Clinical manifestations

Presentation and course

When a fetus is exposed to opioids in utero, due to either maternal use of prescribed opioids, opioid use for the treatment of opiate addiction, or illicit drug use during pregnancy, the fetus is at high risk of developing neonatal abstinence syndrome. Neonatal abstinence syndrome occurs in 50% to 94% of all newborns born to mothers who were addicted to or treated with opioids while pregnant (46; 50). Commonly abused drugs have been prescription opioids, morphine, and heroin. Methadone, a long-acting synthetic µ-opioid receptor agonist, has become the standard of care to treat opioid addiction and is provided by specially licensed facilities.

Placental transfer of opioids results in altered neurotransmitter release secondary to chronic stimulation of opioid receptors in the fetal nervous and gastrointestinal systems. The sudden cessation of opioid exposure after birth leads to dysregulated release of these neurotransmitters, resulting in symptoms of withdrawal (36). Additional symptoms are related to autonomic system dysfunction. The hallmark of neonatal abstinence syndrome is hyperirritability, which can lead to agitation, difficulty sleeping, and inconsolable crying (36). It is important to note that the clinical presentation can be modified by the presence of concomitant conditions. For example, the symptoms of neonatal abstinence syndrome can be masked in an infant with hypothyroidism and only unmasked after therapy for hypothyroidism is started (04). There is evidence in support of a systemic response to perinatal opioid exposure, characterized by immune cell reprogramming and priming, which may contribute to the neurologic injury (50). Additionally, infants with neonatal abstinence syndrome are at greater risk to have a birth weight lower than the 10th percentile for gestational age due to intrauterine growth restriction. Studies also suggest an increased probability of congenital cardiac malformations, but data are inconsistent (79).

Time of onset of drug withdrawal symptoms following birth depends on when the mother took her last dose of the drug prior to delivery as well as the formulation of the drug. Typically, the onset of opioid withdrawal occurs within 48 to 72 hours after birth (usually in the first 5 days) and lasts 8 to 79 days, with the average being 30 days (36) (Table 1).

Table 1. Timing of Onset and Observation Time

Drug	Timing of onset of withdrawal symptoms	Observation time
Short-term opioids	36-72 hours after birth	72 hours
Long-term opioids	48-72 hours after birth (usually in the first 5 days) Can last for 8-79 days (average 30 days)	5-7 days
Heroin	12-24 hours after birth	72 hours
Methadone	48-72 hours after birth (may be delayed 5-7 days)	5-7 days
Buprenorphine	40-70 hours after birth	5-7 days
(29; 36; 46; 55)

Infants with neonatal abstinence syndrome can have multiple acute and chronic signs and symptoms of central and autonomic nervous system, as well as gastrointestinal system dysfunction (Table 2A and 2B). They are nearly three times more likely to have feeding problems than infants without neonatal abstinence syndrome (48). The subacute withdrawal may last up to 6 months. The timing of onset of withdrawal has to be considered in the discharge management of infants exposed to opioids in utero as most newborns are discharged within 24 to 48 hours after birth. It may be necessary to monitor infants for longer periods of time depending on the maternal drug(s) of abuse.

Table 2A. Symptomatology

	Symptoms
Central nervous system	High-pitched cry, excessive or continuous crying, sleep and wake cycle disturbances, tremors, jitteriness, increased muscle tone, excoriation, myoclonic jerks, irritability, seizures, hyper/hyposensibility to stimuli, jitteriness, exaggerated Moro
Metabolic, vasomotor, respiratory	Sweating, fever, frequent yawning, mottling, nasal stuffiness, sneezing, nasal flaring, tachypnea (> 60/min), skin color changes, hiccups
Gastrointestinal	Excessive sucking/incoordination, alterations in feeding (hyperphagia, poor feeding), weight loss, loose or watery stools, regurgitation, projectile vomiting, feeding intolerance, diarrhea
(19; 31; 32; 73)

Table 2B. Evolution of Symptoms

Timing symptoms
Acute (first days and may last up to 1-2 weeks)	• Tremors • Seizures • Irritability • Feeding problems • Hyperthermia • Diarrhea, vomiting
Chronic (up to a few weeks to months)	• Hyperirritability • Sleep disturbances • Hyperphagia • Autonomic signs
(36)

Of newborns with neonatal abstinence syndrome, 2% to 11% manifest with seizure-like presentations. Seizure-like episodes are described as jerking or rhythmic movement of extremities, myoclonus during sleep, apnea, or tremors. The onset of seizure-like episodes is as early as day 1 and as late as day 16 of life. Based on 1 study using electroencephalogram (EEG) monitoring, only 7.5% of the newborns with seizure-like episodes had epileptic seizures. Other EEG abnormalities included mild background slowing (in approximately one fourth) and increased multifocal sharp transients in most infants. Video EEG also showed disturbed quiet sleep (non-rapid eye movement sleep equivalent) with frequent arousals, jittery movements, or sleep myoclonus (55). In studies using amplitude-integrated EEG (aEEG), the majority of infants with neonatal abstinence syndrome had abnormal aEEG patterns (discontinuous background patterns or absent sleep-wake cycling) but they did not identify any seizures (although short or focal seizures may be missed with aEEG) (60; 42). As abnormal movements are frequent in infants with neonatal abstinence syndrome, EEG monitoring should be considered to correlate suspicious movements with EEG findings to guide appropriate treatment. The underlying cause of seizures in neonatal abstinence syndrome is not known, although the threshold for seizure activity may be decreased due to upregulation of sodium channels as a result of receptor instability (17). Benign sleep myoclonus is a distinct disorder, not associated with epilepsy, characterized by rhythmic myoclonic jerks, which occurs during sleep only. The disorder resolves without any intervention and may last for several months. Benign sleep myoclonus is frequently seen in infants with neonatal abstinence syndrome (55).

With the increase in opioid use, polysubstance drug abuse has also increased (68; 78). The risk of neonatal abstinence syndrome increased 30% to 60% with coexposure to antidepressants, benzodiazepines, and gabapentin. Atypical antipsychotics or nonbenzodiazepine hypnotics (eg, zolpidem) did not seem to have an impact (61). Opioids and cocaine are often used simultaneously. Cocaine enhances the analgesic effect of morphine and blocks the tolerance that develops to morphine analgesia. Simultaneous use of cocaine and methadone during pregnancy may result in higher abstinence scores in the newborn initially but not an overall increase in the severity of withdrawal or prolonged management course (45). Tobacco and SSRIs can exacerbate neonatal abstinence syndrome or be associated with a neonatal abstinence syndrome that is more refractory to treatment. Maternal tobacco use has also been shown to increase the severity of methadone withdrawal. Infants born to mothers who smoked 20 or more cigarettes per day had higher abstinence scores (9.8 vs. 4.8) and took longer to peak (113 hours vs. 37.8 hours) than those born to mothers who smoked 10 or less cigarettes per day (10). Likewise, cannabis exposure can modulate the apparition of neonatal abstinence syndrome symptoms and is associated with increased risks of neurodevelopmental impairments (66).

Other drugs or medications can also induce withdrawal symptoms similar to neonatal abstinence syndrome. For example, SSRI use during the third trimester can induce symptoms similar to those seen in neonatal abstinence syndrome and, thus, mimic opioid exposure. Symptoms include continuous crying, irritability, jitteriness, restlessness, shivering, fever, tremors, hypertonia or rigidity, tachypnea or respiratory distress, feeding difficulties, sleep disturbances, hypoglycemia, and seizures; that may last for 1 to 2 weeks (29; 77). Moreover, a study indicated that infants exposed to SSRIs need increased delivery room resuscitation (71). In fact, respiratory support was initiated more often in neonates who were exposed to SSRIs (12.9% vs. 4.2% in nonexposed neonates). In utero SSRI exposure was associated with a higher rate of neonatal intensive care unit admission and a 1-minute Apgar score of 5 or less. However, there is no need for particular pharmacologic treatment except when associated with opioid exposure. Neonatal symptoms associated to SSRIs exposure occur in a minority of cases and are self-limited. Evidence suggests that discontinuing clinically needed antidepressants in women near term is unwarranted and may put the mother at an unjustified perinatal risk, as the risk of major postpartum depression is important (37). Gabapentin exposure also produces an atypical neonatal abstinence syndrome (31). These drugs alone do not cause a withdrawal syndrome severe enough to require treatment.

Prognosis and complications

In general, specific long-term effects of drug abuse are difficult to determine because of the confounding variables and comorbidities such as polydrug use, low socioeconomic status, lack of prenatal care, poor nutrition, and sexually transmitted diseases. Consistent findings in opioid-exposed infants are low birth weight, prematurity, intrauterine growth restriction, and depression at birth, with low 5-minute Apgar score when compared to unexposed infants (19; 70).

A meta-analysis demonstrated higher odds of child maltreatment after neonatal abstinence syndrome. Neglect was the commonest type of maltreatment (51). O’Donnell and colleagues also highlighted that maltreatment was experienced at a younger age (median 1 year) after neonatal abstinence syndrome compared to children without history of neonatal abstinence syndrome (median 3 years). They also reported an increased probability of behavioral or emotional disorders (including conduct disorder) among children with previous neonatal abstinence syndrome, which were also associated with the use of phenobarbital at discharge (51).

Neurodevelopmental difficulties following neonatal abstinence syndrome have been demonstrated in multiple studies. At approximately 18 months, Bayley Scales of Infant and Toddler Development, third edition scores indicate that these children are at higher risk for language delays that may warrant referral for early intervention (12). More specifically, it has been shown that they have poorer receptive and expressive language outcomes at 4.5 years of age (35). Studies show worse neurocognitive performance among children up to 6 years of age with a history of neonatal abstinence syndrome (80). These poorer neurodevelopmental outcomes persist in adolescence with lower test scores in high school (52; 80). Children with a history of prenatal opioid exposure also have higher hyperactivity and impulsivity, inattention, and combined ADHD symptom scores than nonexposed controls (63).

A study linking health and educational outcome data showed that approximately 15% of children with a history of neonatal abstinence syndrome met criteria for educational disability and were eligible for services, compared with 11.6% of children without a history of neonatal abstinence syndrome, and that they were more likely to have speech or language impairments (18).

Moreover, on a physiological basis, studies demonstrate that infants with neonatal abstinence syndrome are more susceptible to having altered frontotemporal-limbic and frontal-subcortical pathways and decreased regional and whole brain volumes, as well as alterations of structural and functional connectivity (08). These changes may underlie the long-term deficits seen in this population. Specific regional volumetric neuroimaging alterations in children with neonatal abstinence syndrome include reduced brain volumes of the thalamus, basal ganglia, and cerebellar white matter in children exposed to opiods (59).

Major confounders in these studies include postnatal environment, prenatal polysubstance abuse, suboptimal follow-up, and reliance on maternal reporting of substance use. Children with neonatal abstinence syndrome are also more likely to be raised in poverty and in many studies, low socioeconomic status and unstable home lives are associated with greater risk for long-term neurodevelopmental impairments (65). A study showed that children diagnosed with neonatal abstinence syndrome had a higher rate of mortality (1.2% vs. 0.4%), specifically, those born at term and from lower socioeconomic groups, with most deaths occurring due to ill-defined and external causes (including assaults and accidents) (70). Also, the odds of mortality in opioid-exposed infants not diagnosed with neonatal abstinence syndrome was 72% greater than the reference population (41).

Clinical vignette

A 3.4 kg birth weight male infant was born at 39 weeks with Apgar scores of 3, 5, and 8 at 1, 5, and 10 minutes, respectively. The baby required resuscitation with positive pressure ventilation briefly with good response and was on room air without need for respiratory support by 10 minutes of age. There was a history of maternal substance abuse, and she was positive for hepatitis B surface antigen. The mother was on a methadone maintenance program using a dose of 40 mg per day.

On admission to the nursery, the newborn received hepatitis B immunoglobulins and vaccine. The newborn's urine drug screen was positive for methadone. Neonatal abstinence scoring was performed using Finnegan scoring method. The infant was breastfed as per recommendation by the American Academy of Pediatrics. By 24 hours of age, the baby was crying and had excessive irritability, nasal stuffiness, poor feeding patterns, and was difficult to console. The neonatal abstinence Finnegan score was 12. The baby's serum electrolytes, calcium, glucose, and complete blood counts were normal. He was started on oral morphine, and the dose was increased in stepwise fashion until the neonatal abstinence score was consistently less than 8. After the score remained lower than 8 for 48 hours, the morphine dose was tapered as long as the abstinence score continued to remain lower than 8. The therapy was discontinued by 25 days of age.

Biological basis

Etiology and pathogenesis

Opioids easily cross the placenta to the developing fetus. Opioids act through different opioid receptors, µ, κ and δ, which are G protein-coupled receptors located in the central nervous system, gastrointestinal system, and other body systems. When an infant is born and is no longer receiving opioid stimulation (ie, opioid withdrawal), there is an increased production of adenyl cyclase, cyclic adenosine monophosphate, protein kinase, and transcription factors. This results in an increase in noradrenaline, acetylcholine, and corticotrophin and a decrease in serotonin and dopamine, all leading to the signs and symptoms seen in neonatal abstinence syndrome (36). Neurotransmitter imbalances, as well as variable levels of opioid receptor expression, are thought to contribute to the underlying pathophysiology of neonatal abstinence syndrome, giving rise to autonomic, sensory, and motor dysregulation (47).

The locus coeruleus, a noradrenergic nucleus containing opioid receptors, regulates arousal, response to stress, and the activity of the autonomic system. When opioid levels fall after birth, an increased production of adenyl cyclase leads to an increase in norepinephrine release, resulting in many of the somatic symptoms of opioid withdrawal (07; 33; 36).

The ventral tegmental area of the midbrain is the primary storage center for dopamine. During opioid withdrawal, dopamine release is decreased leading to hyperirritability and anxiety. The dorsal raphe nucleus stores serotonin, which is decreased during opioid withdrawal, leading to sleep disturbances. In the autonomic nervous system, acetylcholine is a primary neurotransmitter in the preganglionic sympathetic and parasympathetic neurons. During opioid withdrawal, its release is increased, leading to diarrhea, vomiting, yawning, sneezing, and sweating (36).

Other infant and environmental factors can alter the expression of neonatal abstinence syndrome such as genetic and epigenetic factors. Infants with particular genotypes such as mutations in minor alleles in the µ-opioid receptor (OPRM1) and catechol-O-methyltransferase (COMT) genes have less severe presentations (74; 75). Male infants have been reported to have a more severe neonatal abstinence syndrome expression (09). Also, preterm infants have less severe presentations (20).

Epidemiology

The incidence of neonatal abstinence syndrome has increased steadily over the last decade. Infants exposed to opioids represent an extremely vulnerable patient population, with 50% to 94% of those exposed experiencing neonatal abstinence syndrome (46; 50). From 2000 to 2014 there was a nearly 7-fold increase in the number of babies born with neonatal abstinence syndrome (78). This rise in incidence has been attributed to increased use and abuse of prescription drugs. Studies show that 58% of infants of mothers receiving methadone maintenance therapy and 67% of infants of mothers receiving buprenorphine maintenance therapy will develop neonatal abstinence syndrome (47).

Prevention

Primary prevention strategies are needed to address the alarming increase of opioid use in America and the associated neonatal abstinence syndrome. Targeted initiatives to address prescribing practices may help reduce opioid use.

All pregnant mothers should be routinely screened to assess risk for substance use disorder. There are validated screening tools available to providers such as the 4Ps and 4Ps plus, NIDA quick screen, and CRAFFT (11).

Currently there are no established treatment programs for pregnant, opioid-addicted mothers that will prevent the development of neonatal abstinence syndrome in their offspring. Abrupt cessation of opioids can lead to withdrawal, which can compromise the fetus. Also, attempts to lower the maternal methadone dose in order to avoid the development of withdrawal in the newborn may lead to the mother resorting to the use of illicit drugs. Medically assisted treatment of pregnant women with opioid addiction is the standard of care. This treatment results in earlier entry into prenatal care, decreased obstetrical complications, decreased illicit drug use, and improved neonatal outcomes including decreased prematurity and higher birth weights (06; 11). Furthermore, neonatal abstinence syndrome has not been shown to be associated with maternal methadone dose (64). Medically supervised withdrawal during pregnancy is associated with high relapse rates of 41% to 96% and worsened maternal outcomes (34). As previously discussed, other substances such as benzodiazepines, cannabis, SSRIs, and tobacco can modulate signs of neonatal abstinence syndrome. The risks and benefits of all medication taken during pregnancy should be evaluated and smoking cessation strategies should be offered (46; 66).

Differential diagnosis

Confusing conditions

Many neonatal pathologies have symptoms overlapping with neonatal abstinence syndrome (see Table 3). Thus, laboratory and diagnostic investigations should be used to differentiate.

Table 3. Differential Diagnosis of Neonatal Abstinence Syndrome

Sign	Differential diagnosis
Irritability	• Gastroesophageal reflux • Pain • Sepsis • Brain injury, eg, hypoxic-ischemic encephalopathy • Hyperthyroidism
Jitteriness	• Hypoglycemia • Hypocalcemia • Immaturity
Myoclonic jerking	• Benign neonatal sleep myoclonus • Brain injury • Seizures
Seizures	• Hypocalcemia • Hypoglycemia • Brain injury, eg, hypoxic-ischemic encephalopathy
Fever	• Sepsis
Feeding problems	• Dysmorphism/oromotor dysfunction • Immaturity • Brain injury • Gastrointestinal disease • Sepsis • Polycythemia
(31)

Diagnostic workup

Screening of the drug-exposed newborn. All infants should be evaluated for the potential risk of neonatal abstinence syndrome through review of maternal pregnancy history and maternal medications, physical exam, and toxicology screening if indicated. Prenatal drug exposure can be determined by testing urine, maternal plasma, meconium, or umbilical cord blood. Of these, an analysis of the newborn’s urine sample by immunoassay is the most frequently used method. However, the results are qualitative, and the test is positive for 2 to 4 days after maternal drug use and does not distinguish between morphine, codeine, or glucuronide conjugates. Maternal plasma testing can detect an exposure for 12 to 72 hours. Meconium analysis is more specific and yields positive results for drug exposure during the second and third trimester of pregnancy but is not available in all centers. Umbilical cord tissue immunoassay can also be used and appears to be as reliable as meconium testing and has added benefit of being available at the time of birth (05; 31).

At-risk newborns should be monitored for withdrawal symptoms. In an attempt to objectively quantify the severity of withdrawal symptoms, many standardized scoring tools have been developed (46). The Finnegan Neonatal Abstinence Scoring Tool (FNAST) is the most comprehensive and widely used tool in the United States (62; 53). The FNAST is an instrument that contains 21 items that are related to the signs of withdrawal, each with a score assigned. An infant then receives a cumulative score based on the presence or absence of signs or symptoms (19; 29). A Finnegan score of 8 or higher commonly requires an intervention (47). Multiple scoring tools have been created to overcome the limitations of the Finnegan scoring such as MOTHER NAS, Neonatal Withdrawal Inventory (NWI), Neonatal Narcotic Withdrawal Index, and Finnegan Neonatal Abstinence Syndrome Tool – Short Form, but they are not used in many hospitals for reasons that are unclear (02). The Hopkins assessment and intervention tool is a new tool that describes domains of functioning that are affected by neonatal abstinence syndrome as well as the types of nonpharmacologic behavioral and environmental measures used to treat the neonate suffering from neonatal abstinence syndrome (73).

Further evaluations are useful for differentiating neonatal abstinence syndrome from other diseases and detecting comorbidities. Initial testing includes a complete blood count, glucose, and calcium. Additional tests, such as thyroid function studies or investigations and empiric antibiotic treatment for sepsis, should be considered if other diagnoses are suspected. Comorbidities of neonatal abstinence syndrome may include sexually transmitted infections (eg, syphilis, chlamydia, gonorrhea, hepatitis C, and human immunodeficiency virus). Other comorbidities common in women with substance abuse disorder include psychiatric conditions, particularly depression and violence exposure (28).

Management

All infants with documented opioid exposure, or a high probability of exposure should be monitored with a standard assessment tool, such as the FNAST (see Diagnostic workup section for further details of different scoring tools). The assessment should be performed every 3 to 4 hours to monitor the severity of neurologic hyperexcitability, gastrointestinal dysfunction, autonomic instability, and respiratory dysregulation. A FNAST score of 8 or higher is suggestive of opioid exposure, even in the absence of declared use during pregnancy. All infants should be managed initially with nonpharmacologic approaches. Symptom scores will drive the decision for pharmacologic therapy (44).

Nonpharmacologic management. Nonpharmacologic supportive measures should be provided to all infants exhibiting signs of withdrawal. Supportive measures may be the only treatment necessary for some infants, but they should also be continued if an infant requires pharmacologic treatment (29; 36). Velez and colleagues suggest that the atypical level and quality of dysregulated behaviors observed in some opioid-exposed infants could reflect difficulties in their threshold modulation for responses and reactions in four neurobehavioral domains: (1) autonomic control, (2) motor and muscle tone control, (3) state/wake and attentional state control, and (4) sensory processing and modulation (73). The development of self-regulatory capacities is fundamental for a child’s overall development.

Nonpharmacologic supportive therapies include care of the infant and the mother and the promotion of bidirectional communication and dyadic synchrony (72; 73). Parental involvement in the care of these infants, whether it be parental presence at the bedside or rooming-in with mothers or family members has been associated with reduced neonatal abstinence syndrome severity, decreased need for pharmacologic treatment, increased breastfeeding, as well as decreased length of stay (27; 43; 76; 56). In addition, the environment and infant handling should be modified so that they are not overly stimulating, which can exacerbate clinical signs of withdrawal. Also, it is important that the medical team cluster care interventions together temporally as much as possible to decrease disturbances (56). Flexibility and personalized care, along with encouraging the caregiver’s mindfulness of their own state and regulatory capacities and educating them to recognize, interpret, and respond to the unique signs of the infant, are key to optimizing neonatal abstinence syndrome treatment approaches and promoting healthy long-term outcomes of the family (73).

Breastfeeding is known to have significant benefits for all infants, including decreased risk of infections, childhood obesity, diabetes, allergies, leukemia, and sudden infant death syndrome. It also improves psychosocial functioning and mother-infant bonding (30). Studies of breastfeeding in neonatal abstinence syndrome show that there may be an association between breastfeeding and shorter length of stay (01). Unless otherwise contraindicated, mothers on methadone or buprenorphine can breastfeed because the transfer of these drugs through breastmilk is minimal and not sufficient to have a negative impact on the infant. Studies suggest that only low concentrations of opiates are secreted in breast milk and that there were no neurologic sequelae from the exposure of opiates through breast milk (14; 47). However, women may require additional breastfeeding support related to infant latch and suck, milk transfer, and breast milk fortification or supplementation (81).

The “Eat Sleep Console” approach is a novel approach that utilizes a functional assessment of the infant’s overall status instead of the FNAST for assessment. The use of this tool emphasizes maternal involvement with a goal of reducing opioid therapy and length of hospitalization. It is guided by the infant’s clinical signs of withdrawal through the evaluation of an infant’s ability to eat more than 1 oz or breastfeed well, sleep undisturbed for more than an hour, and be consoled (56). Although not yet well studied, it has been suggested that using this approach may result in lower rates of pharmacologic treatment for neonatal abstinence syndrome (21; 22). A longitudinal trial on this approach is underway (NCT04057820) (40).

Some studies suggest acupuncture can have a positive impact through the release of endogenous opioids (44). A study identified a significant decrease in length of stay when adding clonidine as an adjunct to morphine monotherapy (03).

Additionally, nonpharmacologic care of the mother is an important aspect to consider in the treatment of neonatal abstinence syndrome. Mothers are often vulnerable and their implication with the infant is imperative. Encouraging and supporting parenting confidence, promoting maternal self-regulation, and fostering her maternal ability to support her child’s healthy development and maximize her interactional capacity are all central to recovery (31). Parents should be referred to appropriate medical and social health care providers with the goal of providing counseling, education, treatment, and social support.

Pharmacologic management. There is no universally accepted standard of care for pharmacologic management of opioid-exposed infants with neonatal abstinence syndrome, and there is limited evidence to support that treating neonatal abstinence syndrome symptoms improves long-term outcomes (29; 36; 46). However, standardized approaches to the care of these infants have been shown to decrease length of stay and the need for pharmacotherapy (23; 21).

In general, when using the FNAST, pharmacologic management is usually initiated if the infant scores greater than 8 on three consecutive scores or if there are two consecutive scores of greater than 12. The opioid dose is increased until there is good control of the opioid withdrawal symptoms. After approximately 48 hours of stability, the drug is slowly weaned. For the infants who are not well controlled with an opioid alone, adjunctive drugs, such as clonidine or phenobarbital, are added (44).

Table 4. Pharmacologic Treatment of Opioid-Exposed Infants with Neonatal Abstinence Syndrome

Drug	Dosing	Action
Morphine	0.04 mg/kg every 3-4 hours, increase by 0.04 mg/kg/dose if symptoms are not controlled (maximum dose of 0.2 mg/kg/dose) Weaning: 10%-20% of total daily dose every 1-7 days based on scoring and physician discretion	Full agonist µ opioid receptors
Methadone	0.05 to 0.1 mg/kg/dose every 6-12 hours Increase by 0.05 mg/kg/dose or increase frequency to every 4 hours, if symptoms are not controlled Weaning: 10%-20% of total daily dose every 1-2 days	Long acting µ opioid agonist
Buprenorphine	Limited data available, full-term infants Sublingual solution. 5.3 mcg/kg/dose every 8 hours, may be increased in 25% increments Maximum daily dose 60 mcg/kg/day	Partial µ opioid agonist
Phenobarbital	An oral dose of 10 mg/kg (up to 20 mg/kg based on the severity of symptoms), followed by a maintenance dose of 2.5 mg/kg twice daily starting 12-24 hours after the loading dose Weaning: decrease daily dose by 20% once per week	GABA agonist
Clonidine	<35 weeks: 0.5 to 1 mcg/kg/dose every 6 hours Weaning: 0.25 mcg/kg every 6 hours >35 weeks: 0.5-1 mcg/kg/dose every 4-6 hours (up to 12 mcg/kg/day) Weaning: 10% every other day as tolerated	Central alpha-2 agonist
(29; 24; 38; 39)

Opioid therapy. When pharmacologic treatment is indicated, opiate treatment (morphine/methadone) is considered the preferred therapy (29; 54). Morphine is most commonly used as first-line therapy for neonatal abstinence syndrome (62; 76).

Morphine. It is important to monitor for signs of narcosis, which can include decreased stooling, respiratory depression, somnolence, and constipation. Morphine can be discontinued when the oral dose is less than 0.02 mg/kg/dose.

Methadone. A randomized clinical trial concluded that short-term outcomes (including length of stay, length of treatment, and use of phenobarbital) were better in infants receiving methadone compared to morphine (13). For instance, the length of stay was 14% lower with methadone treatment; the length of treatment was 14% lower, and the use of phenobarbital was 17.2% with methadone compared to 29.7% with morphine.

Buprenorphine. There is emerging evidence on the role of buprenorphine in the treatment of neonatal abstinence syndrome. A RCT that compared buprenorphine and morphine revealed that treatment with buprenorphine was associated with shorter duration of treatment and shorter length of stay than treatment with morphine (38). The Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE) demonstrated benefits in time to stabilization and weaning when up-titration rates with buprenorphine increased to 30% (15). Also, a weaning rate of 25% shortened time to cessation.

Adjunct therapies. When symptoms are not controlled with opioids, the use of adjunct therapies are useful. Particularly when there is polysubstance abuse, other therapies may be needed. In such cases, an individualized approach may be necessary, especially if the infant’s symptoms are thought to be due to nonopioid withdrawal.

Phenobarbital. Phenobarbital has been used as both first-line therapy or as an adjunct when symptoms are uncontrolled on maximum doses of opioids. A study suggests that the use of phenobarbital with the combination of an opioid significantly reduced the proportion of infants with a high abstinence severity score, the duration of hospitalization, and the maximal daily dose of opioids. They also reported shorter morphine treatment duration than clonidine-treated infants, but infants were discharged more often on a secondary medication (49). Phenobarbital is the drug of choice if the infant has seizures (44). Oversedation is a potential adverse effect reported in infants treated with phenobarbital in addition to an opioid (82). Another concern with the use of phenobarbital is its potential effect on long-term neurodevelopment (16; 69).

Clonidine. It is a central alpha 2 adrenergic receptor agonist that at low doses stimulates the alpha 2 presynaptic adrenergic receptors, resulting in decreased norepinephrine release in the synapse. This negative feedback reduces the autonomic overactivity, which is part of the withdrawal syndrome. Clonidine treatment may induce low blood pressure with a rebound effect of high blood pressure after clonidine cessation (82).

Once stabilized, meaning that the neonatal abstinence syndrome score remains less than 8 for 48 hours while on morphine therapy, it is suggested to wean by 10% to 20% of the total daily starting dose every 24 to 72 hours as tolerated (44).

Some centers wean adjunctive therapies before cessation of opioids whereas others will wean the opioid first and discontinue the adjunct later (19).

Discharge criteria is clinical stability. The American Academy of Pediatrics recommends a minimum of 3 days of observation for all infants with opioid exposure during pregnancy, or 4 to 7 days for infants exposed to buprenorphine, methadone, or sustained-release opioids (56). If the infant was on pharmacologic therapy, the infant can be discharged if stable 24 hours after medication has been discontinued. Close follow-up and parental guidance must be ensured. Psychosocial difficulties are more frequent in this population. Mothers with a history of substance abuse may have less human and financial support and may lack the ability to interpret and respond appropriately to infant cues (46). Thus, individualized discharge planning should include referral to a primary health care provider and family supportive resources (such as a community social worker, infant development program, or parenting support group).

Outcomes

Regarding acute outcomes, the average length of stay for infants with neonatal abstinence syndrome is 17 days overall but 23 days for those requiring pharmacologic treatment (57). Length of stay varies depending on type of prenatal drug(s) exposure, severity of withdrawal symptoms, treatment, and social factors. Factors associated with decreased length of stay include rooming-in with mothers or family members, which can also reduce neonatal abstinence syndrome severity as well as increase breastfeeding (43), which itself has also been associated with decreased length of stay (01).

Data are limited to differentiate the effects on long-term outcome due to prenatal drug exposure from the effects of opiates used for treatment of neonatal abstinence syndrome. A randomized trial showed that infants treated with either morphine or methadone had similar short- and long-term neurodevelopmental outcomes. However, phenobarbital use, overall health of the infant, and postnatal caregiving environment were found to have an impact on the child’s neurodevelopment (12).

Furthermore, evidence from morphine exposure in preterm newborns suggests that morphine use is associated with impaired cerebellar growth and poorer neurodevelopmental outcomes in early childhood (83). Evaluating the long-term neurodevelopmental outcomes of infants with in utero exposure and the effects of its treatment is complex, as it is also largely affected by environmental factors such as maternal age, socioeconomic status, and parental education levels (65; 52).

Special considerations

Pregnancy

Not applicable. Discussion of treatment of the pregnant woman with opioid dependence is discussed in the prevention section of this article.