103: Infant of Substance-Abusing Mother

Existing studies on the neonatal effects of drug exposure in utero are subject to many confounding factors. Many studies have relied on the history obtained from the mother, which is notoriously inaccurate. In addition to recall bias, there is a considerable incentive to withhold information. Testing of urine for drugs of abuse does not reflect drug exposure throughout pregnancy and does not provide quantitative information. Many women who abuse drugs are multiple drug abusers and also drink alcohol and smoke cigarettes. It is thus difficult to isolate the effects of any one drug. Social and economic deprivation is common among drug abusers, and this factor not only confounds perinatal data but has a major effect on long-term studies of infant outcome.

An infant of a substance-abusing mother (ISAM) is one whose mother has taken drugs that may potentially cause neonatal withdrawal symptoms. The constellation of signs and symptoms associated with withdrawal is called the neonatal withdrawal syndrome. Table 103–1 lists the drugs associated with this syndrome.

Maternal substance abuse has increased over the past decade. It is estimated that ∼5–10% of deliveries nationwide are to women who have abused drugs (excluding alcohol) during pregnancy. The incidence is considerably higher in inner-city hospitals.

Drugs of abuse are of low molecular weight and usually water soluble and lipophilic. These features facilitate their transfer across the placenta and accumulation in the fetus and amniotic fluid. The half-life of drugs is usually prolonged in the fetus compared with an adult. Most drugs of abuse either bind to various central nervous system (CNS) receptors or affect the release and reuptake of various neurotransmitters. This may have a long-lasting trophic effect on developing dendritic structures. Drugs of abuse have also been suggested to alter in-utero or perinatal programming through either epigenetic or other factors. In addition, some drugs are directly toxic to fetal cells. The developing fetus may also be affected by the direct physiologic effects of a drug. Many of the fetal effects of cocaine, including its putative teratogenic effects, are thought to be due to its potent vasoconstrictive property.

Some drugs appear to have a partially beneficial effect. The incidence of respiratory distress syndrome (RDS) is decreased after maternal use of heroin and possibly also cocaine. These effects are probably a reflection of fetal stress rather than a direct maturational effect of these drugs. Particularly in the case of cocaine, the decreased incidence of RDS is more than offset by the considerable increase in preterm deliveries after its use. The major concern in ISAMs is the long-term outcome. The importance of direct and indirect effects of drugs on the developing CNS predominates, and the risks of drug abuse far outweigh the benefits. Pathophysiology of specific drugs are as follows:

1. Opiates. Opiates bind to opiate receptors in the CNS; part of the clinical manifestations of narcotic withdrawal result from α₂-adrenergic supersensitivity (particularly in the locus ceruleus).

2. Cocaine. Cocaine prevents the reuptake of neurotransmitters (epinephrine, norepinephrine, dopamine, and serotonin) at nerve endings and causes a supersensitivity or exaggerated response to neurotransmitters at the effector organs. Cocaine is a CNS stimulant and a sympathetic activator with potent vasoconstrictive properties. It causes a decrease in uterine and placental blood flow with consequent fetal hypoxemia. It causes hypertension in the mother and the fetus with a reduction in fetal cerebral blood flow.

3. Alcohol. Ethanol is an anxiolytic-analgesic with a depressant effect on the CNS. Both ethanol and its metabolite, acetaldehyde, are toxic. Alcohol crosses the placenta and also impairs its function. The risk of affecting the fetus is related to alcohol dose, but there is a continuum of effects and no known safe limit.

Associated with an increased incidence of drug abuse are the following:

1. Maternal history

   1. Poor social and economic circumstances.

   2. Poor antenatal care.

   3. Teenage or unwed mothers.

   4. Poor education.

   5. Associated conditions include infectious diseases (hepatitis B, syphilis, and other sexually transmitted diseases/sexually transmitted infections), human immunodeficiency virus (HIV)-positive serology, multiple drug abuse, poor nutritional status, and anemia.

2. Obstetric complications

   1. Premature delivery.

   2. Premature rupture of membranes.

   3. Chorioamnionitis.

   4. Fetal distress.

   5. Intrauterine growth restriction (IUGR).

   6. With cocaine use, the following may be present (in addition to the conditions just mentioned):

      1. Hypertension.

      2. Abruptio placentae.

      3. Cardiac. Arrhythmias, myocardial ischemia, and infarction.

      4. Cerebrovascular accident.

      5. Respiratory arrest.

      6. Fetal demise.

Signs and symptoms of drug withdrawal are listed in Table 103–2. These signs essentially reflect CNS “irritability,” altered neurobehavioral organization, and abnormal sympathetic activation. Although each drug may have its own effects, these signs and symptoms must be noted for every ISAM (because of multiple drug abuse); conversely, drug abuse should be suspected in infants exhibiting these signs and symptoms. Signs and symptoms for specific drugs are as follows:

1. Opiates. Infants born to opiate-addicted mothers show an increased incidence of IUGR and perinatal distress. Even when these infants are not small for gestational age, they have lower weight and a smaller head circumference compared with drug-free infants.

   1. Signs and symptoms of withdrawal occur in 60–90% of exposed infants. The onset of symptoms may be minutes after delivery up to 1–2 weeks of age, but most infants exhibit signs by 2–3 days of life. The onset of withdrawal may be delayed beyond 2 weeks in infants exposed to methadone (parents should be appropriately informed).

   2. The clinical course is variable, ranging from mild symptoms of brief duration to severe symptoms. The clinical course may be protracted, with exacerbations or recurrence of symptoms after discharge. Restlessness, agitation, tremors, wakefulness, and feeding problems may persist for 3–6 months. There is a reduced incidence of both RDS and hyperbilirubinemia.

2. Cocaine

   1. Symptoms seen in neonates exposed to cocaine in utero. Irritability, tremors, hypertonia, a high-pitched cry, hyperreflexia, frantic fist sucking, feeding problems, sneezing, tachypnea, and abnormal sleep patterns. A specific cocaine withdrawal syndrome has not been described. The symptoms just mentioned may be a reflection of cocaine intoxication rather than withdrawal, and after an initial period of irritability and overactivity, a period of lethargy and decreased tone has been described.

   2. Controversial cocaine associations

      1. In the neonate, the following have been described. Necrotizing enterocolitis, transient hypertension, and reduced cardiac output (on the first day of life), intracranial hemorrhages and infarcts, seizures, apneic spells, periodic breathing, abnormal electroencephalogram, abnormal brainstem auditory evoked potentials, abnormal response to hypoxia and carbon dioxide, and ileal perforation. These reports were mostly case reports or insufficiently controlled case series with numerous confounding factors. There are large case-control studies that have found no association between cocaine exposure and intraventricular hemorrhage. Despite earlier concerns, there does not appear to be an increased risk of sudden infant death syndrome (SIDS).

      2. Cocaine has been suggested as a teratogen. Its teratogenic potential is presumed to be due to its vascular effects, although direct toxicity on various cell lines may also play a role. Numerous CNS anomalies as well as cardiovascular abnormalities, limb reduction defects, intestinal atresias, and other malformations have been attributed to cocaine. However, most of these associations were derived from case reports, case series, or poorly controlled studies, and a detailed examination of the data does not substantiate most of these teratogenic associations. An exception appears to be an increased risk of genitourinary tract defects associated with cocaine exposure during gestation. Moreover, there does not appear to be a dysmorphism recognizable as a “cocaine syndrome.” Cocaine is associated with an increased incidence of spontaneous abortion, stillbirth, abruptio placentae, premature labor, and IUGR.

3. Alcohol. Probably the foremost drug of abuse today. The risk that an alcoholic woman will have a child with fetal alcohol syndrome (FAS) is ∼35–40%. However, even in the absence of FAS, and also with lower alcohol intakes, there is an increased risk of congenital anomalies and impaired intellect. It is estimated that alcohol is the major cause of congenital mental retardation today. FAS consists of the following:

   1. Prenatal or postnatal growth retardation, CNS involvement such as irritability in infancy or hyperactivity in childhood, developmental delay, hypotonia, or intellectual impairment.

   2. Facial dysmorphology. Microcephaly, microphthalmos, or short palpebral fissures, a poorly developed philtrum, a thin upper lip (vermilion border), and hypoplastic maxilla.

      Numerous congenital anomalies have been described after exposure to alcohol in utero both with and without full-blown FAS. CNS symptoms may appear within 24 hours after delivery and include tremors, irritability, hypertonicity, twitching, hyperventilation, hyperacusis, opisthotonos, and seizures. Symptoms may be severe but are usually of short duration. Abdominal distention and vomiting are less frequent than with most other drugs of abuse. In premature infants of women who were heavy alcohol users (>7 drinks/wk), there is an increased risk of both intracranial hemorrhage and white matter CNS damage.

4. Barbiturates. Symptoms and signs of withdrawal are similar to those observed in narcotic-exposed infants, but symptoms usually appear later. Most infants become symptomatic toward the end of the first week of life, although onset may be delayed up to 2 weeks. The duration of symptoms is usually 2–6 weeks.

5. Benzodiazepines. Symptoms are indistinguishable from those of narcotic withdrawal, including seizures. The onset of symptoms may be shortly after birth.

6. Phencyclidine (PCP). Symptoms usually begin within 24 hours of birth, and the infant may show signs of CNS “hyperirritability” as in narcotic withdrawal. Gastrointestinal symptoms of withdrawal are less common.

7. Marijuana. Studies have suggested a slightly shorter duration of gestation and somewhat reduced birthweight, but the extent of these differences was of no clinical importance. The drug may have some mild effect on a variety of newborn neurobehavioral traits.

8. Selective serotonin reuptake inhibitors (SSRIs). Symptoms, occurring in up to 30% of exposed infants, may include irritability, seizures, myoclonus, hyperreflexia, jitteriness, persistent crying, shivering, increased tone, feeding difficulties, tachypnea, and temperature instability. It may be difficult to make a clinical distinction between symptoms of withdrawal and those of a neonatal variant of the serotonin syndrome.

9. Buprenorphine. This drug, a partial μ-receptor opiate agonist, is being increasingly used as an alternative to methadone in the treatment of pregnant opiate users. Its short-term effects on the neonate are similar to that of methadone, although duration of symptoms appears to be decreased. Symptoms of withdrawal usually occur within the first 3 days of life.

1. History. Many, if not most, drug abusers withhold this information. Details of the extent, quantity, and duration of abuse are unreliable. However, the history is the simplest and most convenient means of diagnosis.

2. Laboratory tests. The most commonly used tests to detect drugs of abuse are immunoassays (enzymatic assays or radioimmunoassays). They are, however, subject to a low rate of false-negative and, because of cross-reactivity, false-positive testing. They are thus viewed as screening tests. When it is either medically or legally important, these tests should be supplemented by the more sensitive and specific chromatographic or mass spectrometric tests.

   1. Urine. Easily obtained and is the most common substance used for drug testing. It reflects intake only in the last few days before delivery. Urine may be obtained from both the mother and the infant (in whom the substance may persist for a longer time).

      1. False-negative immunoassays. May be due to dilution (low specific gravity) or high sodium chloride content (detected by high specific gravity). Various adulterants may also affect detection; this is unlikely in the neonate but may occur in maternal urine.

      2. False-positive immunoassays. Although these depend on the specific assay used, the following have been reported:

         1. Detected as morphine. Codeine (found in many cold and cough medications and in analgesics). About 10% of codeine is metabolized to morphine in the liver. The consumption of baked goods containing poppy seeds (eg, bagels) can result in detectable amounts of morphine in the urine. These are “physiologic” false-positive results, but chromatography or mass spectrometry may determine the source by quantitative assays of other metabolites.

         2. Detected as amphetamines. Ranitidine, chlorpromazine, ritodrine, phenylpropanolamine, ephedrine, pseudoephedrine, phenylephrine, phentermine, and phenmetrazine. Some of these (eg, pseudoephedrine) are found in many over-the-counter preparations.

   2. Meconium. Easily obtained, and drugs may be found up to 3 days after delivery. It reflects drug use after the first trimester, has a lower rate of false negatives, is a more sensitive test than urine for detecting drug abuse, and reflects usage over a longer period than is detectable by urine testing. Its main disadvantage is that the specimen requires processing before testing and hence places an additional burden on the laboratory. The ability to detect drugs is reduced after formation of fed stools.

   3. Hair. This is by far the most sensitive test available for detection of drug abuse. Hair grows at 1–2 cm/mo; hence maternal hair can be segmented and each segment analyzed for drugs. Thus details of drug abuse throughout pregnancy may be obtained. There is a quantitative relationship between amounts of drug used and amounts incorporated in growing hair. Hair may be obtained from the mother or the infant (in whom it will reflect usage only during the last trimester). Hair may also be obtained from the infant a long time after delivery should symptoms occur that suggest in-utero drug exposure that was previously unsuspected. The test requires processing before assay, is more expensive, and is currently not as widely available as other test methods

   4. Routine laboratory testing. Routine laboratory tests are usually not required in ISAMs (other than tests to confirm the diagnosis). Laboratory tests are required to rule out other causes of particular signs and symptoms (eg, calcium and glucose for cases of jerky movements) or to follow up and manage some particular complication of drug abuse appropriately.

3. Other studies. A scoring system has been devised for assessment of withdrawal signs. Commonly called the Finnegan score, after its originator, the score was devised for neonates exposed to opiates in utero. Its usefulness for assessing signs after exposure to other drugs or for guiding management in these cases has not been established, but it can be used as a guide. The scoring system is shown in Table 103–3. Other tools for assessing neonatal abstinence are the Lipsitz tool, Neonatal Narcotic Withdrawal Index, and the Neonatal Withdrawal Inventory, but these are less commonly used.

Manifestations of drug withdrawal in many infants resolve within a few days, and drug therapy is not required. Supportive care suffices in many, if not most, infants. It is not appropriate to treat prophylactically infants of drug-dependent mothers. The infant's withdrawal score should be assessed to monitor the progression of symptoms and the adequacy of treatment.

1. Supportive care

   1. Minimal stimulation. Attempt to keep the infant in a darkened, quiet environment. Reduce other noxious stimuli.

   2. Swaddling and positioning. Use gentle swaddling with positioning that encourages flexion rather than extension.

   3. Prevent excessive crying with a pacifier, cuddling, and so on. Feedings should be on demand if possible, and treatment should be individualized based on the infant's level of tolerance.

2. General drug treatment. Warning: Naloxone (Narcan) may precipitate acute drug withdrawal in infants exposed to narcotics. It should not be used in infants born to mothers suspected of abusing opiates.

   The general aim of treatment is to allow sleep and feeding patterns to be as close to normal as possible. When supportive care is insufficient to do this, or if symptoms are particularly severe, drugs are used. Indications for drug treatment are progressive irritability, continued feeding difficulty, and significant weight loss. A score >7 on the Finnegan score for 3 consecutive scorings (done every 4 hours during the first 2 days) may also be regarded as an indication for treatment. However, the Finnegan score should not be followed slavishly and treated as a definitive laboratory value. Many centers use the Finnegan score only every 12 hours and increase the frequency of its application if the infant's scores rapidly escalate. Drugs used for withdrawal are discussed next. Additional treatment may be required for some symptoms (eg, dehydration or convulsions). There have been very few clinical trials in this area, and drug therapy is based largely on anecdotal evidence and hence is variable. Cumulative reports suggest that drugs that act on the relevant receptors are superior to sedatives. When compared with opiates, phenobarbital, at doses required to suppress symptoms of withdrawal, may impair sucking in infants withdrawing from maternal opiates, and may require a more protracted duration of treatment.

   1. Morphine. A recent randomized trial comparing morphine with tincture of opium showed that infants treated with morphine required a somewhat longer duration of treatment but had better weight gain. An appropriate schedule of treatment would be to start at a morphine dose of 0.04 mg/kg every 4 hours. Dosage may be increased every 4 hours at increments of 0.04 mg/kg until symptoms are under control (absent side effects). Once the symptoms are under control (eg, Finnegan score <8), treatment is maintained at that dosage for 72 hours and then weaning is commenced. Weaning is done by decreasing the daily dose by 10% every day, as long as symptoms do not relapse. If the infant becomes symptomatic during weaning, the dose is increased back to the last previous dose that had controlled the symptoms. There are no reports of any maximal dose of morphine used for withdrawal, but prudence suggests that infants be closely watched for side effects, and some centers recommend cardiorespiratory monitoring if morphine dosage exceeds 0.8 mg/kg/d. As mentioned, there is a paucity of controlled trials on this topic, and treatment schedules are highly variable between institutions. The schedule just suggested is within the range of common practice but is not carved in stone.

   2. Paregoric (camphorated opium tincture). This has 0.4 mg/mL morphine equivalent and is thought to be more “physiologic” than nonnarcotic agents but is no longer recommended due to other constituents present in the preparation (eg, camphor, alcohol, benzoic acid).

   3. Opium tincture, also called tincture of opium. This is similar to paregoric and has the advantage of fewer additives. It has a 10 mg/mL morphine equivalent and should be diluted to provide the same morphine dosage as in Section VII.B.1.

   4. Phenobarbital. An adequate drug for controlling withdrawal from narcotics, especially those of irritability, fussiness, and hyperexcitability. It is not as effective as morphine for control of gastrointestinal symptoms. It is not suitable for dose titration because of its long half-life. It is mainly useful for treatment of withdrawal from nonnarcotic agents. The dosage is a 10–20 mg/kg loading dose, followed by 2–4 mg/kg/d maintenance. Once symptoms have been controlled for 1 week, decrease the daily dose by 25% every week.

   5. Chlorpromazine. Quite effective in controlling symptoms of withdrawal from both narcotics and nonnarcotics. It has multiple untoward side effects (it reduces seizure threshold, cerebellar dysfunction, and hematologic problems) that make it potentially undesirable for use in neonates when alternatives can be used. The dosage is 3 mg/kg/d, divided into 3–6 doses per day.

   6. Clonidine. This has been used for withdrawal from both narcotic and nonnarcotic agents. The dosage is 3–4 mcg/kg/d, divided into 4 doses per day.

   7. Diazepam. This has been used to treat withdrawal from narcotics. One study showed a greater incidence of seizures after methadone withdrawal when infants were treated with diazepam rather than paregoric. When used to treat methadone withdrawal, it also impairs nutritive sucking more than methadone does alone. It may produce apnea when used with phenobarbital. It may be used for treatment of withdrawal from benzodiazepines and possibly also for the hyperexcitable phase after cocaine exposure. The dosage is 0.5–2 mg every 6–8 hours.

   8. Bupernorphine. In a randomized trial, sublingual bupernorphine was found to reduce the duration of pharmacotherapy and length of stay in neonatal abstinence syndrome. Results are promising but further trials are required before its widespread use.

   9. Combination therapy (failure of monotherapy). In one study, the combination of diluted tincture of opium (1:25 dilution of opium tincture to water) in combination with phenobarbital was superior to treatment with diluted tincture of opium alone. Patients given this combination spent less time with severe withdrawal and required less diluted tincture of opium, and duration of hospitalization was reduced by 48%. In another randomized trial, clonidine (1 mcg/kg/dose every 4 hours) when combined with tincture of opium was found to reduce duration of pharmacotherapy for neonatal abstinence.

3. Long-term management. If the infant is discharged after 4 days, an early appointment with the pediatrician should be arranged and the parents should be informed as to possible signs of delayed-onset withdrawal. Minor signs and symptoms of drug withdrawal may continue for a few months after discharge. This places a difficult infant in a difficult home situation. There are a few reports of an increased incidence of child abuse in these circumstances. Thus, frequent follow-up visits and close involvement of social services may be required.

4. Breast-feeding. The various drugs of abuse may be presumed to enter breast milk, and there have been case reports of intoxication in breast-fed infants whose mothers had continued to abuse drugs. Mothers on low-dose methadone have been allowed to breast-feed, but this required close supervision, and there was a constant concern that unsupervised weaning would precipitate withdrawal. A recent study demonstrated that concentration of methadone in breast milk, even at peak maternal plasma levels, was low in the perinatal period. The mothers had been receiving methadone doses of 76 ±22 mg. The data support recommendations of breast-feeding for women on methadone maintenance. However, methadone-dependent women require special considerations and support and should also be counseled as to the unknown CNS effects of long-term exposure to small amounts of methadone present in breast milk. Similarly, there is no evidence that breast-feeding should not be discouraged in mothers who are receiving treatment with SSRIs. However, pending definitive evidence, caution suggests that breast-feeding might be discouraged in the particular case of fluoxetine use, due to its long elimination half-life and risk of accumulation.

During the first few years of life, infants exposed to drugs in utero may have various neurobehavioral problems. Prognosis is largely dependent on the drug used.

1. Opiates. There are increased risks of sudden infant death syndrome (SIDS) and strabismus. A substantial proportion of children demonstrate good catch-up growth by 1–2 years of age, although they may still be below the mean. There are limited data on long-term follow-up, but at 5–6 years of age these children appear to function within the normal range of mental and motor development. Some differences have been found in various behavioral, adaptive, and perceptual skills. At 9 years of age, there is a trend, in opiate-exposed children, to score lower than controls in some measures of language processing. Some children require special education classes. A positive and reinforcing environment can improve infant outcome significantly.

2. Cocaine. No major deficits in motor development have been found after gestational exposure to cocaine. By 1–6 years of age, there are no significant differences in weight, height, and head circumference between cocaine-exposed and nonexposed children. Gestational cocaine exposure may, however, be associated with long-term effects on behavior. Cocaine-exposed children exhibited more behavioral problems (both internalizing and externalizing) on follow-up to age 7 years, and these issues were related to degree of cocaine exposure during gestation. A long-term study found a 4.4-point decrease in IQ at 4.5–7 years of age after gestational exposure to cocaine. In addition, cocaine-exposed children are more likely to be referred for special education services at school when compared with unexposed children.

3. Phencyclidine. Very few studies have been done, but at 2 years of age these infants appear to have lower scores in fine motor, adaptive, and language areas of development. Although weight, length, and head circumference are somewhat reduced at birth, most children demonstrate adequate catch-up growth.

4. Marijuana. There is no definitive evidence of long-term dysfunction. Some scientific studies have found that infants born to women who used marijuana during their pregnancy display altered responses to visual stimulation, increased tremors, and a high-pitched cry, which may indicate problems with nervous system development. During preschool and early school years, marijuana-exposed children have been reported to have more behavioral problems and difficulties with sustained attention and memory than nonexposed children.