Neonatal abstinence syndrome

You are asked to examine the infant of a 28-year-old, well-controlled insulin-dependent diabetic admitted at 36 weeks for spontaneous rupture of membranes. Labor progressed uneventfully for about 12 hours when the decision was made to proceed to cesarean delivery because of failure to progress and maternal hyperglycemia.

A 2500-gram male infant was born with Apgar scores of 8 at 1 minute and 10 at 5 and 10 minutes. The infant is admitted to the nursery with a blood sugar of 35 mg/dL and grunting respirations. He is started on an intravenous dextrose infusion and antibiotics, and an assessment for perinatal infection is initiated.

Blood glucoses improve and grunting quickly stabilizes, but at 24 hours of life the nursing staff notices increased jitteriness and tremors that progress on the second day. At 36 hours, rhythmic movements of the tongue and limbs are thought to be seizures, but anticonvulsants are not started. Other symptoms noted over the first 48 hours include feeding intolerance, intermittent tachypnea, temperature instability with pyrexia, and diarrhea.

Review of the labor record was negative for any narcotic analgesia and the mother denied illicit drug use. History is positive for acetaminophen with codeine used for headaches and chronic back pain. Estimated codeine dose exceeds 100 mg/day during the third trimester of pregnancy.

The infant’s workup for infection is negative as are all hematologic and biochemical profiles. Radiography does not indicate respiratory distress syndrome or infiltrates. Head ultrasound is also negative.^1,2

Ultimately you diagnose this infant with narcotic withdrawal or neonatal abstinence syndrome (NAS).

What Is NAS?

Neonatal abstinence syndrome occurs in newborns following discontinuation of various substances following birth. The classical presentation is associated with opioid use during pregnancy, but a number of other prescription medications (eg, benzodiazepines, selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants [TCAs]) and illicit drugs (eg, inhalants and metamphetamines)³ have been implicated.

Clinical presentation is variable and depends on the³:

• Implicated drug and its characteristics (eg, half life, receptor binding capacity, placental transfer, and other pharmacologic properties);

• Timing of the last drug use;

• Gestational age of the infant;

• Maternal and infant metabolism and other factors.

Differential diagnosis

As the case indicates, NAS can be mimicked by a number of other conditions. Symptoms should not be attributed to drug withdrawal without consideration of alternative causes, especially when not treating one of these other conditions may lead to significant morbidity and possible death. Considerations in the differential diagnosis in the case presented include^4,5:

• Hyperthyroidism

• Hypocalcemia

• Hypoglycemia

• Hypoxic ischemic encephalopathy

• Intracranial hemorrhage

• Polycythemia/hyperviscosity syndrome

• Sepsis

NAS symptoms

Symptoms of NAS may be present at birth, but (as in this clinical scenario) many symptoms are nonspecific and also part of other serious clinical entities. Symptom number, onset, duration, and severity depend on several drug characteristics (eg, NAS attributed to methadone may be delayed up to 72 hours while NAS symptoms from heroin usually begin within 24 hours), in addition to maternal and gestational characteristics (eg, preterm infants appear to be at lower risk compared with term infants for NAS).⁵

Symptoms may not peak for 2 to 3 days and may be delayed until 5 to 7 days after birth. Table 1 groups signs and symptoms into 3 categories to assist the practitioner in remembering the multisystem constellation and often nonspecific presentation: central nervous system (CNS) irritability, autonomic dysfunctions, and gastrointestinal dysfunctions.

Hyperirritability is a hallmark of NAS. Other CNS signs such as tremors, jitteriness, and excessive crying are often present at initial diagnosis. Diarrhea is also a common early symptom. Irritability can lead to further agitation: restlessness that results in inconsolable crying, difficulty sleeping, and poor feeding. Seizures, although not common, are a serious manifestation of NAS that require immediate treatment.⁵

Autonomic dysregulation and instability of the autonomic nervous system lead to abnormalities of heart and respiratory rates and temperature instability. Other autonomic symptoms include mottling, sweating, sneezing, and yawning.³

The multisystem effects of NAS often lead to misdiagnosis. Nasal flaring and tachypnea are misinterpreted as respiratory distress. Fever often leads to a diagnosis of possible sepsis.^3,5

Among opioids, heroin tends to produce early symptoms that typically last up to 8 to 10 days. Methadone withdrawal, on the other hand, may not demonstrate symptoms for up to 3 days and symptoms may be present for 30 days or longer. Among nonopioids, SSRIs and TCAs usually demonstrate symptoms early and resolve in 2 to 6 days. Poly drug exposures, particularly with benzodiazepines, increase risk for both severity and duration of withdrawal symptoms. Male gender, good birth weight, maternal smoking, and presence of the mu-opioid receptor (OPRM1) gene and the catechol-O-methyltransferase (COMT) gene are also associated with increased severity and duration of withdrawal symptoms.^3,5

Some signs and symptoms are more common with withdrawal from specific drugs. An exaggerated Moro reflex is more commonly seen in methadone withdrawal whereas diarrhea leading to dehydration and electrolyte abnormalities is more common with heroin withdrawal.^3,5

The course of NAS is often an initial intense phase (1 to 2 weeks) consisting of multisystem signs and symptoms that may be followed by a chronic, relapsing course of continued irritability, sleep disturbances, and feeding problems that are present for weeks to months.³

NAS testing

While there is no specific diagnostic test for NAS per se, toxicologic confirmation to identify the substance causing symptoms is recommended. In cases in which the history does not reveal a substance, drug testing can potentially identify scenarios wherein the mother was abusing or using illicit drugs.

Screening for in utero drug exposure is possible and inexpensive with either urine or meconium testing available in most hospital labs. Definitive confirmation is possible but is more expensive, takes significantly longer, and requires more lab expertise, so it is probably only needed in specific clinical scenarios.³

Urine testing is the most popular method, but it is less sensitive. Also, it will have a shorter window of detection compared with meconium testing (a few days compared with months). Detection will depend on the amount and route of the drug ingested in addition to maternal and fetal metabolism and clearance. Synthetic and semisynthetic drugs are not easily detectable with regular screening tests, and they require more specialized methods.³

It is important to remember that a number of factors can cause false-positive screening tests (eg, cleaning with soap before collection may lead to a false-positive test for amphetamines). Improper storage and collection of specimens as well as a relatively dilute urine in neonates can contribute to false-negative results.³

What type of monitoring is needed?

Similar to vital signs used in clinical practice every day, scoring systems allow clinicians to assess the clinical severity of NAS. Although available tools are subject to individual variability involving the assessment, they remain useful as a way to comprehensively evaluate NAS symptoms systematically, over time, and as objectively as possible.

The Finnegan Neonatal Abstinence Scoring System is a 31-item scale that monitors NAS severity and helps direct treatment.⁶ Symptoms are scored on a 1 to 5 scale every 4 hours in areas such as:

• Stool frequency

• Irritability

• Increased Moro frequency

• Increased crying

• Jitteriness

A score of 8 or greater suggests the need for pharmacologic therapy. Although this is the most comprehensive scale available, it is criticized by clinicians as too complex and time consuming for use in some nurseries. A number of modified versions have been developed in an attempt to preserve clinical utility while decreasing response burden. All versions generally look at identifying a score indicative of a clinical picture requiring pharmacologic management.⁶

The Lipsitz Neonatal Drug-Withdrawal Scoring System is the other system commonly used in clinical practice.⁶ The scale consists of 11 items scored from 0 to 3. A total score of 4 or greater undulates the need for pharmacologic therapy. This scale has been recommended by the American Academy of Pediatrics (AAP), but it is criticized for being subjective and for having a number of items that contain only yes or no response categories. The Ostrea tool, the Neonatal Withdrawal Inventory, and the Neonatal Narcotic Withdrawal Index are other tools published in the literature that assess symptoms and provide a recommendation for pharmacologic treatment.⁶

Infants being monitored and treated for NAS require a unit capable of cardiorespiratory monitoring.

Nonpharmacologic treatment of NAS

Nonpharmacologic care may be sufficient in cases of mild withdrawal and should be implemented in all infants with NAS. Early identification and intervention are important to prevent poor feeding and signs of CNS irritability. No studies comparing effectiveness of the different strategies are available. Strategies include³:

• Swaddling

• Demand feeding

• Avoiding waking the sleeping infant

• Dim light

• Low noise levels

• Pacifiers

• Holding, cuddling, and manual rocking

• Kangaroo care (skin-to-skin contact)

• Music therapy

• Massage therapy

Rooming in and maternal participation has been shown to decrease withdrawal severity.³

Who will need pharmacologic treatment?

As mentioned previously, scoring systems allow for monitoring of infants with NAS and provide a score at which pharmacologic treatment should be considered. The goal of pharmacologic management in symptomatic infants is stabilization or improved ability to eat, sleep, gain weight, and interact with parents and caregivers. After initial stabilization, the goal is reduction of medications that will allow for hospital discharge.

What are appropriate therapies?

Morphine is commonly used for opiate NAS even when the drug of exposure is longer acting, as with methadone. Morphine is a common drug of choice because much is known about the pharmacokinetics of morphine in neonates and weaning parameters compared with other drugs.

Methadone can be used for the treatment of NAS, but it cannot be given as frequently as morphine and it is more difficult to titrate. Phenobarbital is the drug of choice in nonopiate NAS. It is more commonly used adjunctively if symptoms are not controlled with morphine, as may happen with maternal polysubstance abuse. Clonidine and buprenorphine are other options, but these have not been as extensively studied.

Weight basis vs symptom dosing

Morphine can be dosed based either on the symptom score or on a more traditional milligrams per kilo as most other medications are dosed. Jansson and colleagues⁶ recommend treatment based on scoring of their modified Finnegan instrument.

Symptom-based dosing has some advantages over weight-based dosing. With weight-based dosing, the goal is to achieve a certain plasma concentration, whereas NAS treatment focuses on relief of symptoms. Because of variable physiologic and behavioral aspects of withdrawal, symptom-based treatment may be more feasible and effective. By utilizing symptom-based treatment, doses can be quickly increased until symptoms stabilize.

An infant with a score of 0 to 8 is monitored and receives supportive care. An infant scoring greater than 8 is reassessed in 1 hour with medication instituted based on Table 2 if the reassessment score is greater than 8. Reassessing in 1 hour before giving meds disallows for temporary agitations such as a wet diaper. If the score remains greater than 8, then pharmacologic treatment is started.

Dosing is increased every 4 hours for continued symptoms. Longer dosing intervals are not recommended because they are associated with longer lengths of stay.

Once symptoms have stabilized for 48 hours, weaning can begin. One common weaning pattern is decreasing 0.02 mg of morphine every 24 hours provided the Finnegan score is 9 or less.^6,7

Discharge issues

An infant is a candidate for discharge when withdrawal scores are stable and the infant requires minimal pharmacologic support. Optimally, the infant will be managed by a multidisciplinary team with close follow-up. The infant will require close growth, developmental, and behavioral assessments. In addition, the infant will need to be monitored for a number of visual abnormalities such as nystagmus and strabismus. Finally, monitoring for signs of child abuse and substance abuse in the family are essential parts of discharge follow-up.³

Is breastfeeding safe?

Breastfeeding is relaxing for both mother and infant and promotes maternal/infant bonding. In general, methadone and buprenorphine are found in low levels in breast milk. The AAP encourages breastfeeding in women on methadone in methadone-maintenance programs. Breastfeeding is contraindicated if the mother is using illicit drugs, has polysubstance abuse, or is HIV positive. The Academy of Breastfeeding Medicine has developed a guideline for breast-feeding in drug-dependent women.³

REFERENCES

1. Khan K, Chang J. Neonatal abstinence syndrome due to codeine. Arch Dis Child Fetal Neonatal Ed. 1997;76(1):F59-F60.

2. Reynolds EW, Riel-Romero RM, Bada HS. Neonatal abstinence syndrome and cerebral infarction following maternal codeine use during pregnancy. Clin Pediatr (Phila). 2007;46(7):639-645.

3. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134(2):e547-e561.

4. Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence syndrome. J Perinatol. 2011;31(11):692-701.

5. Hudak ML, Tan RC; Committee on Drugs; Committee on Fetus and Newborn; American Academy of Pediatrics. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560.

6. Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009;5(1):47-55.

7. Jansson LM, Dipietro JA, Elko A, Velez M. Infant autonomic functioning and neonatal abstinence syndrome. Drug Alcohol Depend. 2010;109(1-3):198-204. 

Dr Bass is chief medical information officer and associate professor of medicine and pediatrics, Louisiana State University Health Science Center–Shreveport. The author has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.