar to cocaine, and they act by enhancing the presynaptic release of norepinephrine, which causes vasoconstriction and hypertension. 46 A more potent form, methamphetamine or "crystal," which can be smoked in the "rock" form has become more popular, especially among poor white adolescents in their mid-20s.72, 131 Very little information is known about the effects of amphetamines on the fetus and newborn baby. In cases where low-dose amphetamines were used medically, abnormalities were not describedY In the 1970s, case reports described newborns who were exposed to street amphetamines as agitated, "glassy-eyed," and listless. 142 Theoretically, many of the fetal effects should resemble those of cocaine. Decreased head circumference,72, 101, 131 length,l01 and birth weight72, 101 are described in babies who were born to amphetamine-abusing mothers. Increased rates of maternal abruption,9 prematurity,s6, 57, 131 and babies that are small for gestational age 57, 131 are reported. Little or no prenatal care is common among mothers who use amphetamines.57 No increase in congenital abnormalities has been demonstrated as a result of in utero amphetamine exposure. 101 An increase in perinatal mortality (7.5%) was described in Sweden. 56 Symptoms of babies who are exposed to stimulants include abnormal sleep patterns (81%), tremors (71%), hypertonia (52%), high-pitched cry (42%), poor feeding (58%), vomiting (51%), sneezing (45%), frantic sucking (42%), and tachypnea (18%).46 In utero amphetamine exposure can also lead to congenital brain lesions diagnosed ultrasonographically in term babies, which include hemorrhage, infarction, or cavitary lesions, and the location of these lesions were frontal lobes, basal ganglia, posterior fossa, or general atrophy.45 The author theorized that these areas may be associated with more complex visual-motor and social cognition tasks, and these effects may not appear until later. In Swedish long-term follow-up studies of babies exposed to amphetamines, normal somatic and psychosocial development was reported at 1 year and 8 years,55 but increased aggressiveness and peerrelated problems were noted at 8 years. Temporary drowsiness, problems with lethargy, poor feeding, poor alertness, and lassitide were noted in the first year of life, but normal developmental milestones were achieved during the first year. Another indicator, the Fagan Test of Infant Intelligence, which uses visual recognition to evaluate cognition, showed that stimulant-exposed infants had lower scores than nonexposed infants. 168 Poor performance

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on visual recognition tests were confirmed on a different group of babies although visual-evoked potentials were normal. 77 Thus, in utero amphetamine exposure does lead to subtle neurobehavioral problems (both short term and long term) similar to problems of those exposed in utero to cocaine.

HEROIN AND METHADONE

An estimated 9000 babies are born to narcotic addicts each year in the United States. In 1992, approximately 88,000 women were using heroin regularly,174 and 650,000 had used it at least once. Narcotic withdrawal management is usually the most immediate problem in the newborn period. The acronym WITHDRAWAL is used to easily remember the following symptoms: W = wakefulness; I = irritability; T = tremulousness, temperature variation, and tachypnea; H = hyperactivity, high-pitched persistent cry, hyperacusis, hyperreflexia, and hypertonus; D = diarrhea, diaphoresis, and disorganized suck; R = rub marks, respiratory distress, and rhinorrhea; A = apnea and autonomic dysfunction, manifesting vague symptoms such as yawning, hiccups, and sneezing; W = weight loss or failure to gain weight; A = alkalosis (respiratory); and L = lacrimation. 140 Symptoms generally begin in heroin-affected babies earlier than in those born to mothers who have been methadone-maintained because of heroin's shorter halflife. Effects from heroin begin within 24 hours, while methadone abstinence symptoms begin 2 to 7 days after birth. Acute symptoms may persist for several weeks, and subacute symptoms may persist 4 to 6 months. 140 These subacute symptoms continue to include irritability, sleep problems, hyperactivity, feeding difficulties, and hypertonia. 24 Neonatal narcotic abstinence syndrome (i.e., withdrawal) is present in the majority of exposed babies, approximately 42% to 68% in heroin addicts 6, 62, 130 and 63% to 85% in methadone exposed newbornsY, 97, 106, 129, 130, 146, 173 Several studies are able to correlate methadone dose and severity of withdrawal,47, 79, 132 and some are not. 108 Decreased symptoms in children born to mothers who have been weaned to less than 20 mg per day of methadone have been shown. 156 This dose is the goal if weaning of the addict is possible.1l16 The pediatrician will probably not be able to predict how any individual newborn baby will fare based on this maternal history. Because of known narcotic eNS effects, investigators have examined neurologic effects on the neonate. On the Brazelton Newborn Assessment Scale, increased depression of interactive behaviors and disruptive state control have been demonstrated for methadone exposed babies. 25 A hyperactive moro reflex has been demonstrated and advocated as one indicator to follow through withdrawal. 16 Decreased head circumference has been reported in some studies l6, 24, 25 and follow-up examination at 18 months showed a significant percentage that maintained head circumference below the third percentile. 146 This is not a constant finding,

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however, because other studies have shown a normal head circumference.102, 106 Rates of low birth weight,24, 62, 102, 130 decreased length,24, 102 small for gestational age,62,97, 129, 146 and prematurity62,97, 102, 129, 146, 173 have been shown to be increased in neonates who are exposed to opiates. Other neurologic effects from in utero opiate exposure have been documented, including an increased incidence of seizures. 128 Seemingly more seizures occur with methadone use (7.8%) than with heroin use (1.2%).82 These seizures are generalized in nature together with myoclonic jerks. Mean age of seizure onset is reported to be 10 days and extends to 30 days, which reinforces the need for prolonged observation. 82 Sleep alterations have been observed by many researchers and have been documented as decreased quiet sleep and increased active sleep.138 Strabismus has been noted to be increased among infants of methadonedependent women, especially those with multi-drug abuse.123, 146 There does not seem to be an increase in congenital anomalies102 with opiate abuse; however, increases in sexually transmitted diseases,97 hyperbilirubinemia,173 low socioeconomic status, poor environment, and family instability are associated with opiate abuse.

Long Term It is difficult to separate the environmental and drug-exposure factors that result in a poor outcome for these babies. Children at 18 months that were exposed to methadone prenatally have been shown to have lower Bayley developmental scores than control at 18 months. 146 Ten percent were found to be definitely abnormal on neurologic evaluation. 146 In one population in a 1- to lO-year follow-up examination of opiate-exposed children, only 25% were found to be completely normal with the majority of abnormalities being hyperactivity, aggressiveness, and lack of social inhibition. 91 In that same study, 43% of the children were removed from the home, which exemplifies how difficult it is to sort out confounding variables. Other studies have not found such dramatic differences. 91 The overall impression is that although intellectual deficit is mild or nonexistent, behavioral abnormalities may persist into the school years. l44 The risk of SIDS is increased in opiate-exposed infants and varies from 2.5% to 4%.6,26,29 Despite this, no breathing pattern abnormalities have been detected. 26 Narcotics remain a threat to unborn children in the 1990s. Shortterm effects of growth inhibition and withdrawal are almost overshadowed by the long-term neurologic deficits experienced by these children.

ALCOHOL

The teratogenic effects of alcohol, recognized as fetal alcohol syndrome (FAS), were first described by Jones, Smith, and colleagues89 in

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1973. No single feature can be used to diagnose FAS, which makes it very difficult to be identified during the newborn period. 103 The Fetal Alcohol Study Group of the Research Society on Alcoholism defined the following three criteria to make a diagnosis of FAS.l48, 153 Prenatal or postnatal growth retardation, or both CNS involvement Specific craniofacial dysmorphic features Some infants of alcoholic mothers only show parts of the syndrome, and they are termed as having the Fetal Alcohol Effects (FAE).43, 153 FAS and FAE may be considered as being different points on a continual spectrum of clinical deficits. The relationship of alcohol consumption and FAE is much more ambiguous. Sokol and Clarren153 suggested to use the term Alcohol Related Birth Defects (ARBD) instead of FAE to avoid confusion. FAS is the most common recognizable cause of mental retardation2 with a worldwide incidence of 1.9 per 1000 live births. 3 The incidence of FAS in the United States is 2.2 per 1000 live births. 32 The true incidences of FAS and ARBD are probably greater because the signs and symptoms of FAS may be under-recognized. 103 An estimated 65% of fetuses are exposed to alcohol prenatally in the United States.137 As many as 5% of all congenital anomalies may be attributed to prenatal alcohol exposure. 137 Conservative estimates of the economic costs of FAS have ranged from $321 million per year in the United States (up to 21 years) to $1.4 million across the lifetime of one child.157 In 1992, the NIDA Household Survey on Drug Abuse estimated that 75%174 of women of childbearing age (15-44 years) used alcohol in the past year. Of high school seniors, 20% had consumed more than a total of 5 drinks in the past two weeks.175 Little and colleagues104 investigated the effects of alcohol consumption on the offspring of lactating mothers. Even though a very small fraction (0.5%-3.3% of maternal dose) of alcohol is distributed in breast milk, its effect on the infant is almost instant.ll5 These infants sucked more frequently but consumed less milk. In contrast to the significant consequences seen in prenatal alcohol exposure, the long-term effects of alcohol exposure through lactation are still unknown. The effects of alcohol on the developing fetus can be grouped under the following categories. Antenatal complications and prematurity Congenital anomalies Growth retardation Neurobehavioral disorders

Antenatal Complications and Prematurity

Alcohol abuse in pregnancy is associated with a two- to fourfold increase in the incidence of spontaneous second trimester abortion in

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moderate to heavy drinkers. 78,94 Infants with FAS have three-times an increased chance of being born prematurelyl28; however, the association of prematurity in infants who do not exhibit the full-blown picture of FAS is still unclear. Abruptio placentae 110 and breech presentation75 have been observed to be more common in patients with FAS.

Congenital Anomalies

Clarren and Smith35 summarized the major features observed in 245 patients with FAS. Fifty percent to 80% of the patients had microcephaly, short palpebral fissure, short upturned nose, hypoplastic philtrum, hypoplastic maxilla, thinned upper lip, retrognathia in infancy, micrognathia, or relative prognathia in adolescence. They also reported offspring of chronic alcoholic women born with multiple brain abnormalities. 34 Other minor features, which mayor may not co-exist with FAS, have also been reported. 35, 71, 73, 180 Because not all infants who are exposed to high levels of alcohol in utero develop FAS, Sokol and coworkers 152 conducted a study with 8331 pregnancies to compare and contrast the FAS and nonFAS groups. They identified four significant prenatal risk factors that include high percentage rates of drinking days during pregnancy, positive Michigan Alcoholism Screening Test, African-American race, and high parity. The overall incidence of FAS in infants born to women who have a history of drinking alcohol during pregnancy is approximately 2% to 3%.110 The risk is increased to 85.2% if all four risk factors are present. 152 The risk of having ARBD is believed to be much higher. Despite the fact that ARBD may account for as much as 5% of all congenital anomalies, most reports fail to demonstrate an association of fetal malformation with mild to moderate drinking during pregnancy yo, 116, 172 Research indicates that alcohol exerts a dose-response effect on both the animal and the human fetus. 165 In utero alcohol exposure in the animal model has demonstrated the effects of chronic fetal hypoxia, decrease in brain weight, suppression of cell division, and abnormal formation of the brain. l34 A positive relationship between craniofacial abnormalities and the amount of alcohol consumption during pregnancy has been demonstrated. l33 Features compatible with FAS were seen in about 10% of infants who were exposed daily to one to two ounces of absolute alcohoF6 The risk increased to 19% and 40% in those infants exposed to more than two or more than five ounces per day, respectively?6 The teratogenic effects of alcohol are also closely related to the timing and to the peak level of in utero exposure. Alcohol exposure during the first trimester is associated with multiple anomalies,147, 170 and second and third trimester exposure is associated with growth retardation and neurobehavioral disturbances.8, 170 The effects of light, moderate, and heavy maternal alcohol consumption on fetal development were observed. 147 Congenital abnormalities were associated with heavy alcohol consumption only. There was no difference between the infants born

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to light and moderate drinkers. Infants who were born to heavily drinking mothers who did reduce their alcohol intake during pregnancy showed no difference in growth compared with offspring of other groups, but they demonstrated an increased frequency of congenital anomalies. There is no safe amount of alcohol consumption during pregnancy.116 The amount that is safe for one woman might not be safe for another woman. Growth Retardation

Infants with FAS are on average 700 g smaller at birth than other infants. 99 Growth retardation in these infants tends to persist throughout childhood, although they may experience some catch-up growth. lOS, 163 The association is much less consistent in infants with only ARBD. In the Seattle longitudinal prospective study on alcohol in pregnancy,166 prenatal alcohol consumption in the first and second months of pregnancy was found to be associated with an increased risk of having a baby with low birth weight. Jones and colleagues89 also reported a lower birth weight, shorter birth length, and decreased head circumference in the offspring of alcoholic mothers who drank continuously throughout pregnancy. These abnormalities persisted to school age. Other investigators110, 172 found no neonatal growth deficit with moderate prenatal alcohol exposure. Neurobehavioral Disturbance

One of the adverse effects of alcohol exposure in utero is withdrawal during the newborn period. The symptoms are more commonly seen in neonates with FAS, which may include abdominal distension, apnea, cyanosis, agitation, tremor, opisthotonus, or even convulsion.36,136 Most commonly, symptoms present within the first few hours and resolve within a few days.36,136 Subtle neurobehavioral changes exist, Neonates of mothers who were moderate to heavy drinkers tend to have sleep disturbances, such as diminished REM and quiet sleep. 160, 166 Diverse neurobehavioral disturbances, such as increased body activity and less habituation to aversive stimuli as measured by the Brazelton Neonatal Behavioral Assessment Scale (BNBAS), are also noticed,37 A low level of prenatal alcohol exposure was only weakly associated with slightly lowered nervous system arousal. 66 Adverse effects on neurobehavior with prenatal alcohol exposure tend to persist beyond the neonatal period. Natural home observations of the behavior of those children exposed to a moderate level of alcohol prenatally show that they were less attentive and less compliant to parental commands. 98 They also have longer reaction time on vigilance tasks in laboratory settings. lS8 Behavorial problems such as distracti1;>ility, excitability, disciplinary problems, autism, and learning disabilities have been described in chil-

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dren with FAS.l2l When the Stanford-Binet intelligence scale and Bayley Scale of Infant Motor Development were administered based on the ageappropriateness of each scale, most children with FAS were found to have motor, mental, and social delay.89 The Canadian study showed that a moderate level of prenatal alcohol exposure was associated with lower mental scores at least up to the age of 6 years. 65, 67, 68 The effects of relatively low levels of alcohol exposure were no longer measurable after 48 months, however.68 Streissguth and coworkers 163, 164, 167 reported that children with FAS or ARBD have IQs that range from severely retarded to low normal. The finding persisted at the ages of 4 and 7.5 years. 162 Also estimated was that for every 2 or more drinks consumed per day during pregnancy, there will be a decrease of IQ of 5 points at age 4 years,161 7 points at age 7 years. 163 Except in infants with FAS and high levels of in utero alcohol exposure, the effects of mild to moderate alcohol exposure are still unclear.74,169

Long-Term Follow-up Examination

Long-term follow-up examination of infants diagnosed at birth with FAS showed persistence of postnatal growth retardation at 3 years,44 6 years,163 adolescence, and adulthood. The facial features of FAS may disappear into adulthood. Some features, such as long philtrum and microcephaly, tend to persist. 157 The average comprehensive and cognitive skills for adolescents and adults were between second- and fourthgrade levels. Many of these patients showed maladaptive behaviors and attention deficit disorders. 59

CIGARETTES

The 1992 National Household Survey of Drug Abuse174 showed that 32% of women between the ages of 18 and 34 years smoked at least one pack of cigarettes per day during the past month. Heavier smokers were unlikely to change their smoking behavior during pregnancy.59,70 Smoking has been associated with adverse outcome of pregnancy.7, 78, 96 The active components of cigarette smoke consist of nicotine, tar, and harmful gases, such as carbon monoxide and cyanide. Levels of carbon monoxide are increased in the fetus. 38 Nicotine transfers readily across the placenta and passes into breast milk. 1 Nicotine may reduce placental blood circulation, and it may contribute to fetal hypoxia. 85,177 The resultant fetal hypoxia may account for the increased fetal 10ss.85 The rate of perinatal death among infants who were born to smokers was 40% higher than infants of nonsmokers.38 Women who smoke throughout pregnancy have a three-times increased risk for placenta previa. 18o Spontaneous abortion increased by a factor of 1.2 for every 10 cigarettes per day after controlling other covariates.? Increase in morphologic changes in the placenta, such as decidual necrosis, was

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also observed among chronic smokers.12o Cigarette smoking has been shown to have a dose-dependent increase in risk of spontaneous abortion,96 preterm labor,179 and SIDS.109 An association of maternal smoking and congenital heart disease has been reported. 5 Other studies showed no concrete association of congenital anomalies and fetal dysmorphogenesis with maternal smoking during pregnancy.l09 Since the first report of the growth retardation in offsprings of smoking mothers in 1957,151 subsequent studies have been confirmatory.SO,95 Birthweight reduction is directly proportional to the number of cigarettes smoked per day.n 4 On average, infants exposed to tobacco in utero tend to have intrauterine growth retardation and weigh 150 g to 250 g less than normal at birth. 1, 14, 114 They tend to be shorter, but the length discrepancy resolves when corrected for the birth weight. It is now speculated that both the quantity and quality of cigarettes smoked are important determinants of the pregnancy outcome. The content of tar, nicotine, and carbon monoxide may be important factors. Pregnant women who stop smoking in their first trimester have newborn infants whose birth weights are comparable to babies of nonsmokers.114 It is beneficial to quit smoking during pregnancy. Observations of abnormal neurobehavior in neonates of smoking mothers have been inconsistent. Poor auditory response,136 increase in tremors, heightened startle response,66 and symptoms resembling mild withdrawal were observed in different groups of patients studied. Follow-up studies in Ottawa indicated that children born to heavy smokers had lower scores in all measurements in mental development compared with children of lighter smokers.70 Children who were prenatally exposed to smoking performed less well in language comprehension and in expression as measured by the Reynell Scale at the ages of 1 and 2 years. 68 The influence of postnatal factors became more significant at the age of 24 months, however. After controlling other confounding variables, prenatal exposure to smoking was still negatively associated with the auditory, language, and cognitive performances at the age of 6 years among the same group of children. 65,70 Hyperactivity and attention deficit disorders were also commonly detected in children born to smoking mothers. A significant decrease in the IQ among children of smoking mothers was reported by Olds and coworkers 127 but the long-term effects of prenatal cigarette exposure are still unclear. Although the negative effects of cigarette smoking on fetal growth have been emphasized through the years, adverse neurobehavioral effects are now recognized by many investigators. These neurobehavioral effects are more subtle than growth effects, but they are probably even more important. DIAGNOSTIC INDICATORS OF MATERNAL SUBSTANCE ABUSE

The most common way to make the diagnosis of maternal substance abuse is for the physician to have a high index of suspicion and to recall

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that drug abuse knows no boundaries. The physician should take the history from the patient in a professional, nonaccusing manner, and he or she should make it clear that the goal is the same for all: the wellbeing of the baby. Some form of drug screening is appropriate when substance abuse is suspected. It is not recommended that all neonates be screened. 167 Urine is the most-used available screen, but meconium or hair screening may have the advantage of easier collection and a longer period of illicit substance collection. As pointed out earlier, physical examination, especially of neurobehavioral characteristics, contributes to the diagnosis.

MANAGEMENT OF THE DRUG-EXPOSED NEWBORN INFANT

The management of the baby born to substance abuse follows the same common themes. Initial management of stimulant-, narcotic-, and alcohol-exposed babies is more general than specific. Decreased environmental stimulation, swaddling, darkened environment, and small frequent feedings are often helpful. Nonoscillating waterbeds may be an inexpensive component of this supportive therapy, because this strategy has demonstrated better and consistent weight gain in opiate-exposed babies. 131 Withdrawal in the opiate-exposed babies that needs to be treated with medicine is best treated with paregoric. 22, 83, 107 The dose is 0.1 mL/kg every 4 hours and titrated according to symptomatology. With polydrug use, phenobarbital is recommended at a dose of 5 mg/ kg/day.107 Phenobarbital also is occasionally needed for the sedative effect for babies with direct toxic effects from stimulants. Breastfeeding is contraindicated for mothers with continued use of stimulants, heroin, or methadone (> 20 mg/ day). Breastfeeding is allowed with appropriately prescribed narcotics (codeine, morphine, methadone [< 20 mg/ day]).184 These children tend to have an increased environmental susceptibility to poor outcome that can be positively affected by improvement of environmental conditions. Improvement of these conditions by aid to the parents is probably as helpful therapy for the child as anything else.

SUMMARY

Substance abuse during pregnancy can be teratogenic for the fetus and can cause decreased growth parameters in the newborn infant. Short-term and long-term neurobehavioral problems have been documented also in babies born to substance-abusing mothers. The problem of substance abuse during pregnancy and its effects on the fetus is unique in medicine in that it is 100% preventable. Physicians will need to take an active role in leading society to take action in preventing substance abuse during pregnancy, and emphasis on this action should

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Gary 1. Bell, MD Division of Neonatology T. C. Thompson Children's Hospital 910 Blackford Street Chattanooga, TN 37403