Neonatal Abstinence Syndrome (NAS)

What is Neonatal Abstinence Syndrome (NAS)

Neonatal abstinence syndrome is a group of withdrawal symptoms that affect newborns.

9 Interesting Facts of Neonatal Abstinence Syndrome

1. Neonatal abstinence syndrome is a postnatal drug withdrawal syndrome exhibited in some opioid-exposed neonates as a result of abrupt postpartum discontinuation of fetal opioid exposure; syndrome is characterized by central nervous system hyperirritability, autonomic dysfunction, and gastrointestinal hyperactivity
2. Some experts apply a more liberal definition to include exposure to nonopioid substances (eg, cocaine, methamphetamines, benzodiazepines, tetracyclic antidepressants, selective serotonin reuptake inhibitors, ethanol, nicotine) that may result in neonatal withdrawal manifestations; however, intrauterine opioid exposure is the most common cause of clinically significant neonatal abstinence syndrome. Polysubstance use is also very common among opioid users
3. Testing for substance use in newborns can be accomplished by urine (maternal or newborn) or meconium testing as an adjunct to verbal history. Meconium testing has advantage of identifying substance exposure from about 20 weeks of gestation; urine identifies recent exposure 
4. Monitor neonates for development of withdrawal manifestations for 3 days after exposure to short-acting opioids (eg, heroin, morphine) and 5 to 7 days after exposure to long-acting opioids (eg, methadone, buprenorphine) 
5. Diagnosis is based on cardinal manifestations of neonatal withdrawal; clinical scoring tools quantify severity of manifestations, guide pharmacologic management, and facilitate structured weaning of medication 
6. Begin nonpharmacologic treatment (eg, encourage breastfeeding or high-calorie formula, in-rooming of mother-infant dyad, avoid excessive environmental stimulus) for all neonates with suspected neonatal abstinence syndrome accompanied by serial clinical scoring tool assessments
7. Pharmacotherapy is indicated when nonpharmacologic treatment fails to effectively control manifestations, moderate to severe signs of withdrawal develop with persistently high withdrawal scores, and severe manifestations or complications (eg, seizures, fever, dehydration, weight loss) develop 
   • First line pharmacotherapy is morphine or methadone; second line adjunct pharmacotherapy options include phenobarbital and clonidine
   • Initiate, escalate, and wean treatment medications in a standardized protocol-driven fashion; consult regional and institutional protocols for guidance
8. Initial phase of withdrawal may be intense and last a few days up to 2 weeks; most neonates eventually recover with effective treatment and supportive care
9. Universal screening for maternal substance use during pregnancy with validated screening tool is recommended at first prenatal visit; screening for potential neonatal exposure is based on regional policy

What are the causes?

This condition happens after a baby’s mother misuses a substance while she is pregnant, causing the baby to become addicted to the substance. The condition develops once the baby is born and is no longer exposed to the substance.

The mother’s use of any of the following substances can lead to this condition:

• Opioids. These include:
  • Street drugs such as heroin and opium.
  • Certain prescription pain medicines.
• Amphetamines, barbiturates, and benzodiazepines.
• Cocaine.
• Marijuana.
• Alcohol.
• Some mental health medicines.
• Substitution drugs used to treat addiction.

What are the symptoms of Neonatal Abstinence Syndrome?

Symptoms of this condition depend on which substance the baby is addicted to, and how much of the substance the mother used. Symptoms are usually seen within 2 weeks of birth, but they can also appear within the first 24–72 hours. Symptoms may include:

• Extreme agitation and trouble being calmed down.
• Crying a lot.
• A high-pitched cry.
• Spasms, tremors, or seizures.
• Constant sucking.
• Fever.
• Loose stools.
• Blotchy skin.
• Rapid breathing.
• Poor feeding.
• Trouble sleeping.
• Vomiting.
• Dehydration.
• Low birth weight.
• Poor weight gain.
• Sweating.
• Sneezing or stuffy nose.

How is Neonatal Abstinence Syndrome diagnosed?

This condition may be diagnosed based on:

• Your baby’s medical history.
• The mother’s medical history.
• A physical exam.
• A test of a sample of urine, stool, hair, or blood. Blood tests may involve a sample of blood from the umbilical cord.

How is Neonatal Abstinence Syndrome treated?

Neonatal Abstinence Syndrome may be treated with:

• Supportive care. This may involve holding your baby and soothing him or her in a quiet, calm environment.
• Medicines. These may be given to reduce symptoms.
• Extra nutrition.
• Fluids given through an IV tube.
• Swaddling the baby.
• Music therapy or massage.

Your baby may need to be treated at the hospital, where her or his symptoms can be watched.

Follow these instructions at home:

• Feed your baby as told by your health care provider. Ask your health care provider if and when breastfeeding is safe for your baby.
• Create a calm, quiet environment for your baby so your baby can rest.
• Give over-the-counter and prescription medicines only as told by your child’s health care provider.
• Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• Your baby continues to have symptoms.

Pitfalls

• Maintain a high degree of suspicion for neonatal withdrawal in patients with concerning potential manifestations
  • Historical account of maternal exposure is often inaccurate
  • Constellation of manifestations is highly variable among individual neonates in withdrawal
  • Timing and severity of manifestations is highly variable and dependent on a number of potential confounding factors (eg, use of other substances, pharmacologic profile of opioid, timing of last maternal use, genetic factors)
• Carefully consider and exclude any potential alternate diagnosis (eg, withdrawal from other substances, sepsis, hypoglycemia, hypocalcemia)
  • Presenting signs and symptoms are generally nonspecific and may mimic a number of other serious conditions in neonates
• Toxicologic testing for neonatal substance exposure is not standardized; consult regional and institutional protocols for guidance
• Bag specimen urine testing for substance exposure in neonates is convenient; however, sensitivity is low and window of detection for substance exposure is minimal (ie, only capable of detecting exposure from up to a few days before birth)
  • Negative test result cannot be used to exclude significant exposure and presence of neonatal withdrawal
• Clinical scoring tools are not rigorously validated and interobserver reliability may be low; many modified versions of available scoring tools are in use, further compounding potential confusion among practitioners
• Maintain awareness that breastfeeding is encouraged when contraindications are absent; breastfeeding is a proven, important treatment measure for neonates with possible withdrawal
  • Contraindications include HIV infection, hepatitis C with nipple trauma, active substance misuse, and polysubstance abuse; breastfeeding is not recommended for mothers taking codeine 
  • Maternal medication-assisted treatment (eg, buprenorphine, methadone), regardless of dose, is not a contraindication to breastfeeding; amount of methadone or buprenorphine transferred in breast milk is low
• No universally accepted regimen or standard of care exists for initiation, escalation, stabilization, or weaning of pharmacotherapy
  • Variations in current practice involving a number of pharmacologic treatment areas are not uncommon
  • Consult regional and institutional protocols for guidance regarding preferred local treatment practices

Neonatal abstinence syndrome is a postnatal drug withdrawal syndrome exhibited in some opioid-exposed neonates as a result of abrupt postpartum discontinuation of fetal opioid exposure; syndrome is characterized by central nervous system hyperirritability, autonomic dysfunction, and gastrointestinal hyperactivity 

Some experts apply a more liberal definition to include exposure to nonopioid substances (eg, cocaine, methamphetamines, benzodiazepines, tetracyclic antidepressants, selective serotonin reuptake inhibitors, ethanol, nicotine) that may result in neonatal withdrawal manifestations; however, intrauterine opioid exposure is the most common cause of clinically significant neonatal abstinence syndrome

Polysubstance use is very common among opioid users and may affect withdrawal syndrome 

Clinical Presentation

History

• Pregnant women may not disclose an honest account of drug use for various reasons (eg, fear of consequences, denial, shame, guilt); interviewing partner, friends, and parents may improve accuracy of history 
  • Mother may report use of opioids (eg, prescription opioid analgesics, heroin, methadone, buprenorphine); maintain awareness that self-reporting often underestimates drug exposure 
  • Review of narcotic prescription registry may reveal presence of frequent opioid prescriptions or medication-assisted treatment
  • Polysubstance use is common; history may reveal concomitant use of other drugs of abuse or prescribed medications 
  • Maintain high degree of suspicion for possible opioid use in women with conditions associated with chronic pain (eg, sickle cell disease), lack of prenatal care, and other risk factors associated with drug use during pregnancy
    • Many women with opioid use disorder do not seek prenatal care and may be in labor at first presentation 
• Manifestations typically develop in the first few days after birth; however, timing and severity of presentation may depend on several factors: 
  • Pharmacologic profile of opioid
    • Neonates exposed to opioids with longer half-life present later than neonates exposed to agents with shorter half-life
      • Earliest onset of manifestations (24-48 hours) and overall shortest period of withdrawal are associated with opioids with shorter half-life (eg, heroin, morphine) 
      • Latest onset of manifestations (36-72 hours) and overall longer period of withdrawal are associated with opioids with longer half-life (eg, methadone, buprenorphine) 
    • Buprenorphine may be associated with reduced incidence and less severe withdrawal syndrome than that of methadone 
  • Exposure to additional substances
    • Some substances (eg, selective serotonin reuptake inhibitors, benzodiazepines, gabapentin, nicotine, cocaine) may alter timing of onset and severity of manifestations, as well as complicate evaluation and management 
      • Impact of concurrent use of several substances has not been fully characterized; data are limited 
        • Combination of cocaine or heroin with methadone may worsen severity of withdrawal 
        • Onset may be delayed and prolonged with concomitant use of benzodiazepines 
        • Use of selective serotonin reuptake inhibitors may be associated with higher peak withdrawal scores and a need for higher total drug dose during treatment 
        • Data on concomitant nicotine use are conflicting; however:
          • Several studies report higher peak withdrawal scores among infants born to maternal smokers 
          • Higher levels of nicotine intake around the time of delivery may be associated with increased need for treatment and higher total dose of required treatment medication 
          • Greater nicotine use around time of delivery may be associated with higher rates of treatment and increased total dose of medication required for treatment 
  • Timing of last use
    • Risk of acute signs may be diminished if last opioid use was 1 or more weeks before delivery 
• Symptom severity is variable, ranging from mild (tremors and irritability only) to severe 
  • Symptoms may include the following manifestations:
    • Central nervous system
      • Hyperirritability (hallmark of syndrome) 
      • Excessive crying and inconsolability
      • Sleep disturbances
      • Agitation, jitteriness, and excessive movements
      • Seizures
    • Metabolic, vasomotor, and respiratory
      • Frequent yawning
      • Sneezing
      • Nasal stuffiness
      • Fever
    • Gastrointestinal
      • Vomiting, may be projectile
      • Excessive regurgitation
      • Loose or watery stools
      • Poor feeding or hyperphagia with frantic, uncoordinated sucking
      • Excessive sucking

Physical examination

• Central nervous system manifestations
  • Irritability
  • Tremors
  • High-pitched cry
  • Hypertonia
  • Hyperactive deep tendon reflexes
  • Exaggerated Moro reflex
  • Agitation resulting in skin excoriation
  • Myoclonic jerks may mimic seizure activity 
  • Seizures (up to 11% of patients)
    • Primarily myoclonic in nature and typically responsive to opiates 
• Metabolic, vasomotor, and respiratory manifestations
  • Temperature instability and fever (rarely exceeds 38.9°C)
  • Sweating
  • Tachypnea (respiratory rate exceeding 60 breaths per minute, with or without retractions and nasal flaring) 
  • Mottling
• Gastrointestinal manifestations
  • Weight loss secondary to excessive gastrointestinal losses
  • Perianal excoriation secondary to loose stools

Causes

• Specific dose and duration of opioid sufficient to result in syndrome is not definitively known 
• Onset, duration, constellation of manifestations, and severity of syndrome are poorly understood and highly variable; may depend on many factors, including:
  • Pharmaceutical profile (eg, half-life) of opioid used by mother
  • Timing of last drug use, duration of exposure, and total accumulation of exposure
  • Concomitant maternal use of additional types of drugs and maternal comorbidity
  • Differences in placental opioid metabolism and pharmacokinetics of mother and neonate 
  • Pharmacogenomics 
  • Neonatal conditions (eg, gestational age, birth weight) and comorbidity 

Risk factors and/or associations

Sex

• Male sex may be associated with increasingly severe and more prolonged withdrawal; however, limited data are conflicting 

Genetics

• Genetic and epigenetic differences play an important role in incidence and severity of neonatal abstinence syndrome
  • Infants treated for syndrome are more likely to carry homozygous allele for CYP2B6 that encodes for CYP2D6 cytochrome P450 mono-oxygenase enzyme 
  • Known epigenetic changes (eg, methylation of DNA that does not alter coding sequence itself but does alter gene expression and protein function) associated with increased need for pharmacotherapy include hypermethylation at -10 and -14 CpG in OPRM1 promoter region sites 
  • There are many known single nucleotide polymorphisms in both infant and maternal alleles that are associated with severity of neonatal abstinence syndrome. These may eventually be useful for prediction of best pharmacotherapy strategy 
    • Infant alleles include OPRM1, COMT, PNOC, and OPRK1
    • Maternal alleles include COMT, PNOC, and OPRD1

Other risk factors/associations

• Risk is about 60% to 80% of neonates after in utero exposure to opioids in pregnancy 
• Factors associated with less severe manifestations and/or possibly diminished risk of syndrome in neonate
  • Buprenorphine use (compared with methadone use) 
  • Preterm neonates and infants with lower birth weights 
  • Absent polysubstance exposure 
• Risk factors for increasingly severe and more prolonged withdrawal in neonate
  • Polysubstance exposure 
  • Full-term birth (compared with preterm) 
  • Neonates with higher birth weight (compared with lower birth weight) 
  • Methadone use (compared with buprenorphine use)
  • Concomitant use of benzodiazepines 
  • Delayed neonatal drug metabolism 
  • Maternal smoking and concomitant use of selective serotonin reuptake inhibitors may increase risk 
• Risk factors for maternal substance use disorder
  • Poor or no prenatal care 
  • Previous documented or admitted history of substance use 
  • Previously unexplained late fetal demise and repeated spontaneous abortions 
  • Unexplained intrauterine growth restriction 
  • Maternal hypertension 
  • Precipitous labor, premature delivery, and placental abruption 
  • Severe mood swings 
  • Sexually transmitted infections such as HIV and hepatitis C 
  • Cigarette smoking 
  • Poor maternal nutritional status 

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis is clinical based on history and physical examination findings
• Clinical scoring tools
  • Quantify severity of manifestations, guide pharmacologic management, and facilitate structured weaning of medication(s) 
  • Method of evaluating neonates is not standardized; a number of scoring tools are available; consult regional and institutional protocols regarding preferred tool to employ
  • Finnegan Neonatal Abstinence Scoring Tool is most widely used; several modified versions (including a version from the American Academy of Pediatrics) with fewer assessment items are available to improve practical ease of use 
• Toxicologic testing
  • Not rigorously standardized
    • Some experts consider detection of substance exposure a necessary adjunct to clinical assessment in providing potential additional information that may help in ongoing care of infant-mother dyad 
    • Other experts suggest that confirmation of substance is necessary to confirm or exclude use of additional substances during pregnancy 
  • Legal implications of testing and need for maternal consent may vary from state to state
    • Consult regional and institutional policies regarding consent requirements for specimens 
      • Maternal toxicologic testing usually requires consent
      • Policy is not consistent on maternal consent for biologic specimens in neonate, and often consent is not needed
    • Consider potential additional ramifications of positive test results before ordering
      • Some states consider positive newborn urine drug screen to be evidence of child abuse 
  • Urine and meconium testing samples are most commonly used screening specimens 
    • Combined screening of both maternal urine and neonatal meconium often yields best results 
    • Use of umbilical cord tissue and neonatal hair testing is often limited to research settings; may detect minor and remote exposures 
  • Confirm positive screening test with definitive secondary testing (eg, mass spectrometry, gas chromatography) 
• Focused additional testing may be required at time of presentation to exclude alternate diagnosis and identify comorbidity
  • EEG to assess for seizure activity versus excessive myoclonic jerking and/or tremors 
  • Chest radiograph to exclude respiratory pathology in infants presenting with primarily respiratory manifestations
  • Cultures (and empiric antibiotic coverage) with concern for sepsis, particularly in infants with temperature instability (Related: Sepsis in neonates)
  • Appropriate focused laboratory testing with concern for hypoglycemia, hypocalcemia, or hyperthyroidism
  • Imaging with concern for intracranial pathology
  • Maternal screening for comorbidities (eg, HIV, hepatitis C, substance use) may be indicated 

Laboratory

• Neonatal screening tests for substance exposure
  • General notes regarding testing for opioids
    • Natural opioids are easily detectable and synthetic opioids are not 
    • Peripartum use of opioids for maternal analgesia can result in positive test result 
    • Confirm positive screening results with definitive testing method (eg, mass spectrometry, gas chromatography) 
  • Urine testing
    • Immunoassay screening is capable of detecting drug exposure during the last few days before birth 
    • Method of collection: noninvasive bag specimen 
    • Optimal specimen for collection from neonates is first urine void after birth to increase accuracy 
    • False-negative results can occur secondary to dilute urine common to newborns 
  • Meconium testing
    • More sensitive than urine testing 
    • Organic-solvent extraction method is capable of detecting drug exposure from beginning of second trimester 
    • Method of collection: 0.5 mg stool sample collected and stored at −20 to −80°C before testing 
    • Optimal specimen is collected before contamination with human milk or formula to improve accuracy 
    • Avoid specimen contamination with urine 

Other diagnostic tools

• Assessment tools developed for infants exposed to opioids 
  • Subjective nature of available scoring tools lends to variable reliability and validity 
    • Many lack rigorous validation to establish utility in improving outcomes for patients 
  • Improved test characteristics (interobserver reliability) may result from ongoing staff training with use of scoring tool
  • Tools include:
    • Finnegan Neonatal Abstinence Scoring Tool (also referred to as Neonatal Abstinence Scoring System) 
      • Most common tool used; useful for term but not preterm infants 
      • Traditional version is a lengthy 31-item tool. Several modified versions are available; most modified versions lack rigorous validation 
        • Slight variability exists among scoring of individual items between different modified versions of tool
      • Optimal threshold score for directing treatment decisions is not definitively known; threshold for abnormal score is often institution-dependent 
        • Average score among newborns without neonatal abstinence syndrome in the first few days of life is 2 
        • Score of 8 or greater is generally considered abnormal and highly suggestive of neonatal abstinence syndrome 
        • Score of 8 or greater on 3 consecutive evaluations generally indicates need for pharmacologic treatment 
        • Score of greater than 12 on 1 or 2 occasions generally indicates need for initiation of treatment

Manifestations	Score
Presence of excessive cry	2-3
Less than 1 hour	3
Less than 2 hours	2
Less than 3 hours	1
Hyperactive Moro	2
Markedly hyperactive Moro	3
When neonate is disturbed	Mild tremors = 1; moderate to severe tremors = 2
When neonate is undisturbed	Mild tremors = 3; moderate to severe tremors = 4
Increased muscle tone	2
Presence of excoriation	1
Myoclonic jerks	3
Generalized seizure	5
Fever	38-38.3°C = 1; higher than 38.3°C = 2
Sweating	1
Mottling	1
Frequent yawning (greater than 3-4 times per interval)	1
Nasal stuffiness	1
Sneezing (greater than 3-4 times per interval)	1
Tachypnea	Respiratory rate greater than 60 breaths per minute = 1; respiratory rate greater than 60 breaths per minute with retractions = 2
Nasal flaring	2
Excessive sucking	1
Poor feeding (infrequent or uncoordinated suck)	2
Regurgitation	2
Projectile vomiting	3
Stools	Loose = 2; watery = 3

Caption: Total score is compiled by addition of all individual categorical score values; median score is 2 for non–opioid exposed infants in the first few days of life; 95th percentile scores are 5.5 on first day of life and 7 on second day of life [Zimmermann-Baer U et al: Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants. Addiction. 105(3):524-8, 2010].

Citation: Data from Hudak ML et al: Neonatal drug withdrawal. Pediatrics. 129(2):e540-60, 2012; and from Finnegan LP: Neonatal abstinence. In: Nelson NM, ed: Current Therapy in Neonatal–Perinatal Medicine. 2nd ed. Toronto, Ontario: BC Decker Inc; 1990.

• • MOTHER NAS Scale 
    • Length of tool is moderate in comparison with traditional Finnegan scoring tool
    • Represents a modified version of Finnegan Neonatal Abstinence Scoring Tool with improved interobserver reliability
    • Score of 9 or greater on 2 consecutive evaluations indicates need for pharmacologic treatment
  • Other tools include: 
    • Lipsitz Neonatal Drug Withdrawal Scoring System: 11 items; interobserver reliability not established; score of 4 or higher indicates need for pharmacologic treatment 
    • Neonatal Narcotic Withdrawal Index: 7 items; high level of interobserver reliability; score of 5 or higher in 2 evaluations over 24 hours indicates need for pharmacologic treatment
    • Neonatal Withdrawal Inventory: 7 items; high sensitivity, specificity, and interobserver reliability; score of 8 or higher indicates need for pharmacologic treatment 

Differential Diagnosis

Most common

• Neonatal abstinence syndrome caused by nonopioid substances
• Respiratory distress syndrome in neonates
• Hyperthyroidism in Newborn
• Sepsis in neonates
• Hypocalcemia in Newborn
• Hypoxic ischemic encephalopathy

Treatment Goals

• Promote normal growth, development, and maternal bonding 
• Relieve moderate to severe manifestations such as fever, weight loss, dehydration, and seizures 
• Avert or minimize negative consequences such as discomfort and failure to thrive 

Admission criteria

Most patients receive inpatient treatment for duration of syndrome; many remain inpatient until first line pharmacotherapy wean is tolerated for at least 48 hours 

• In some cases, inpatient treatment is coupled with completion of pharmacotherapy weaning as outpatient 
• Combination approach may reduce length of hospital stay but is associated with longer total duration of treatment (based on limited data) 

Hospital setting for treatment is not standardized and often based on individual institutional protocol or practice; some infants may be managed in newborn nursery while others are managed in the neonatal ICU or general inpatient pediatric floor 

Criteria for ICU admission

• Neonatal ICU or intermediate care nursery may be required in certain instances, such as:
  • Escalating or high doses of opioid therapy 
  • Need for adjunct pharmacotherapy (ie, clonidine, phenobarbital) 
  • Serious manifestations (eg, seizures)
  • Need for gavage feedings to maintain adequate intake 

Recommendations for specialist referral

• Consultation with a physician specializing in addiction medicine may be beneficial and should be done for severe cases (ICU admissions)

Treatment Options

Treatment should always be started based on a presumptive diagnosis before toxicologic laboratory confirmation or after negative initial toxicologic screening, as false negative testing does occur

Initial care for all neonates is individualized, supportive, and nonpharmacologic in nature

• Initiate nonpharmacotherapeutic measures in any infant at risk 
• Strong evidence supports breastfeeding and in-rooming with minimal separation of mother-infant dyad 
• Nutritional support and monitoring for weight loss is essential 
• Other common supportive measures include provision of tranquil environment with minimal stimulation 

Pharmacologic treatment

• No universally accepted regimen or standard of care exists for initiation, escalation, stabilization, or weaning of pharmacotherapy 
  • Variations in current practice involving a number of pharmacologic treatments are not uncommon; heterogeneity in approaches includes: 
    • Threshold for initiating treatment
    • Pharmacotherapy dosing (starting dose, usage of weight-based versus symptom-based dosing)
    • Threshold for initiating adjunctive medications
    • Weaning protocols
  • Protocol-driven treatment results in fewer total treatment days and shortened hospital stays than non–protocol-driven treatment; however, optimal treatment protocol has yet to be established 
• General indications for initiation of pharmacologic management include: 
  • Failure to control symptoms with nonpharmacologic management
  • Moderate to severe signs of withdrawal 
  • Persistently high withdrawal scores 
  • Development of most severe manifestations and/or complications (eg, seizures, fever, weight loss, dehydration) 
• First and second line medication options
  • Opioid therapy is recognized as first line pharmacotherapy for most patients 
    • Options include oral morphine or methadone 
      • Morphine treatment diminishes incidence of seizures, improves feeding, decreases diarrhea, decreases agitation, and may control severe symptoms 
      • There is a lack of comparative effectiveness research between these 2 drugs
        • Modestly shorter length of hospital stay with methadone versus morphine in recent large cohort study, but variations in hospital protocols may have affected results; additional study is needed 
      • Rapid up-titration in dose is recommended to control and stabilize symptoms 
      • A variety of published approaches are available 
      • Usage of a standardized protocol for pharmacologic treatment (initiation, dosing, and weaning) may be more important than drug choice 
        • Consult institutional and regional protocols for guidance; several suggested protocols are published

Stages of protocol	Overview of protocol stages	Comments
Nonpharmacologic supportive care	Swaddling, comfort measures, and feeding	Encourage swaddling and continuous holding. Provide low stimulation environment. Encourage frequent feeding. Encourage breastfeeding. Feed nonbreastfed infants with 22 kcal/oz formula with consideration for use of lactose-free formula
Treatment with morphine or methadone	Begin pharmacotherapy with morphine or methadone based on Finnegan Neonatal Abstinence Score-modified version; initiate treatment with score of greater than 8 on 3 occasions or if score is 12 or greater on any 2 subsequent measures	Measure score with tool every 3 to 4 hours around feedings. Provide refresher training for staff using scoring tool. Maintain consistency of medication choice (ie, either methadone or morphine) within each center as standard treatment for all neonates. Specific dosing is updated in original treatment protocol
Initiation of dose	Methadone is initiated in a fixed stepwise manner; initial recommended dose of morphine is 0.05 mg/kg/dose orally every 3 hours	Specific recommendations regarding stepwise dosing of methadone is detailed in protocol
Dose escalation	Increase dosage based on Finnegan scores if scores remain elevated for both methadone and morphine	Specific recommendations regarding dose escalation are detailed in protocol.  For morphine, increase dose every 3 hours until controlled (average score less than or equal to 8 in 24 hours); give rescue dose if infant has 2 sequential scores of 9 to 12, and increase morphine by 0.02 mg/kg/dose; increase morphine by 0.04 mg/kg/dose if infant has 2 sequential scores over 12. Suggested maximum morphine dose is approximately 0.2 mg/kg/dose. Consider adjunct therapy if dose equals or exceeds 0.3 mg/kg/dose
Adjunct therapy	Add phenobarbital or clonidine; consider phenobarbital instead of clonidine in infants with suspected or confirmed polysubstance exposure, when central nervous system findings predominate, and if high-dose morphine (greater than 0.3 mg/kg/dose) is required or in infants that cannot wean for 2 consecutive days	Maintain consistency of medication choice within institution (ie, either phenobarbital or clonidine) as standard treatment for neonates requiring adjunct therapy, unless additional indications exist for alternate drug
Stabilization	Maintain stable dose after achievement of a set Finnegan score	Goal is for score to remain at 8 or less for at least 48 hours before weaning of stable morphine dose begins (72 hours of stabilization may be used if dose has increased to over 0.4 mg/kg/dose or if phenobarbital has been added) and 24 hours before weaning of methadone begins
Weaning	Morphine weaning is based on Finnegan score; methadone weaning is performed in stepwise downward increments as tolerated based on Finnegan scores; 2 approaches for discontinuation of phenobarbital are suggested	Wean morphine dose by 10% every 24 hours until point of discontinuation (single dose less than 0.02 mg/kg/dose); observe for 48 hours after discontinuation of morphine before discharging. Wean methadone by fixed increment decrease in daily dose and observe for 48 hours after methadone discontinuation before discharge

Caption: Suspected or confirmed polysubstance exposure includes use of substances such as benzodiazepines, barbiturates, antipsychotics, antidepressants, other sedatives/hypnotics, and nicotine.

Citation: Data from McQueen K et al: Neonatal abstinence syndrome. N Engl J Med. 375(25):2468-79, 2016; and from Ohio Perinatal Quality Collaborative: Updates/Changes to the Recommended OPQC NAS Protocol. OPQC website. Updated 2018. Accessed February 7, 2019. https://opqc.net/sites/bmidrupalpopqc.chmcres.cchmc.org/files/NAS/OPQC%20Recommended%20NAS%20Protocol%20Changes%202017.pdf.

• • Emerging data suggest sublingual buprenorphine may be superior to both morphine and methadone in terms of duration of treatment and length of hospitalization; however, safety of use has not been sufficiently established 

Treat dehydration and electrolyte abnormalities in standard fashion

Drug therapy

• Opioids
  • Morphine
    • Short half-life (in comparison to methadone) facilitates dose adjustment; however, more frequent dosing is required and interpatient pharmacokinetic variability may be significant. Solution does not contain ethanol 
    • Morphine may be associated with increased risk of respiratory depression and sedation, as well as prolonged hospital stay when compared with methadone 
    • Morphine Sulfate Oral solution; Neonates: 0.03 to 0.1 mg/kg/dose PO every 3 to 4 hours. Increase by 20% every 8 hours until symptoms controlled (max: 0.2 mg/kg/dose). Once dose is stabilized, individualize weaning based on symptoms.
    • Down-titration is usually appropriate after 48 hours of stable dose; daily incremental decrease by about 10% is usually well tolerated. Medication may be discontinued when dose reaches about 0.15 mg/kg/day 
  • Methadone
    • Longer half-life (25-32 hours) compared with morphine; therefore, may provide more steady blood concentrations and result in less frequent dosing, but potentially leads to drug accumulation; pharmacokinetics in neonates is largely undefined 
    • May be more difficult to titrate than morphine, commercially available noncompounded preparations contain ethanol, and drug-drug interactions (eg, phenobarbital, antiretrovirals, rifampin) may occur with use of methadone 
    • Methadone Hydrochloride Oral solution; Neonates: 0.05 to 0.1 mg/kg PO every 6 to 12 hours. Titrate by 0.05 mg/kg every 48 hours until symptoms are controlled. Maximum suggested dose: 1 mg/kg/day. 
    • Downward dose adjustment and diminished frequency of dosing is usually appropriate after 24 to 48 hours of stable dose; methadone weaning protocols vary widely between institutions. Medication may be discontinued when dose reaches about 0.01 mg/dose every 24 hours 
• Second line adjunctive agents
  • Phenobarbital
    • Disadvantages include poor treatment efficacy for gastrointestinal manifestations, lack of seizure prevention at dose administered for withdrawal, many preparations contain ethanol, adverse effects (eg, central nervous system depression or paradoxical hyperactivity, impaired sucking reflex), prolonged half-life (45-100 hours), and possibility for drug interactions (cytochrome P450 inducer) 
    • Drug of choice for nonopioid withdrawal 
    • Phenobarbital Oral solution; Neonates: 16 mg/kg PO/IV loading dose; 24 hours after load, begin 1 to 4 mg/kg/dose PO every 12 hours. Adjust dose to abstinence score and serum concentration; decrease dose by 10% to 20% per day as tolerated until able to stop.
    • When monitoring phenobarbital concentrations, effective control of neonatal abstinence syndrome manifestations is associated with therapeutic levels of between 20 to 30 mg/dL 
    • Weaning methods vary; 1 method is discharge on stable dose with goal of allowing infants to outgrow dose over time 
  • Clonidine
    • Clonidine Hydrochloride Oral tablet; Neonates: 0.5 to 1 mcg/kg/dose PO every 3 to 6 hours (Max: 8 mcg/kg/day). Dosages of 2 to 6 mcg/kg/day PO given in divided doses every 4 to 6 hours have been effective. Limited use in premature neonates.
    • May be associated with hypotension and metabolic acidosis; abrupt discontinuation may result in rebound hypertension and increased heart rate. Available data suggest that most hemodynamic changes are clinically insignificant 
    • Weaning process is not prolonged; discontinuation is commonly accomplished before discharge home 

Nondrug and supportive care

• Guidelines are lacking to support specific interventions and rigorous data are scarce for many commonly employed measures
  • Best data supporting efficacy of specific measures includes:
    • Encouragement and promotion of breastfeeding when contraindications are absent
      • Breastfed infants may experience less severe symptoms, require less pharmacologic treatment, and experience shorter length of hospital stay compared with formula-fed infants 
      • Contraindications include HIV infection, hepatitis C with nipple trauma, active substance use disorder, and polysubstance use; breastfeeding is not recommended for mothers taking codeine 
      • Maternal medication-assisted treatment (eg, buprenorphine, methadone), regardless of dose, is not a contraindication to breastfeeding; amount of methadone or buprenorphine transferred in breast milk is low 
      • Postpartum women in opioid cessation programs experience high breastfeeding cessation rates; abrupt discontinuation of breastfeeding while on medication-assisted treatment may place infants at risk of withdrawal despite low concentration of medications in breast milk 
    • Encouragement of in-rooming of mother-infant dyad
      • Active maternal involvement is considered one of the best nonpharmacologic interventions 
      • Infants roomed with mothers may experience shorter hospital stay and duration of therapy, and they are more likely to be discharged with the mother when compared with infants separated from mothers 
      • Minimize separation of mother-infant dyad 
      • Active maternal and family involvement may improve outcome 
    • Support of adequate nutrition
      • Provide adequate nutrition to minimize weight loss 
        • Neonates and infants may require 150 to 250 calories/kg/day 
        • Encourage frequent feeding 
        • If bottle feeding:
          • Many experts advocate for routine higher than standard (22 kcal/oz versus 20 kcal/oz, respectively) calorie feeds 
          • Lactose-free formula may be required to help with gastrointestinal manifestations 
          • Thickening of feeds in bottle-fed infants is suggested by some experts 
      • Inadequate weight gain requires additional intervention
        • Options include increased frequency of feedings, increased caloric density of feeds, and gavage feedings 
        • Weight loss or failure to gain weight may be secondary to general central nervous system hyperactivity, poor feeding, and/or excessive gastrointestinal losses
  • Data are scarce for many other commonly employed supportive measures
    • Provide tranquil environment with minimal stimulation
      • Maintain a gentle and soothing environment
        • Minimize exposure to light and noise 
        • Minimize stimulation
          • Promote clustering of nursing care to minimize handling and promote rest 
          • Swaddle and hold infant; encourage skin to skin contact with mother 
          • Provide opportunities for nonnutritive sucking 
        • Additional supportive measures variably employed may include:
          • Music therapy, massage, use of water bed, and recruitment of volunteers to cuddle neonate 
    • Protect skin with gloves and soft sheets for infants with motor agitation 
• Psychosocial issues
  • Comprehensive psychosocial evaluation of family is recommended to ensure adequate support and safety of newborn 
  • Report concerns about safety of neonate to child protective services 
  • Refer mother for medication-assisted treatment when appropriate 

Monitoring

• Monitoring of opioid-exposed neonates for development of syndrome before discharge
  • Monitor all such infants for onset of withdrawal symptoms
  • Perform serial assessments with scoring tool
    • Observe for at least 3 days after exposure to short-acting opioids 
    • Observe for at least 5 to 7 days after exposure to long-acting opioids 
  • Hospital setting for observation is not standardized and often based on individual institutional protocol or practice; options include regular postpartum room, newborn nursery, and neonatal ICU 
• Monitoring of infants with neonatal abstinence syndrome
  • Monitor withdrawal manifestations with scoring tool preferred by institution; frequency depends on severity of withdrawal manifestations. General recommendations include:
    • Reassessment of scores exceeding 8 every 2 hours 
    • Reassessment of scores of 8 or less every 4 hours 
  • Monitor daily weight and input/output and perform clinical assessment for dehydration 
    • More frequent weights are indicated in patients with excessive gastrointestinal losses 
  • Neonates requiring pharmacotherapy need monitoring for respiratory rate, oxygen saturation, apnea events, and signs of oversedation 
  • Phenobarbital levels are not routinely monitored if patient is responding to typical maintenance dosing 
    • Consider checking level if patient remains symptomatic before adjusting phenobarbital dose
    • Effective control of neonatal abstinence syndrome manifestations is associated with therapeutic levels between 20 and 30 mg/dL 
  • Monitor for appropriateness of discharge
    • Discharge criteria to safe and stable home environment include the following: 
      • No major signs of withdrawal
      • Maintenance of stable withdrawal scores with minimal medication support
      • Established weight gain
      • Feeding well
      • Follow-up with pediatrician established in 2 days
• Long-term monitoring of affected infants and children
  • Recommended medical follow-up
    • Neurodevelopmental assessments to closely monitor and address emerging developmental delays (eg, motor deficits, cognitive delays) 
    • Psychobehavioral assessments to identify hyperactivity, impulsivity, and attention deficits in preschool-aged children 
    • Ophthalmologic assessment to monitor for nystagmus, strabismus, refractive errors, and other visual deficits that may complicate long-term course after neonatal abstinence syndrome 
    • Growth and nutritional assessment to identify failure to thrive 
  • Social services follow-up
    • Periodic monitoring of family for resource needs is suggested 
    • Family support assessments may identify need for additional services and help exclude continuous maternal substance use and potential child abuse 

Complications

• Consequences of maternal opioid use 
  • Outcomes for pregnant women (that may secondarily affect fetus and newborn) include increased risk for the following:
    • Infectious diseases (eg, sexually transmitted infections and HIV, hepatitis, endocarditis, osteomyelitis, cellulitis, sepsis)
    • Chaotic lifestyle (eg, prostitution, violence, theft)
    • Decreased commitment to medical and health care
    • Decreased receptiveness to social services
  • Outcomes for fetus include increased risk for:
    • Death
    • Placental abruption
    • Preterm labor
    • Growth restriction
    • Cardiac anomalies, including conoventricular septal defects, atrioventricular septal defects, and hypoplastic left-sided heart syndrome 
  • Outcomes for newborn include increased risk for:
    • Low birth weight
    • Preterm delivery
    • Small head circumference
    • Jaundice
    • Sleep myoclonus
    • Feeding difficulties
    • Poor weight gain 
    • Dehydration and electrolyte imbalances 
    • Child maltreatment and living in unsafe environment
    • Visual disturbances
    • Disrupted bonding with mother

Prognosis

• Short-term prognosis among affected neonates
  • Up to 80% of neonates require pharmacologic treatment 
    • Delay in administration of pharmacotherapy is associated with prolonged hospital stay and higher morbidity 
  • Symptomatic neonates require prolonged hospitalization
    • Average length of hospitalization is about 17 days overall and 21 days for neonates requiring pharmacologic treatment 
  • Initial phase of withdrawal may be intense and last a few days up to 2 weeks
  • Occasionally the initial withdrawal phase is followed by a long chronic and relapsing post–acute withdrawal phase lasting a few weeks to months 
    • Manifestations may include hyperirritability, sleep disturbances, hyperphagia, and mild autonomic signs
  • Development of seizures is not associated with increased risk for a poor outcome; seizures respond to opioid treatment when secondary to opioid withdrawal 
  • Most neonates eventually recover with effective treatment and supportive care 
• Long-term neurodevelopmental prognosis among children
  • Difficult to ascertain owing to numerous potential confounding environmental and social variables associated with substance-using mothers (eg, presence of polysubstance use, comorbid psychiatric and medical problems, ongoing socioeconomic sequelae of drug use) 
    • Some experts suggest that environmental and social factors may have more influence on development than brief perinatal exposure to opioids 
  • Rigorous long-term data on outcomes are lacking 
  • Some suggested adverse outcomes include child maltreatment, mental health and behavioral disorders, neurodevelopmental impairment, and visual disorders 
  • Reduced brain volume, thinner cortices, reduced cognitive ability, and more behavioral problems are noted among polysubstance-exposed children compared to nonexposed control populations 

Screening

At-risk populations

• Regional and institutional policies vary regarding universal or targeted screening for neonatal substance exposure 
• Routine universal screening for maternal opioid use and opioid use disorder in pregnancy is recommended 

Screening tests

• Screening for neonatal substance exposure
  • May include any individual or combination of maternal urine, maternal hair, fetal urine, fetal meconium, fetal cord, and fetal hair testing for exposures
• Screening for maternal opioid use and opioid use disorder in pregnancy (Related: Opioid use disorder)
  • Recommended to be part of first prenatal visit with use of validated screening tools (eg, 4Ps [Parents, Partner, Past, Pregnancy], NIDA [National Institute on Drug Abuse], Quick Screen, CRAFFT [Car, Relax, Alone, Forget, Friends, Trouble]) 
  • Refer pregnant women with positive screen result for further evaluation and possible need for medication-assisted treatment
    • SBIRT technique (Screening, Brief Intervention, Referral for Treatment) is recommended to help identify patients with substance use disorders and initiate steps toward treatment 
    • Medication-assisted treatment is preferred for pregnant women with opioid use disorder rather than medically supervised withdrawal 
    • Maternal opioid substitution programs improve pregnancy outcomes, minimize use of additional potentially hazardous substances, reduce withdrawal and high-risk behaviors, and improve prenatal care compliance 
• Laboratory testing for suspected maternal substance use and fetal exposure should be in compliance with local laws and avoid risk of discriminatory practice 

Prevention

• Primary prevention strategies focus on addressing opioid use epidemic, thereby diminishing development of neonatal abstinence syndrome 
  • Various strategies may include:
    • Targeted efforts to address overprescribing practices in women of childbearing age (eg, prescription monitoring programs, regulation of pain management clinics, establishment of opioid dosing thresholds)
    • Promotion of safe and judicious opioid prescribing practices in women of childbearing age
    • Education of patients, in particular women of childbearing age, regarding risk for syndrome development with opioid use during pregnancy
    • Development of substance use programs specifically designed for pregnant women
    • Discouragement of punitive legislation involving substance use during pregnancy (negative consequences related to disclosure among pregnant women may prevent them for seeking prenatal care)

Sources

McQueen K et al: Neonatal abstinence syndrome. N Engl J Med. 375(25):2468-79, 2016 Reference