Neonatal Abstinence Syndrome

Neonatal abstinence syndrome is a withdrawal syndrome in newborns after in utero exposure to substances that are suddenly stopped at birth. It is most often caused by opioids (heroin, methadone, buprenorphine, codeine, tramadol), and also by benzodiazepines, gabapentin, alcohol and, less severely, antidepressants.

It occurs in a variable proportion of exposed infants, with roughly half to three quarters of opioid exposed infants needing treatment in some series. Onset is usually 24 to 72 hours after birth for short acting opioids, and up to 5 to 7 days for methadone and long acting agents.

Severity depends on the drug, dose, timing of last use, gestation (milder in preterm infants), maternal metabolism, polydrug use and the infant's genetic variation.

Pathophysiology.

Opioids suppress noradrenergic activity in the locus coeruleus. After birth, the infant loses the placental supply and noradrenergic activity rebounds, causing sympathetic overactivity.

Dysregulation of other systems adds to central nervous system hyperirritability, gastrointestinal hypermotility and autonomic instability.

• Central nervous system: tremor, irritability, high pitched cry, hypertonia, hyperreflexia, sleeplessness, myoclonus and seizures (about 2 to 11%).
• Autonomic: sweating, fever, sneezing, yawning, nasal stuffiness, mottling and tachypnoea.
• Gastrointestinal: poor feeding, uncoordinated sucking, vomiting, loose stools and weight loss.

Red flags.

• Seizures, apnoea or marked weight loss (over 10% of birth weight).
• Fever or poor feeding suggesting sepsis.
• Withdrawal signs persisting beyond 4 to 6 weeks or recurring after discharge.

• Maternal history of exposure, with timing and dose of last use, and consented maternal and infant toxicology (urine, meconium or cord tissue).
• Serial assessment every 3 to 4 hours using a validated withdrawal scoring system or the eat, sleep, console approach, starting 2 hours after birth for exposed infants.
• Exclude other causes: glucose, calcium, magnesium, sodium, thyroid function, sepsis screen, cranial ultrasound if neurological signs are present.
• Test the mother and infant for HIV, hepatitis B, hepatitis C and syphilis when risk factors are present.

Differential diagnosis. Sepsis, hypoglycaemia, hypocalcaemia, hypomagnesaemia, hyperthyroidism, hypoxic ischaemic encephalopathy, intracranial haemorrhage, exposure to antidepressants (poor neonatal adaptation) and other drug withdrawal.

Non-pharmacological care (first line for all).

• Rooming in with the parent, skin-to-skin contact, a low stimulation environment, swaddling, on demand feeding with frequent small feeds and breastfeeding where the mother is stable on methadone or buprenorphine, is not using illicit drugs and does not have HIV.
• Calorie dense feeds (up to 150 kcal/kg/day) for poor weight gain.

Pharmacological treatment when non-drug measures fail (scores over the treatment threshold, or inability to eat, sleep or be consoled).

• Opioid withdrawal: oral morphine 0.04 mg/kg every 4 hours, increased by 10 to 20% of the dose each 24 hours to a usual maximum of 0.2 mg/kg for each dose. Alternatives are methadone 0.05 to 0.1 mg/kg every 6 hours and buprenorphine sublingual 5 to 15 micrograms/kg every 8 hours under specialist direction.
• Wean by about 10% of the peak dose every 24 hours once symptoms are controlled.
• Adjunct: clonidine 1 microgram/kg orally every 4 to 6 hours, or phenobarbital loading 20 mg/kg then 3 to 5 mg/kg/day for non-opioid withdrawal or poor response. Monitor heart rate and blood pressure with clonidine.
• Do not give naloxone, as it can precipitate acute withdrawal with seizures.
• Treat seizures with phenobarbital 20 mg/kg IV over 20 minutes.

Monitoring. Observe for at least 72 hours (5 to 7 days for methadone). Weight daily, withdrawal scores, feeding and sleep.

Referral and escalation. Early referral to social care and addiction services, with a plan for discharge and support at home. Refer to paediatrics for seizures or failure to respond.

Special groups. Preterm infants have milder and later onset signs and may need a lower threshold for assessment. Benzodiazepine and alcohol exposure may cause late withdrawal.