Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS), or neonatal withdrawal syndrome (NWS), occurs when in-utero addictive substances are suddenly discontinued due to birth. The most common substances include alcohol, nicotine, and rapidly increasing opioids. Some infants can also develop withdrawal symptoms from intrapartum or postnatal exposure to medication used for pain control during labor. Clinical symptoms such as irritability, a high-pitched cry, tremor, fever, poor feeding, and hypertonia can begin within hours of life and vary depending on the substance of exposure and, in some cases, multiple substances. Diagnosis is made by history, clinical presentation, and laboratory findings. Treatment is dependent on the substance(s) of exposure and severity of symptoms. The complications can be lifelong and include growth restrictions, decreased cognition, poor academic achievement, and fetal anomalies as seen in infants with fetal alcohol syndrome.

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Epidemiology and Etiology

Epidemiology

  • Incidence: 6.5 per 1,000 hospital births per year in the United States
  • 433% increase in neonatal abstinence syndrome (NAS) from 2004 to 2014, mainly from patients’ use of opioids
  • Drugs most likely to cause NAS: opioids, heroin, and methadone
  • Length of hospital stay: 7 times longer than normal postnatal hospitalization of 2–3 days
  • Increased admissions to neonatal intensive care unit (NICU)
  • Increased risk of sudden infant death syndrome (SIDS)
  • Newborns with NAS are likely to have low birth weight, premature birth, developmental delays, and birth defects similar to those seen in fetal alcohol syndrome.  
Drug use in pregnant women in the United States
Percentage of casesDrug use
20Marijuana
16Cigarette smoking
8.5Alcohol use (any amount is considered unsafe)
5.9Illicit drugs

Etiology

Different substances are associated with NAS.

  • Opioids: morphine, heroin, methadone, fentanyl, and prescription opioids such as oxycodone and hydrocodone
  • Cocaine
  • Alcohol
  • Cigarettes (nicotine)
  • Antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • Benzodiazepines
  • Barbiturates

Pathophysiology

The pathophysiology of NAS is complex and not clearly understood. 

  • Drugs transfer across the placenta to the fetus 
    • Lipophilic and low-molecular-weight drugs cross the placenta and the fetal blood-brain barrier easier than hydrophilic drugs. 
    • Examples of lipophilic drugs include opioids, cocaine, alcohol, benzodiazepines, and barbiturates. 
  • The drugs cannot be metabolized or excreted due to the immaturity of the fetal liver and kidney.
  • Drugs accumulate in the fetal tissues, altering levels of neurotransmitters such as norepinephrine, dopamine, serotonin, and gamma-aminobutyric acid (GABA).
  • After delivery, abrupt discontinuation of the drug(s) results in a withdrawal syndrome.
Neonatal abstinence syndrome

Neonatal abstinence syndrome

Image by Lecturio.

Clinical Presentation

Presentation can vary depending upon different factors, including:

  • Presence of more than 1 substance
  • Level of mother’s drug usage
  • Gestational age of exposure
  • Timing of the last dose prior to birth
  • Gestational age at birth: premature infants appear to have less severe presentations than full-term infants
  • Prenatal conditions: nutrition, infections, stress
  • Genetics 
  • Presence of other medical conditions in the infant
  • Presence of maternal comorbid psychiatric conditions
Clinical presentation of NAS
Gastrointestinal symptomsCentral nervous system symptomsAutonomic symptoms
  • Vomiting
  • Diarrhea
  • Poor weight gain
  • Uncoordinated suck reflex OR constant suckling reflex
  • Irritability
  • High-pitched cry
  • Hypertonia
  • Myoclonic jerks
  • Seizures
  • Altered sleep-wake rhythm
  • Tremors
  • Hypotonia (floppy infant syndrome)
  • Fever
  • Sweating
  • Tachycardia
  • Tachypnea
  • Sneezing
  • Hypertension
  • Apnea or respiratory depression
  • Hyper- or hypothermia
Timing of onset of NAS
Drug classExamplesOnset after birthWithdrawal duration
Short-acting opioidsHeroin, hydrocodone, oxycodone, fentanyl24–48 hours8–30 days
Long-acting opioidsMethadone, buprenorphine24–72 hours, but can be delayed to up to 5 daysUp to 30 days
BenzodiazepinesDiazepam, alprazolam, lorazepam24–48 hoursUp to 14 days
AntidepressantsSSRIs, SNRIs, tricyclics24–48 hours2–8 days
NicotineCigarettes24–48 hours7 days
AlcoholBeer, wine, hard liquor2–12 hours3 days

Diagnosis

  • Detailed medical history and toxicology testing from the mother
  • Physical examination of neonate
  • Toxicology testing of neonate (see table below)
  • Laboratory testing
    • If suspicion for infection: complete blood count (CBC), serum glucose, serum calcium, thyroid function testing, blood cultures
    • If there is maternal history, presence of high-risk behavior, lack of prenatal care, or sexually transmitted infections (STIs)
  • Differential diagnosis
    • Especially important to consider alternative diagnoses when there is a lack of history and toxicology results are not available
    • Hypocalcemia, hypoglycemia, brain injury, hypoxic-ischemic encephalopathy, sepsis, hyperthyroidism, and myoclonic jerks
Toxicology testing for neonates
SpecimenDetectionConsiderations
Urine or blood (common method)Detects exposure from a few days before birthNoninvasive bag collection; best sample is the first urine
Cord bloodDetects exposure from few days to few hours before birthDrug concentrations can be low. Thus, results can be falsely negative.
Meconium stool (stool from the first bowel movement)Detects exposure from the second trimester
  • Can be contaminated by human milk or formula consumption
  • May be unavailable if the first bowel movement occurred in utero
  • Can be delayed if meconium passage takes several days
HairDetects exposure from the third trimester to 3 months after birthMust cut hair close to the scalp and therefore can be limited if there is insufficient hair at birth or growth

Hospital course

  • Symptoms can start within hours after birth.
  • Opioid-exposed infants should be observed for at least 3–7 days.
  • Discharge requirements:
    • Completely weaned off medication and maintains NAS score less than 8 for 48 hours 
    • Medically cleared: established follow-up with pediatric and subspecialty physicians
    • Socially cleared:
      • Established maternal substance abuse treatment plan
      • Home environment assessment
      • Established support systems
      • Education on properly caring for an infant including risk of sudden infant death syndrome (SIDS)
      • Follow-up with mental health services arragned, if needed

Management

The goal of management is to minimize the severity of NAS signs through supportive measures and, in severe cases, the use of pharmacological measures. 

Non-pharmacologic therapy for infants

  • Maintain temperature stability
  • Breastfeeding if possible
  • Fluid resuscitation if needed
  • Scheduled, adequate nutrition
  • Pacifier usage
  • Skin-to-skin if possible
  • Swaddling
  • Vertical rocking
  • Positioning (side-lying in C-shaped position)
  • Minimal sensory stimulation
  • Dark, quiet room
  • Rooming-in mother and infant

Pharmacologic therapy for infants

  • If infants continue to display NAS symptoms that are not ameliorated by supportive measures
  • Modified Finnegan Neonatal Abstinence Scoring System (FNASS):
    • Gold-standard assessment tool to determine initiation of treatment, medical management, and discharge planning
    • Assesses severity of symptoms
    • Should be initiated within the first 24 hours after birth 
    • Scoring should be done consistently at least every 3–4 hours
    • If 3 consecutive scores of > 8 or 2 scores > 12: prompt treatment
  • Other screening testing test available include:
    • Neonatal drug withdrawal scoring system (the Lipsitz)
    • Neonatal narcotic withdrawal index (NNWI)
    • Neonatal withdrawal inventory (NWI)
  • Opioids
    • First-line treament: morphine
      • Monitor for respiratory suppression!
    • Alternatives: 
      • Methadone: Beware of QT prolongation!
      • Buprenorphine: Be careful in infants with alcohol exposure due to the additive effect
    • Adjuvant therapies: 
      • Clonidine 
      • Phenobarbital (useful in infants exposed to opioids and barbiturates/benzodiazepines)
  • Benzodiazepines: reintroduction of the benzodiazepine followed by slow taper to discontinuation
  • Stimulants: Phenobarbital can be used for extreme cases.
  • Alcohol: benzodiazepines, slowly tapered
  • Antidepressants: if the infant develops seizures →  anticonvulsant
  • Nicotine: focus on tapering cigarette smoking during the prenatal period

Prognosis

  • Correlates with the gestational age of exposure 
  • Amount of substance able to cross the placenta into fetal tissues, in particular, the fetal central nervous system 
  • Genetic variations in fetal receptor expression such as mu-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) affect the severity of NAS
  • Maternal involvement in an addiction treatment program is important, as it tends to lead to fewer neurodevelopmental delays.
Developmental effects of prenatal substance exposure
OpioidsAlcoholStimulantsAntidepressantsNicotine
Short-term effects
Fetal growth restriction+++++
Anomalies++
Withdrawal++++
Neurobehavioral+++++
Long-term effects
Growth restriction+++
Behavioral difficulties++++
Cognition++++
Delayed language development++++
Lower academic achievements++++

Clinical Relevance

Fetal alcohol spectrum disorder: a group of conditions that can occur in neonates whose mothers consume heavy amounts of alcohol during their pregnancy. Problems may include characteristic craniofacial changes, short height, low body weight, small head size, low intelligence, behavior issues, and hearing impairments.

References

  1. National Institute on Drug Abuse, National Institutes of Health, and U.S. Department of Health and Human Services (2019). Dramatic Increases in Maternal Opioid Use and Neonatal Abstinence Syndrome. Retrieved from https://www.drugabuse.gov/related-topics/trends-statistics/infographics/dramatic-increases-in-maternal-opioid-use-neonatal-abstinence-syndrome
  2. Jilani SM, Frey MT, Pepin D, et al. (2019). Evaluation of State-Mandated Reporting of Neonatal Abstinence Syndrome — Six States, 2013–2017.  Retrieved from https://www.cdc.gov/mmwr/volumes/68/wr/mm6801a2.htm
  3. Karen McQueen, R.N., Ph.D., and Jodie Murphy-Oikonen, M.S.W., Ph.D. (2016). Neonatal Abstinence Syndrome. Retrieved from https://www.nejm.org/doi/10.1056/NEJMra1600879?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov
  4. Emily J Ross, Devon L Graham, Kelli M Money, and Gregg D Stanwood (2015). Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262892/
  5. Marylou Behnke,  Vincent C. Smith, COMMITTEE ON SUBSTANCE ABUSE, and COMMITTEE ON FETUS AND NEWBORN (2013). Technical report: Prenatal Substance Abuse: Short- and Long-term Effects on the Exposed Fetus. Retrieved from https://pediatrics.aappublications.org/content/pediatrics/131/3/e1009.full.pdf

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