CHAPTER 148

Infants of Substance-Using Mothers

Sara T. Stewart, MD, MPH, FAAP

Maternal substance use during pregnancy places neonates at risk for several medical, psychosocial, and developmental problems. The particular problems experienced by newborns depend on the drug (or drugs) to which they have been exposed; many have been exposed to multiple drugs in addition to cigarettes and alcohol. The long-lasting effects of alcohol exposure are well established (see Chapter 147), but the effects of newer drugs are less well defined. Illicit drugs change in their popularity, form of use, and availability at different points in time.

The environment into which a child is born also affects the child’s health and development. Environments in which substance use is common are frequently suboptimal for normal growth and development because of the effect of substance use on parenting; fragmentation of families; intimate partner violence; incarceration of significant family members; illnesses, including HIV infection; limited financial resources; homelessness or substandard housing; unemployment; child abuse and neglect; and limited access to health care. Because of these environmental issues, many drug-exposed neonates are cared for by foster parents or non-parental family members. These factors also make it difficult to determine, in a given newborn, which problems are caused by the drug exposure versus accompanying environmental conditions. This differentiation is of less significance to the physician than the researcher or epidemiologist because the physician will care for the problems exhibited by the drug-exposed newborn regardless of etiology.

Epidemiology

In 2016, 13% of women between the ages of 15 and 44 years in the United States reported having used illicit substances in the past month, which is an increase from prior years. Although data collected via maternal self-report are typically an underestimate of prevalence, a national survey reported that 6.3% of women used illicit substances in the past month while pregnant. The same survey also found that 8% of women reported drinking alcohol and 10% reported smoking cigarettes in the past month while pregnant. Meconium analysis has demonstrated not only extensive differences in the prevalence of in utero drug exposure between hospitals (eg, public versus private) but has also shown differences in the substances of choice in different geographic areas. Polysubstance use is the most common clinical scenario in all communities, and national data on women of childbearing age have shown marijuana to be the most commonly used substance, followed by opiates, hallucinogens, cocaine, and methamphetamine.

Clinical Presentation

Many of the different substances that women use while pregnant can result in similar sequelae in the newborn, infant, or child. In utero growth restriction, irritability, disordered eating or sleeping, and hypertonicity may be seen in affected newborns and infants. Older children may have developmental delays, symptoms of attention-deficit/hyperactivity disorder, learning disabilities, or behavioral difficulties (eg, oppositional or impulsive behavior). Prenatal exposure to opiates, such as heroin or methadone, may cause symptoms in the newborn of neonatal abstinence syndrome (NAS) (ie, drug withdrawal), including respiratory, gastrointestinal (GI), or nervous system effects, such as apnea, tachypnea, emesis, diarrhea, irritability, hypertonicity, tremors, seizures, temperature instability, and sneezing. Symptoms often occur within 72 hours of birth, but because of the long half-life of methadone, symptoms of methadone withdrawal may take up to 5 days to manifest.

Alcohol and cocaine have been associated with birth defects as well. Abnormalities such as absent limbs, cardiac defects, genitourinary anomalies, ocular anomalies, and microcephaly have been reported with cocaine exposure. Alcohol has been associated with a spectrum of effects, termed fetal alcohol spectrum disorder (see Chapter 147). Within this spectrum, a subset of patients fit the well-defined criteria for a diagnosis of fetal alcohol syndrome, including facial dysmorphology, growth deficiency, and neurodevelopmental disabilities. The presence of the following 3 sentinel features in the facial dysmorphology is the most sensitive and specific diagnostic finding for fetal alcohol syndrome: a flat philtrum, thin upper lip, and short palpebral fissures. The spectrum of neurodevelopmental problems includes diagnoses such as microcephaly and seizures, as well as many types of developmental, cognitive, and behavioral difficulties. Also included within fetal alcohol spectrum disorder is a category for alcohol-related birth defects, which includes anomalies such as congenital heart defects, skeletal deformities, renal anomalies, hearing loss, ophthalmologic abnormalities, and cleft lip and palate.

With the legalization of marijuana in some states, prenatal marijuana exposure is under increased discussion. Studies on marijuana exposure have shown inconsistent results on the neonatal outcomes of intrauterine growth restriction, increased arousal, and sleep disturbance. More consistent results exist concerning neurobehavioral effects on the older child. When tested in the elementary years, children exposed to marijuana in utero had an increased likelihood of difficulty with visual perception as well as memory and language tasks. Risk for attention difficulties is increased in childhood, and adolescents are at risk for problems with executive functioning.

Pathophysiology

Drugs used by pregnant women may affect newborns in 3 different ways: the drugs may be addictive and result in symptoms of withdrawal during the neonatal period; they may be toxic and lead to impaired functioning and neurodevelopmental disabilities; and they may be teratogenic and cause congenital anomalies and a dysmorphic appearance. The ultimate effects of the drugs are a complex interaction of environmental and genetic influences that are variable depending on the timing of the prenatal exposure. Differences in maternal metabolism of drugs result in differences in fetal exposure to toxins, and genetically determined differences in fetal susceptibility to the toxins lead to a spectrum of effects in exposed neonates. During gestation, the effects of drug exposure also vary depending on the timing of exposure. Each organ has a unique period of susceptibility as it forms during the first trimester. Prenatal substance exposure during this period is more likely to result in organ malformation. The second and third trimesters primarily involve organ growth, cell differentiation, and functional maturation of organs; thus, exposure during this period is more likely to result in growth abnormalities or functional difficulties. The specific effects of the different substances on the developing fetus can be understood in terms of their biochemical properties.

In utero exposure to opiates, such as heroin and methadone, results in physiological addiction. These drugs bind to opiate receptor sites in the brain and GI tract. When the drugs are no longer present after birth, the newborn experiences withdrawal. Animal models have also found that prenatal exposure to opiates can result in decreased density of cortical neurons and decreased development of neurons.

Cocaine and its metabolites cross the placenta and concentrate in amniotic fluid. Cocaine is toxic and teratogenic, and it interferes with 3 neurotransmitter pathways in the brain. Cocaine blocks the reuptake of norepinephrine. This is associated with tachycardia, hypertension, diaphoresis, and an increased incidence of preterm labor. Diffuse vasoconstriction may affect the placenta and result in anomalies such as placental infarcts or abruptio placentae. The fetus may also be affected by the vasoconstriction and its resultant hypoperfusion and ischemia and may develop anomalies, such as atresia of the GI tract, stroke, or absent limbs. Cocaine decreases the reuptake of dopamine. This effect is apparent in cocaine-using mothers who have decreased appetite and subsequent poor nutrition during pregnancy. Stereotypical behavior, hyperactivity, euphoria, confidence, and heightened sexuality may be associated with sexual promiscuity and increased risk of acquiring HIV and sexually transmitted infections (STIs). Cocaine decreases serotonin reuptake, resulting in decreased sleep. The sleep cycle of neonates who were exposed to cocaine in utero is often disrupted.

Methamphetamine is commonly manufactured from ephedrine or pseudoephedrine and has greater central nervous system (CNS) penetration than its metabolite, amphetamine. It has direct toxic effects on the CNS and causes increased release and decreased reuptake of dopamine, norepinephrine, and serotonin. These neurotransmitter alterations result in symptoms that are similar to those described for cocaine. A large prospective study of infants prenatally exposed to methamphetamine did not find increased risk of cardiac, skeletal, craniofacial, or respiratory issues, as had been previously reported; however, these newborns are at risk of being born small for gestational age.

Direct effects of methamphetamine use are dose- and frequency- dependent in the adult user. It has been shown to have cardiovascular, pulmonary, renal, and hepatic toxicity. Higher dose and increased frequency have also been associated with psychosis and toxicity to subcortical structures. More recent data have noted subcortical white matter and gray matter changes in children with prenatal exposure to methamphetamine.

Prenatal marijuana exposure results in toxic effects to the developing brain, with resultant risk of neurodevelopmental effects. Existing studies show no association between cannabis use during pregnancy and fetal anomalies, but exposed neonates may show some mild symptoms of increased arousal and sleep difficulties; no physiologic withdrawal from marijuana occurs as does with opiates. Endogenous cannabinoid receptors are present in the fetal brain, and it is believed that exposure to exogenous cannabinoids results in supraphysiologic stimulation of the receptors. This, in turn, affects synaptogenesis and developing neurotransmitter systems.

Reports have documented the occurrence of withdrawal symptoms within days after birth in neonates with prenatal alcohol exposure, but more common effects of prenatal alcohol exposure are direct cellular toxicity and teratogenesis. The specific mechanism by which alcohol and its metabolites damage fetal tissues is unknown, but it has been shown to affect CNS neuronal migration and synaptogenesis. For a given level of alcohol intake, the precise level of fetal exposure to metabolites is likely to vary among women, depending on maternal genetic makeup and the resulting variability in alcohol metabolism. Timing of the exposure during different periods of development can also result in different teratogenic effects on the fetus. Exposure during the first trimester may affect organogenesis or craniofacial development; exposure in the second and third trimesters can cause poor growth and neurotoxicity. Maternal alcohol use may also be associated with poor nutrition, resulting in poor delivery of nutrients to the fetus.

Phencyclidine (PCP) has sympathomimetic effects, including increases in blood pressure, heart rate, respiratory rate, deep tendon reflexes, and tone. Additionally, PCP has cholinergic effects, causing sweating, flushing, drooling, and pupillary constriction. Neonates exposed to PCP in utero do not exhibit these symptoms but display neurologic and developmental disorganization.

Differential Diagnosis

Major differential diagnoses relate to the symptomatology produced by the used substance or substances (Box 148.1). Neonates exposed to addictive substances, most commonly opiates such as methadone and heroin, may present with symptoms of withdrawal (Box 148.2). Irritability and jitteriness may be symptoms of drug withdrawal or direct drug neurotoxicity but may also be caused by hypoglycemia, hypocalcemia, hypomagnesemia, and sepsis. Seizures occur in 1% to 3% of neonates exposed to heroin in utero, and the differential diagnosis for neonatal seizures includes intracranial hemorrhage, hypoxic-ischemic encephalopathy, CNS infection, CNS malformation, and metabolic disorders. Gastrointestinal symptoms, such as vomiting or diarrhea, may be confused with reflux, formula intolerance, obstruction, or infectious gastroenteritis.

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