Definitions
Neonatal abstinence syndrome (NAS), also known as neonatal drug withdrawal or neonatal passive addiction, is defined as a group of clinical signs in a neonate resulting from prolonged exposure to illicit or prescribed drugs.
Drug withdrawal: NAS signs and symptoms worsen as drug levels in the infant decrease, due to physical dependence.
Drug toxicity: Signs and symptoms improve with drug elimination.
Incidence
NAS is more common in infants born to opioid-dependent women than in infants born to women dependent on other drugs or alcohol.
It is estimated that 60% to 90% of infants born to substance using mothers will develop signs of NAS, and of these, 50% to 75% will require treatment.
Pathophysiology
Presentation of NAS depends on several maternal and infant factors, such as dosages, most recent use, placental transfer, and metabolism.
Prolonged drug use causes physical dependence. Abrupt discontinuation results in excessive release of noradrenaline, producing the autonomic, behavioral, and GI signs characteristic of NAS.
Transient signs of acute toxicity may be seen immediately postdelivery, whereas withdrawal signs may be delayed as the drug is metabolized and cleared by the infant.
Iatrogenic NAS may result from use of narcotics for prolonged mechanical ventilation, surgeries, and extracorporeal membrane oxygenation (ECMO).
Risk factors
Common drugs that cause NAS
The most common drugs that cause NAS include opioids, central nervous system (CNS) depressants, CNS stimulants, hallucinogens, and selective serotonin reuptake inhibitors (Table 37-1).
Opioids
Natural, endogenous, or synthetic opioids produce analgesia by binding opioid receptors in the CNS, peripheral nervous system, and gastrointestinal (GI) system and inhibiting noradrenaline release.
Opioids cause sedation, euphoria, respiratory depression, and decreased GI motility.
Neonates exposed to opioids in utero show signs of withdrawal 55% to 99% of the time.
Heroin (diacetylmorphine)
A short-acting opioid agonist that typically produces withdrawal symptoms in the first 24 hours of life. Babies born to heroin-addicted mothers have marked decrease in RDS in premature infants. Heroin may cause enzyme induction and increases in surfactant production. There is also a decrease incidence of neonatal jaundice, because heroin accelerates bilirubin conjugation. Recent findings of heroin use have indicated that quinine is often mixed with heroin prior to use. Quinine has been shown to cause hemolytic anemia.
Methadone
A pure opioid agonist has withdrawal signs that are delayed for several days after birth up to a month due to its long half-life. Up to 80% of neonates show moderate to severe withdrawal signs. Doses greater than 20 mg daily will cause NAS in >95% of infants. However, the dose that is usually needed to control maternal craving is 40 to 60 mg. Symptoms in neonates are less severe if the dose of maternal methadone is decreased to less than 20 mg a minimum of 4 weeks prior to delivery. Since abrupt change in maternal doses are contraindicated due to fetal harm, most mothers are unable to be weaned off during pregnancy, and use in the third trimester will increase the risk of withdrawal in the newborn.
Buprenorphine
A partial opioid agonist that offers potential advantages to the neonate. As compared to methadone, it has demonstrated lower transference through the placenta due to its greater molecular weight. There is reduced severity and rate of withdrawal signs by 50% to 70%, and the treatment time for withdrawal is significantly less in the neonate. The usual daily dose for opioid dependence during pregnancy is 0.8 to 4 mg. Higher maternal doses can cause prolonged withdrawal signs in the infant. Signs typically occur within the first 72 hours.
Cocaine
The use of cocaine is highly associated with other illicit drugs.
Cocaine has many negative effects on the fetus’ brain, which can complicate the withdrawal assessment.
Cocaine can cause vasoconstriction in the fetus, negatively affects fetal development directly by altering the development of the monoaminergic system in the brain, and is associated with prenatal strokes.
Cocaine has a short half-life and often does not require any pharmacologic treatment.
Acute signs of toxicity or withdrawal will present within the first 72 hours of life and include tremors, high-pitched cry, irritability, excessive suck, hyperalertness, apnea, and tachycardia.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs can cause withdrawal-like signs in 30% of infants.
Neonates can exhibit signs of irritability, constant crying, jitteriness, vomiting, sleeping difficulties, increased tone, respiratory distress, and tachypnea for up to several weeks of life.
Clinical effects are more commonly reported in infants whose mothers were taking a short-acting SSRI, such as paroxetine.
Ethanol
Signs of alcohol withdrawal may present within 3 to 12 hours after delivery and continue until age 18 months.
Acute signs of withdrawal include hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping patterns, hyperphagia, and diaphoresis.
The fetal alcohol spectrum disorder caused by significant prenatal alcohol exposure results in serious lasting effects, including facial anomalies, growth retardation, as well as sensory, behavioral, and cognitive abnormalities.
Marijuana
Rarely requires treatment.
Many infants may present with a mild opiate-like withdrawal syndrome and require supportive care.
Tobacco
Coexposure with nicotine may increase the severity and duration of neonatal abstinence syndrome.
Antipsychotics
Atypical antipsychotic use in mothers has more recently been implicated in potential causes of neonatal withdrawal or extrapyramidal signs.
The signs that have been reported in neonates include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders, which have occurred from birth to 1 month of life.
Clinical presentation
Signs of neonatal withdrawal
Neonatal withdrawal signs may begin to appear during the first 24 to 48 hours of life, but onset of signs can range from birth to the end of the second week or longer, with acute and subacute phases lasting for up to 12 months.
The severity and course of the syndrome is extremely varied. Although the withdrawal phase is transient, there may be lasting effects of the in utero or postnatal exposure due to drug neurotoxicity.
Clinical features of NAS from opioids include neurologic excitability, GI dysfunction, and autonomic signs (Table 37-2).
Signs of drug toxicity
Drug toxicity from in utero exposure may manifest in poorer neurobehavioral scores for autonomic instability, motor maturity and tone, and increased number of abnormal reflexes.
Withdrawal in premature infants
Premature infants are at lower risk of developing NAS.
This is due to the developmental immaturity of their CNS, lower total exposure than term infants, lower storage in fat cells, and poor evaluation tools for NAS in preterm infants.
Scales used to assess NAS were designed for full-term neonates. Extrapolation to preterm neonates is very difficult.
Diagnosis
NAS is diagnosed clinically. Screening laboratory tests for drug exposure (eg, urine or meconium toxicology screen) may indicate maternal drug use during pregnancy; however, neonatal drug withdrawal is a clinical diagnosis made by observing the infant’s neurologic, GI, and autonomic status.
Withdrawal assessment tools
The most common assessment tool for NAS is the Modified Finnegan Scoring System or the Neonatal Abstinence Scoring System. This scale consists of 21 items that helps quantify severity of withdrawal symptoms to guide treatment. Assessments are performed every 4 hours if scores are <8 and increases to 2-hour assessments if scores are ≥8. This has only been studied in term infants with in utero drug exposure.
The Lipsitz Neonatal Drug Withdrawal Scoring System, which is advocated by the AAP, is also commonly used. This scale has 11 items and provides only subjective ratings.
The Neonatal Withdrawal Inventory consists of an 8-point checklist of 7 NAS signs with a 4-point behavioral distress scale. Patients scoring greater than 8 will receive drug therapy.
The Neonatal Narcotic Withdrawal Index consists of 6 NAS signs plus an additional “other” category. Patients with a score greater than 5 will receive drug therapy.
The Withdrawal Assessment Tool is an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. It is commonly used for iatrogenic withdrawal assessments in the pediatric ICU, but it has not been validated in neonatal patients. It evaluates 19 withdrawal symptoms under a scoring system of 0 to 10, with 10 indicating the most severe.
Management
Supportive care
The initial treatment approaches of neonatal drug withdrawal from maternal drug exposure should include supportive care.
Forty percent of all withdrawing infants may successfully be treated without medication.
Positioning, swaddling to avoid self-stimulation, and minimal environmental stimuli, such as a dark and quiet room, have been shown to decrease signs of NAS.
Providers should cluster care for the infants, and they should respond quickly to withdrawal cues.
Feeding issues
Breast-feeding or use of human milk is recommended and associated with less severe NAS, resulting in delayed signs of withdrawal and less requirement of pharmacologic treatment.
Breast-feeding rates among opioid dependent women are low. Seventy-five percent of eligible mothers choose not to breast-feed, and of those who initiate breast-feeding, greater than half stop within 7 days.
In the industrialized world, it is not recommended that HIV-positive mothers breast-feed. However, adequately nourished narcotic-dependent mothers can be encouraged to breast-feed if they are enrolled in a supervised methadone maintenance program and have negative screening for HIV infection and illicit drugs. Mothers using street drugs or polysubstances should not breast-feed.
Infants with NAS have increased energy needs. Their high metabolic demands may warrant a caloric intake up to 200 cal/kg/d to establish growth.
In addition to the catabolism resulting from withdrawal, they may have poor feeding skills and loss of calories from vomiting and/or loose stools.
Evaluating the infants’ feeding skills and providing small and frequent feedings may be necessary.
Monitor closely for dehydration and weight loss and feed based on hunger cues. Many infants may require supplementation with IV fluids, gavage supplemental feeds, and higher calorie additives or formula.
Minimizing gas pains, vomiting, gastroesophageal reflux, diarrhea, and inadequate weight gain may help decrease the risks of facilitating clinical features of NAS. Gas pains are often worsened by “frantic hunger” and swallowing air when crying. Allow infants to feed ad lib on demand, use bottles and nipples that are appropriate for reducing air swallowing, burp frequently, and consider infant massage.
Strategies for minimizing the risk of GI dysfunction include using a low-lactose formula to improve gassiness and diarrhea, a low-osmolality formula that may improve gastric emptying time and reflux, or a thickened formula.
For excessive sucking, consider using a pacifier.
Diaper dermatitis is common in infants who have loose stools. Proper skin care and frequent diaper changes can minimize discomfort associated with skin breakdown.
Pharmacotherapy
Drug therapy is indicated when nonpharmacologic support is ineffective. It should be initiated to relieve moderate to severe signs of NAS (score ≥8 × 3, ≥10 × 2, or ≥12 × 1 by modified Finnegan) and to prevent significant complications such as seizures or inability to gain weight (Table 37-3).
Pharmacotherapy will prolong drug exposure, increase hospital length of stay, and impact maternal-infant bonding. Although drug therapy may decrease acute signs of NAS, the long-term risk and benefits have not been conclusive.
Whenever possible, treatment should contain drugs of the same class of intrauterine or iatrogenic exposure.
Opioids have traditionally been the mainstay for drug treatment of NAS from single opiate abuse. Treatment with short-acting opiates, such as tincture of opium, paregoric, and morphine are preferred first choices. There have been safety concerns with tincture of opium and paregoric due to the alcohol content.
Morphine elixir is emerging as the first-line choice and may allow for better weight gain compared to tincture of opium.
For maternal use of heroin or other short-acting opiates
Add morphine IV/PO 0.02 mg/kg/dose IV q6h or 0.05 mg/kg/dose PO q6h.
Adjust dose and interval based on patient response and use the lowest dose and interval needed.
Weaning: Decrease dose by 10% to 20% of the original dose q24-48h.
For maternal methadone/long-acting opiate use and poorly responding to morphine
Start methadone at 0.05 to 0.1 mg/kg IV/PO q8h (start at the lowest dose of methadone that is tolerated).
Start PRN morphine for breakthrough: 0.02 mg/kg/dose IV or 0.05 mg/kg/dose PO q4h PRN score ≥8 × 3, ≥10 × 2, or ≥12 × 1.
Dose titration/weaning: Assess the number of morphine doses given.
If >3 PRN doses within 24 hours, consider increasing methadone dose by 10% to 20% of original dose up to 0.025 mg/kg/dose.
If no doses were given within the past 48 hours, consider weaning methadone by 10% to 20% of the original dose q48h.
If methadone has been increased 2 times, consider adding phenobarbital to help facilitate weaning off methadone.
The use of sublingual buprenorphine for the treatment of neonatal withdrawal from maternal buprenorphine may be beneficial in some infants. Efficacy, dosing, and safety of its use have not been established.
Benzodiazepines are less commonly used for maternal exposure but are frequently used if withdrawing from iatrogenic use. Long-acting benzodiazepines, like diazepam, may be considered in infants with alcohol withdrawal although studies have not shown effectiveness.
Clonidine, an α-2 adrenergic receptor agonist, has been shown to help treat NAS by activating the inhibitory neuron and decreasing sympathetic outflow of norepinephrine.
For maternal nonopioid polysubstance abuse: consider phenobarbital with persistent or severe NAS.
Load with 10 mg/kg/dose, maintenance 3 to 5 mg/kg/d.
Do not need to follow levels unless there is respiratory depression, oversedation, liver insufficiency, initiating or discontinuing drugs that decrease the clearance of phenobarbital.
If levels are obtained, goal 10 to 20 μg/mL.
Weaning: If the patient is receiving scheduled morphine, consider initiating wean once morphine has been discontinued or is PRN. Decrease phenobarbital dose by 20% of the original dose q48h until off.
Management of iatrogenic withdrawal
Tolerance and physical dependence develop more rapidly with shorter acting drugs and after continuous infusions rather than intermittent administration. Larger doses are needed to maintain the same effects after several days, and continued administration of the drug is required to prevent withdrawal.
Withdrawal signs can develop after 5 days of fentanyl and 7 days of morphine usage.
Accumulation of highly lipophilic drugs, like fentanyl and midazolam, in the adipose tissue can cause significant withdrawal, prolonging total exposure of drug to the infant due to the release from fat storage over time as plasma levels decrease when the drug is decreased or stopped.
ECMO circuits may alter the volume of distribution and clearance of medications, and high doses may be needed during ECMO. Judiciously weaning opiates and sedatives at the time patients are cycled off ECMO should be considered to prevent accumulation and more profound withdrawal.
Patients with neurological disease may require an extended weaning time.
It is important to review the duration of opioid or benzodiazepine therapy, calculate the total cumulative doses including PRN doses, and treat with the same class of drug.
For <7 days exposure: Alternating wean by decreasing opiate or benzodiazepine q12-24h by 20% of the original dose. Consider faster wean for patients who have had very minimal exposure.
For 7 to 14 days exposure: Alternating wean by decreasing opiate or benzodiazepine q24h by 10% of the original dose (ie, each drug will be weaned every other day).
For >14 days exposure: Consider alternating wean by decreasing opiate or benzodiazepine q24-48h by 10% of the original dose (ie, each drug will be weaned every other day to every fourth day based on tolerance).
Consider weaning the current infusion down before transitioning to intermittent doses. When transitioning to intermittent doses
Calculate daily requirement and divide into four intermittent doses of lorazepam and morphine q6h alternating.
After one intermittent dose of each is given, decrease rate of benzodiazepine or opiate infusion by 25%; after second dose, decrease rate by 50%; after third dose, decrease rate by 75%; after fourth dose, discontinue infusion.
If a longer acting agent is warranted, especially in patients receiving prolonged infusions, substitute with methadone and diazepam. The conversion of fentanyl equivalents to methadone is 100:1. The daily equivalent of methadone should be divided by a factor of 6 to account for the long half-life of methadone.
When converting to long-acting agents, treat breakthrough episodes with short-acting drugs, since there will be a delay in the peak onset of action of the long-acting drugs.
Phenobarbital may be added to facilitate weaning of opiates and benzodiazepines while providing additional sedation. This should be weaned last. Decrease dose by 20% of the original dose q48h until off.
Patients requiring prolonged analgesics or sedatives may be initiated on dexmedetomidine to help decrease the need for increased continuous rates of opiates and benzodiazepines and to facilitate weaning off these drips. Dexmedetomidine, a potent α-2-adrenoreceptor agonist with eight-times higher affinity for the α-2 receptor than clonidine, has sedative, analgesic, and anxiolytic effects. After prolonged exposure, it cannot be abruptly discontinued and should be weaned off to avoid cardiovascular and neurological withdrawal signs in the infant.
If <7 days: Wean by 0.2 μg/kg/h q12-24h. May wean faster if minimal exposure.
If 7 to 14 days: Initial wean by 0.2 μg/kg/h q24h. Adjust based on patient response.
If >14 days: Initial wean by 0.1 μg/kg/h q24h. Adjust based on patient response.
Consider clonidine for refractory withdrawal: Use first-line if the patient has hypertension in combination with withdrawal symptoms and is tolerating medications enterally. Consider initiating when patient has been exposed to opiates or benzodiazepines for >7 days and is not tolerating the wean. Initiate if patient has been on dexmedetomidine infusion for a prolonged duration to facilitate weaning off dexmedetomidine.
Clonidine dose: 5 to 12 μg/kg/d PO ÷ q6-8h
Weaning: Once off other agents, decrease by 20% of the original dose q24-48h until off.
Developmental/therapeutic interventions
Supportive care, as described above, is an essential treatment environment for infants with NAS.
Physical therapy to assist with state regulation problems and hypertonia associated with NAS. Consider use of massage therapy.
Speech therapy and lactation specialists to assist with feeding difficulties seen frequently in babies with NAS.
Prognosis/outcomes
Studies at 2 years suggest that the mean scores on the Bayley Scales of Infant Development were not statistically significantly different between infants who did not require pharmacologic interventions and infants who were treated. The severity of withdrawal or treatment regimen did not affect the scores.
Withdrawal-associated seizures have not been shown to change neurologic examinations at 1 year of age. The recovery of normal concentrations of neurotransmitters, which are lowered during the withdrawal phase, is believed to be associated with the eventual normalization of EEGs and neurologic development in infants.
Infants exposed to illicit drugs and alcohol in utero are at an increased risk of sudden infant death, developmental delay, and poor school performance and learning disabilities. There are also more reports of behavioral problems including higher sensitivity to their environment resulting in irritability, agitation, aggression, and poor social skills.
Prenatal cocaine exposure has been shown to have a statistically significant decrease in neurobehavioral, cognitive, and language function, unlike intrauterine exposure of opiates.
Prenatal exposure to marijuana has been associated with increased levels of depression during childhood, increased hyperactivity, impulsivity, and inattention. Marijuana and alcohol exposure through breast milk has been shown to decrease motor development in infants at age 1 year.
The home environment plays a significant role in the developmental outcomes of exposed children.
Long-term studies are needed to evaluate outcomes of NAS in school-age children, adolescents, and adults.
Discharge
Infants at risk for NAS should be monitored in the hospital until the risk for severe withdrawal has passed. This will depend on
Maternal drug history or known hospital use
How well the infant is tolerating an established wean while in the hospital
If the home environment and support system is appropriate for discharge
Minimal time of observation in the hospital for infants who are not requiring pharmacotherapy
Infants born to mothers receiving low-dose opiates or benzodiazepines with a short half-life may be safely discharged to home at day of life 3 if there are no signs of withdrawal.
Infants born to mothers receiving opiates or benzodiazepines with a prolonged half-life, such as methadone or clonazepam, should be observed for a minimum of 5 to 7 days. Since withdrawal may occur weeks after prolonged intrauterine exposure, these infants should have close follow-up and thorough parental education of withdrawal signs.
It is recommended that buprenorphine exposed infants be observed for a minimum of 3 to 5 days as the peak onset of withdrawal signs from buprenorphine is usually 72 hours.
Infants exposed to SSRIs in utero may need to be monitored for at least 48 hours after birth.
If the infant requires pharmacotherapy, the infant should continue to be assessed for 72 hours after the cessation of drug.
To reduce length of stay in the hospital, education and protocols are necessary for all staff caring for mothers and infants at risk for NAS. The use of a published abstinence assessment tool should be implemented for screening and management decision making.
Discharge should occur after the following minimal clinical criteria are met.
The infant has normal vital signs.
The infant is tolerating feeds and gaining weight appropriately.
The infant can reach a full alert state, responds to social stimuli, and can be consoled appropriately.
Discharge counseling should include how to identify signs of NAS, education on how to create a home environment that would minimize risks of worsening NAS, empowering skills to feed and comfort the infant, and appropriate teaching of how to administer the medications.
Sending families home with a medication weaning schedule will help ensure that infants receive appropriate doses safely.
Clearly display the generic names and concentrations of medications.
If possible, consolidate doses to minimize frequency of administration and avoid two decimal points for volumes of doses to prevent inadvertent errors in measuring liquid medications.
Consider creating a calendar for patients on prolonged weaning regimens with multiple drugs to optimize compliance and safety.
Ensure that a prescription is written for sufficient supply in case escalation of doses is needed at the direction of the provider.
Establish a weaning schedule that the infant has demonstrated to tolerate prior to discharge. Do not make a wean the day of discharge!
Discharge to home should only be considered for infants being discharged to a stable social environment with close follow-up scheduled.
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