NAS Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) refers to the constellation of signs and symptoms exhibited by infants with drug dependencies. The 2 major types of NAS are prenatal NAS and postnatal NAS. Maternal substance abuse, the cause of prenatal NAS, has both medical and developmental consequences for the newborn, in addition to the legal, health, and economic consequences for the mother. Postnatal NAS results when an abrupt discontinuation of opioid analgesia occurs, usually after prolonged drug exposure. NAS is more pronounced in neonates with long-term exposure to fentanyl than in those exposed to morphine.

Physical:

Infants exposed to cocaine may exhibit signs and symptoms of withdrawal of lower intensity and shorter duration than seen in infants with opiate dependency. Newborn behavior often prompts the examiner to suspect in utero drug exposure. The newborn examination may reveal low birth weight for gestational age, drug-related or alcohol-related birth defects, and characteristic facial abnormalities.

Central nervous system dysfunction

  • High-pitched cry
  • Restlessness, with sleep duration less than 1-3 hours after feeding
  • Hyperactive reflexes
  • Tremors
  • Increased muscle tone
  • Myoclonic jerks
  • Generalized convulsions

Metabolic, vasomotor, and respiratory disturbances

  • Sweating
  • Fever
  • Mottling
  • Frequent yawning
  • Sneezing, more than 3 times per interval
  • Nasal flaring
  • Respiratory rate greater than 60/min without retractions
  • Apnea

Gastrointestinal dysfunction

  • Excessive (frantic) sucking or rooting
  • Poor feeding
  • Regurgitation or projectile vomiting
  • Loose or watery stools

Alcohol-specific
Withdrawal presenting within the first 24 hours of life is reported among infants with the dysmorphic features of fetal alcohol syndrome.
Neonates also exhibit irritability, tremors, seizures, opisthotonus, and abdominal distention.
Lysergic acid
The effect of lysergic acid (LSD) on the fetus is clouded by the high incidence of poly-drug abuse.
Withdrawal symptoms manifest as hypertonia, tremors, poor feeding, and abnormal feeding patterns.
Other
Nicotine does not produce withdrawal symptoms in infants.
Caffeine withdrawal includes feeding difficulties, vomiting, excessive crying, irritability, and poor sleep patterns. Onset of symptoms may occur up to 5 days after birth and persist for weeks or months.


Evaluation and assessment
The best and most widely used scale to evaluate the neonate for NAS is the modified version of a scale developed by Finnegan. Using 31 items, it allows a semiquantitative measure of the degree to which the newborn is experiencing symptoms of withdrawal. This scale can also be used to assess the resolution of signs and symptoms after initiating treatment.
To obtain a daily average score, measurements are performed every 4 hours until the patient is stable. If 3 consecutive scores are equal to or greater than 8, treatment for withdrawal is started.
The infant is best cared for in a unit with experienced personnel who can recognize problems, perform constant evaluations, and institute the necessary interventions.


Causes: Current resurgence in heroin use is associated with the introduction of a cheap, smokeable form that is comparable to crack cocaine, only more potent. Cocaine's current popularity is related to increased availability and the presence of newer, cheaper forms.

Lab Studies:
Early drug screening during pregnancy reveals the need for maternal counseling for mothers with a history of drug abuse.
Radioimmunoassay and enzyme immunoassay
These are the most commonly used drug screens. Both are semiquantitative and highly sensitive, but enzyme immunoassay takes less time to perform and is less expensive.
These tests inform the clinician about the presence or absence of substance abuse, rather than quantifying the drug level, as in toxicology screens.
Blood tests are not useful and provide no information about the pattern, frequency, and timing of drug use.
Urine toxicology assays
Newborn urine analysis is the best screening method to detect maternal drug use. The test is readily available, while meconium and hair analysis are available at only a few centers.
These tests detect recent use of cocaine and its metabolites, amphetamines, marijuana, barbiturates, and opiates.
Alcohol is detected in blood only 12 hours after ingestion. On the other hand, cocaine can be detected in urine 6-8 hours after use in the mother and up to 48-72 hours in the newborn.
Detection of drugs depends on many variables, including individual drug metabolism, hydration status of the subject, route of administration, and frequency of ingestion.
No drugs are known to cross-react with the immunoassays for cocaine and marijuana. Several over-the-counter remedies and herbal preparations may contain ephedrine and phenylpropanolamine (recalled from US market), which can produce false-positive enzyme immunoassay test results for amphetamines. Therefore, confirmatory testing is required.
Immunoassay for opiates does not distinguish between codeine, morphine, or their glucuronide conjugates.
Meconium analysis
Meconium is first detected at 18 weeks of gestation, when drugs begin to accumulate in meconium (by direct deposition from the biliary tree or when the fetus ingests amniotic fluid).
Meconium analysis reliably determines the cumulative exposure to cocaine and its metabolites. However, this method is not widely available.
Hair analysis
This method is useful for detection of narcotics, marijuana, cocaine, and cocaine-alcohol metabolites, but it is expensive and is not widely available.
Analysis of 1.5 cm of maternal hair will reveal the maternal drug use pattern during the previous 3 months. Drug metabolites can be detected in infant hair for 2-3 months after birth.
Medical Care:
Vomiting and diarrhea associated with dehydration and poor weight gain, in the absence of other diagnoses, are indications for treatment, even in the absence of a high drug-withdrawal score.
Naloxone administration is an absolute contraindication in the resuscitation of a neonate born to a mother who used narcotics in the weeks prior to delivery. A fetus develops tolerance to and physical dependence on the medication, and use of naloxone leads to abrupt withdrawal.
Nonpharmacologic approaches
Assess daily for signs of withdrawal, including sleeping habits, feeding patterns, and weight gain.
Minimize noise and encourage swaddling.
Provide frequent small feeds of hypercaloric formula.
Pharmacologic Approaches:

Drug Category: Antiepileptic agents -- These drugs are the first and best choice for treatment. They have a long half-life that increases with age, allowing for the neonate to be discharged and treated as an outpatient.
Disadvantages include lack of effect on GI symptoms and ineffectiveness in treating seizures secondary to withdrawal. In addition, antiepileptics contain 14-25% alcohol, and larger doses are required to achieve the desired effect.

  • Phenobarbital (Luminal) -- Interferes with transmission of impulses from thalamus to cortex of brain. Used as a sedative. Irritability and insomnia are controlled. It is available in PO and IV preparations.

Opiates -- CNS depressants with advantages including oral administration, mild sedation that improves the effectiveness of sucking, and their effectiveness in treating seizures secondary to opiate withdrawal.

  • Morphine sulfate (Roxanol, Astramorph PF) -- Administered to neonates as diluted oral solution containing 0.4 mg/mL. Also may administer diluted parenteral solution orally. Use preservative-free product. Recommended that Neonatal Abstinence Scoring System be used to guide treatment management of NAS.


The term NAS was traditionally used to describe withdrawal from opioids, but the definition has been expanded to include withdrawal from other drugs, such as selective serotonin reuptake inhibitors (SSRIs) and alcohol. Multiple possible drug combinations in maternal polydrug use may raise the risk in the developing fetus. Concurrent use of cocaine and opioids has been commonly reported. Infants exposed to cocaine in the intrauterine environment typically do not demonstrate classic postnatal withdrawal; instead, the clinical manifestations reflect the ongoing effects of cocaine exposure.
Drugs frequently associated with neonatal problems include the following:

  • Opiates and narcotics
  • Codeine
  • Fentanyl
  • Heroin and methadone
  • Meperidine (Demerol)
  • Morphine
  • Pentazocine
  • Propoxyphene
  • Other drugs
  • Barbiturates
  • Caffeine
  • Chlordiazepoxide
  • Cocaine
  • Diazepam and lorazepam
  • Diphenhydramine
  • Ethanol
  • Marijuana
  • Nicotine
  • Phencyclidine
  • SSRIs

Pathophysiology:

NAS is often a multisystem disorder that frequently involves the central nervous and gastrointestinal systems. Manifestations of NAS depend on various factors, including the drug used, its dose, frequency of use, and the infant's own metabolism and excretion of the active compound or compounds. In addition, prenatal NAS depends on the infant's last intrauterine drug exposure and the mother's drug metabolism and excretion. Withdrawal is generally a function of the drug's half-life. For example, withdrawal generally occurs later with drugs that have a longer half-life.
Opiates produce the most dramatic effects on both the mother and fetus. Aside from the withdrawal symptoms, common findings in infants exposed to opiates include low birth weight, prematurity, and intrauterine growth retardation (IUGR). Because of its short half-life, heroin withdrawal occurs within 48-72 hours in 50-80% of infants born to mothers who are opiate-dependent. Some delayed withdrawal may occur up to 6 days after birth.
Methadone is used to treat heroin addiction, and its effects on the fetus are similar to the effects of heroin. Methadone's half-life is longer than 24 hours, and acute withdrawal occurs within the first 48 hours after birth and up to 7-14 days later. Neonates face an increased risk of fetal distress and demise, impaired fetal growth, and an increased risk of sudden infant death syndrome (SIDS). Thrombocytosis occurs in the second week of life and may continue until 4 months. The severity of methadone withdrawal, in relation to dose, is difficult to establish, but higher maternal doses are associated with more significant withdrawal symptoms in the neonate, especially if the maternal dose is higher than 20 mg/d.
Cocaine and amphetamines are stimulants with potent vasoconstrictor effects that stimulate the release and block the reuptake of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin. Cocaine is a potent central nervous system (CNS) stimulant that alters the major neurotransmitters and rapidly crosses the placenta. Early studies suggest that cocaine-exposed neonates demonstrated a hyperactive Moro reflex, jitteriness, and excessive sucking. More recent studies do not conclude that neonates who have been exposed to cocaine differ behaviorally from unexposed infants. The unresolved question is whether or not cocaine acts to limit head growth or disrupt brain development. The possibility of a synergistic effect between cocaine and other CNS toxins still exists.
Methylxanthine accumulates in the blood of breastfed infants whose mothers consume caffeine substances regularly. Nicotine is transferred through the placenta and may reach concentrations 15% higher than maternal levels. In utero exposure impairs neonatal habituation, orientation, autonomic regulation, and orientation to sound. Exposure also affects the infant's ability to be comforted and is associated with exaggerated startle reflex and tremor.
No evidence exists for neonatal withdrawal problems associated with maternal use of marijuana during pregnancy. Exposure to marijuana may lead to hypoglycemia, hypocalcemia, sepsis, hypoxic encephalopathy, intracranial hemorrhage, and jitteriness. Effects on the fetus are dose-dependent, with evidence of IUGR in cases of heavier usage. Neonates exposed to marijuana while in utero may also exhibit signs of nicotine toxicity, such as tachycardia, poor perfusion, irritability, and poor feeding. Growth inhibition is pronounced at birth and affects weight, length, and head circumference. Catch-up growth occurs within the first year in each growth category. Cognitive effects may persist to school age. However, withdrawal symptoms are not noted in neonates. Extended follow-up does not show any effect in children aged 5-6 years.
Several studies have demonstrated that maternal cigarette smoking during pregnancy increases the risk of having a low birth weight infant. Neonates born to mothers who smoke during pregnancy weigh an average of 150-250 grams less at birth than neonates born to mothers who do not smoke during pregnancy. Research findings also suggest that infants of mothers who smoke during pregnancy may develop nicotine withdrawal in a pattern that is related to the magnitude of in utero exposure. Infants who have been exposed to tobacco have been found to be more excitable and hypertonic and demonstrate more stress and abstinence signs.
SSRIs (fluoxetine, paroxetine, sertraline, citalopram) are used to treat depression and a wide spectrum of other mood and behavioral disorders. Infants exposed to SSRIs during the last trimester of pregnancy may exhibit neonatal adaptation syndrome. This is primarily manifested as central nervous system (eg, irritability), motor (eg, agitation, tremors), respiratory (eg, increased respiratory rate, nasal congestion), and gastrointestinal signs (eg, emesis, diarrhea). These manifestations are self-limiting and usually disappear by age 2 weeks. Symptoms are more commonly reported with fluoxetine and paroxetine exposure. A decrease in maternal SSRI use during the third trimester may lower the neonatal risk of developing withdrawal syndrome, but this needs to be balanced against the harmful effects of depression during pregnancy.
Frequency:
In the US: Incidence is difficult to determine because of unreliable histories of maternal drug abuse and limited health provider skills in eliciting drug histories and diagnosing nonopiate drug exposure in the newborn period. In addition, maternal use of more than 1 drug makes it difficult to ascribe a given effect on the neonate to a specific drug. Based on the National Survey on Drug Use and Health in the United States in 2003, the prevalence of illicit drug use among Americans is 8.2%, and, among pregnant females aged 15-44 years, the prevalence is 4.3%. Marijuana is the most common illicit drug used.
Internationally: No accurate data are available concerning worldwide incidence.
Mortality/Morbidity: Long-term mortality rate is likely to be extremely low, although the risk for SIDS is significantly higher among infants who are exposed to opiates. Infants exposed to methadone have a 3.7-fold higher risk of SIDS in comparison to controls, whereas infants exposed to cocaine have a 2.3-fold higher risk for SIDS. Infants exposed to cocaine have an almost 2-fold higher risk for SIDS compared with infants with no exposure. This increased risk is related to a complex interplay of factors; the compromised home environment associated with a mother who is drug addicted is an important variable.

Further Inpatient Care:
The length of hospitalization varies, depending on the drug, withdrawal symptoms, and social factors.
Complications:
Narcotics may have a direct effect on the development of the respiratory center in the brain stem, but effect of opiates on long-term postnatal growth is not evident. In longitudinal studies, developmental sequelae have not been proven. Problems with habituation, visual and auditory responsiveness, and interactive patterns are observed in the first months of life.
Prognosis:
Prognosis varies widely and depends on the family, socioeconomic variables, and whether either or both parents continue to use illicit drugs. A home environment with an addicted mother is a compromising variable.
 
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