Perinatal Drug Abuse and Neonatal Drug Withdrawal Clinical Presentation

Pregnancy actually offers an excellent opportunity for a mother to seek help and to change her life to protect another. However, given the large numbers of mothers who abuse drugs and whose use goes undetected by their obstetricians and pediatricians, the history-taking practice in prenatal settings must change if this part of the medical evaluation is to be useful.

• Previous attempts at universal toxicology screens for women who are pregnant typically have uncovered one half of all women who abuse drugs. Urine toxicology in combination with a well-performed history is likely to have synergistic results in discovering mothers who abuse substances.
• All too often, the wish to perform an efficient prenatal screening consists solely of asking whether the woman who is pregnant uses drugs. Such questioning carries such stigma and lack of empathy that it is likely to prevent a mother-to-be from admitting her habit of substance abuse. Questioning should be nonjudgmental (ie, ask in a neutral tone of voice), specific (ie, ask about each potential drug of abuse starting with the least innocuous to the most), and asked in succession with the other standard screening inquiries (eg, general medical condition, diet).
• Although several perinatal complications have been thought to be highly associated with in utero drug use, none are pathognomonic. Multiple studies have reported an association of maternal cocaine and tobacco use and placental abruption.
• Methadone is perhaps the most commonly seen medication in the withdrawing infant. Clinicians can be somewhat prepared to care for these infants because such information is made available during the prenatal visit. In assessing the history of the maternal methadone dose, one must consider a great deal of conflicting data concerning the predictability of withdrawal severity with maternal methadone concentrations. Whether the relationship between maternal methadone dose and severity of neonatal withdrawal is linear remains a subject of debate.^{[7, 8, 9, 10, 11]} One study noted that infants who were conceived while the mother was on methadone had better drug treatment outcomes for withdrawal compared with infants who were only exposed in the third trimester.^[12] Withdrawal severity was similar for both groups.
• Buprenorphine has become a rapidly popular withdrawal treatment medication for pregnant women.^{[13, 14, 15, 16]} As a partial opiate agonist, it has a ceiling effect in pleasurable effects and has shown increased compliance while also demonstrating lower transference through the placenta compared with methadone due to its greater molecular weight.

Severity of newborn withdrawal from substances depends on the drugs and the frequency of use by the mother during pregnancy.

• Nonopiate drug withdrawal: Withdrawal syndromes that are related to individual nonopiate drugs have been difficult to study. The high prevalence of polydrug use prevents clinicians from witnessing the effects of isolated medications. At this time, little data supports a description of a cocaine-abstinence syndrome.
• Alcohol withdrawal: Signs of alcohol withdrawal may include hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping patterns, hyperphagia, and diaphoresis. Signs usually appear at birth and may continue until age 18 months. Withdrawal typically appears within 3-12 hours after delivery.
• Barbiturate withdrawal: Signs may include irritability, severe tremors, hyperacusis, excessive crying, vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting, and disturbed sleep.
• Marijuana withdrawal: For marijuana, a mild opiatelike withdrawal syndrome has been observed. Signs may include fine tremors, hyperacusis, and a prominent Moro reflex; however, these symptoms rarely require treatment.
• Nicotine withdrawal: Mild signs are observed, including fine tremors and variations in tone; recent data have shown that maternal smoking was associated with subtle neonatal behaviors, such as poor self-regulation and an increased need for handling.^[17] These behaviors are suggestive that neonatal withdrawal is possible for nicotine exposure in utero.
• Acute narcotic withdrawal: This withdrawal usually begins 24-48 hours after birth, depending on the time of last dose. However, signs may not appear in the infant until 3-4 days after birth.
• Methadone withdrawal: Symptoms typically appear within 48-72 hours but may not start until the infant is aged 3 weeks. This is particularly true for infants whose mothers took excessively higher doses. Conflicting data have emerged concerning withdrawal severity and higher in-utero methadone doses. Data have shown that coexposure with nicotine increases the severity and duration of the neonatal withdrawal.
• Buprenorphine withdrawal: Symptoms typically occur within the first 72 hours. Typically, fewer postnatal complications are reported compared with methadone, but 10% of infants exposed to buprenorphine are delivered prematurely compared with 7% of infants who are not exposed.^[15]

  • A neurological follow-up study revealed no significant differences in infants who received buprenorphine compared with infants who did not at age 4 months. However, some studies have seen increased levels of jitteriness, jerky movements, and lower limb hypertonia as late as age 9 months. However, effects of polydrug use cannot be ruled out.
  • As many as 85% of infants exposed to buprenorphine have shown signs of neonatal withdrawal; however, the syndromes and duration of treatment appear to be milder in comparison with infants exposed to methadone. Data have also shown that buprenorphine concentration in meconium may be linearly related to the onset and frequency of neonatal abstinence syndrome (NAS).^[13]
• Opiate withdrawal: Signs of NAS include hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic symptoms (eg, yawning, sneezing, mottling, fever). Tremors and jittery movements, high-pitched cries, increased muscle tone, and irritability are common. Normal reflexes may be exaggerated. Loose stools are common, leading to possible electrolyte imbalances and diaper dermatitis.

  • Long-term symptoms have been difficult to study, but evidence supports that these children show hyperphagia, increased oral drive, sweating, hyperacusis, irregular sleep patterns, poor tolerance to environmental changes, and continued loose stools.
  • NAS appears to be less severe if the mother has used opiates longer than one week prior to delivery.
• Cocaine: Acute signs such as tremors, high-pitched cry, irritability, excess suck, hyperalertness, apnea, and tachycardia can be seen with the first 72 hours of life. However, because these signs can be seen before the typical half-life of a dose immediately prior to delivery, one can argue that these signs are more typical of intoxication, rather than withdrawal.
• Amphetamines: Whether amphetamine use during pregnancy affects neonatal outcome remains unclear. Increasing evidence suggests that it is associated with an increased risk of prematurity and intrauterine growth restriction and the risk of congenital anomalies does not appear to be increased.^{[18, 19]} As well, although several reports of neonatal amphetamine withdrawal are documented, each case involved polydrug use during the pregnancies.
• Phencyclidine: Because the number of known phencyclidine use during pregnancies is limited, little is known of the neonatal consequences. Some studies have reported neurobehavioral abnormalities in the immediate neonatal period, such as hypertonicity, irritability, sleep problems, and temperature instability. However, as in many other observational reports, these typically include patients with polydrug use during the pregnancy.
• Antidepressants: Perhaps no class of medications is more studied than the current generation of selective serotonin reuptake inhibitors (SSRI). Because of their widespread use, concern over possible fetal or infant effects have been well studied.^[20] In general, no withdrawal syndrome has been associated with SSRIs. However, infants have been noted to show jitteriness, respiratory distress, and other neonatal complications. They are more commonly observed in newborns whose mothers were taking a short-acting SSRI such paroxetine (Paxil). Debate rises over whether these symptoms are actually withdrawal or, more likely, a drug intoxication effect. Of all SSRIs studied, intrapartum use of sertraline (Zoloft) has shown the safest neonatal clinical profile.

Through multiple mechanisms, all drugs of abuse can cause molecular and cellular changes that ultimately lead to changes in neural migration, cell structure, neurotransmitter dynamics, and overall brain formation. These alterations are likely associated with a whole range of behavioral and cognitive changes. Maternal polydrug use is likely to be far more damaging than use of any single drug.

• Ethanol

  • Alcohol produces teratogenic effects associated with fetal alcohol syndrome (FAS) and its variations. The suggested pathway for teratogenicity involves a direct effect on the anterior neural tube and surrounding structures. This leads to decreased brain development as well as typical FAS facies. The continuum of clinical outcomes within this disorder is broad. From the most severe form (FAS) to milder forms, such as alcohol-related neurodevelopmental disorder (alcohol-related neurodevelopmental disorder [ARND]), issues of somatic growth, brain growth and development, and facial dysmorphisms can occur.
  • In animal models, evidence shows disruption in the hippocampus, cortical cytostructure, and neuronal migration. Changes in subsequent behavior in animal models reveal deficits in object permanence, increased distractibility, and delays in gross motor development.
• Nicotine

  • Studies on in utero effects of nicotine have typically focused on low birth weight and smaller head circumference. Evidence suggests that nicotine causes more than 50% of all low birth weight babies.
  • Further studies on nicotine's effects on behavior and neurochemistry are eagerly anticipated.
• Cocaine

  • Cocaine can freely cross the placental barrier. A widely held belief was that cocaine caused fetal hypoxia due to placental vasoconstriction.
  • Animal studies have shown disruptions in the neural and glial organization and migration.
  • Dopamine, serotonin, or both may mediate withdrawal from cocaine.
  • From a behavioral standpoint, cocaine has been shown to attenuate an animal's classic conditioning ability to noxious stimuli. Adult animal models of cocaine exposure tend to show a higher predisposition to self-administration for reward.
• Opiates

  • In utero opioid exposure has consistently shown a decrease in nucleic acid synthesis and protein production in the brain, suggesting that overall brain growth is compromised. Effects on neurotransmitter concentrations and production have not been confirmed.
  • Behaviorally, prenatally exposed animals tend to show decreased exploration and increased response latency to noxious stimuli.