Neonatal opioid withdrawal syndrome

General Child Neurology

Updated 07.28.2023
Released 10.10.2002
Expires For CME 07.28.2026

Neonatal opioid withdrawal syndrome

Authors: Pouneh Amir Yazdani MD, Sophie Tremblay MD PhD, Elana Pinchefsky MDCM FRCPC MSc

See Contributor Disclosures

Editor: Ann Tilton MD

Neonatal opioid withdrawal syndrome

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Introduction

Overview

Neonatal abstinence syndrome, including neonatal opioid withdrawal syndrome, is a clinical diagnosis that describes the constellation of symptoms that result from the abrupt discontinuation of chronic fetal exposure to, most commonly, opioid use in pregnancy. Neonatal abstinence syndrome describes newborns at risk for polysubstance exposure, including opioids, whereas neonatal opioid withdrawal syndrome describes opioid-only withdrawal symptoms (87). In this article, the term “neonatal abstinence syndrome” is used for both opioid-only and polysubstance exposure. The authors provide a brief historical background and information on the pathophysiology, clinical spectrum, and management of neonatal abstinence syndrome. The clinical or consulting neurologist will find this information useful in formulating a differential diagnosis when faced with a newborn with signs and symptoms pertaining to central nervous system/autonomic dysfunction.

Key points

	• From 2010 to 2017, the estimated rate of neonatal abstinence syndrome significantly increased by 3.3 per 1000 birth hospitalizations (from 4.0 to 7.3) (39).
	• Management of neonatal abstinence syndrome involves appropriately identifying infants at risk for withdrawal, assessing symptoms with objective assessment tools, and managing symptoms with supportive measures and pharmacologic therapy where appropriate.
	• Standardization of care, which includes standardization of scoring, use of nonpharmacologic and pharmacologic therapy, and strict adherence to treatment protocols, have all been shown to decrease the duration of pharmacologic therapy and length of hospital stay.

Historical note and terminology

Medical use of opium dates to Mesopotamian and Egyptian cultures. However, morphine, named after Morpheus, the Greek god of dreams, was only isolated from opium in 1806, followed by the isolation of codeine. Congenital morphinism was first described in Germany in 1875 in a newborn with signs of opioid withdrawal at birth. The first report of successful treatment in an infant was in 1903 (76).

Opioids can be divided into natural, semisynthetic, and synthetic opioids. Opium, morphine, and codeine are examples of natural opiates. Semisynthetic opioids are derived from opium, and examples include heroin, hydromorphone, oxycodone, and buprenorphine. Examples of synthetic substances with morphine-like activities include meperidine, fentanyl, methadone, and propoxyphene (40). Methadone has become the most commonly used opiate during pregnancy associated with neonatal abstinence syndrome (31%) (88).

Other substances such as alcohol, tobacco, benzodiazepine, and selective serotonin-reuptake inhibitors (SSRIs) can provoke neurobehavioral dysregulation symptoms similar to those occurring in neonatal abstinence syndrome (98).

Neonatal opioid withdrawal syndrome describes the clinical withdrawal syndrome seen in infants born to mothers who have used opioids only during pregnancy. As polysubstance use is common, it is not always possible to attribute the cause of neonatal abstinence syndrome to exposure to opioids alone (64). Thus, this article focuses on neonatal abstinence syndrome as a postnatal withdrawal syndrome that occurs among opioid-exposed infants with or without polysubstance exposure. An expert consensus panel proposed a standardized definition that requires a known history of in-utero opioid exposure (by history, not necessarily by toxicology) and the presence of at least two of the five most common clinical signs characteristic of withdrawal (excessive/continuous crying, fragmented sleep, tremors, increased muscle tone, gastrointestinal dysfunction) (46).

Clinical manifestations

Presentation and course

When a fetus is exposed to opioids in utero due to maternal use of prescribed opioids, opioid use for treating 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 (64; 68). 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 withdrawal symptoms (51). 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 (51). It is important to note that concomitant conditions can modify the clinical presentations. 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 (06). Evidence supports a systemic response to perinatal opioid exposure, characterized by immune cell reprogramming and priming, which may contribute to the neurologic injury (68).

Infants with neonatal abstinence syndrome are at greater risk of having a birth weight lower than the 10th percentile for gestational age due to intrauterine growth restriction. Additionally, neonatal abstinence syndrome may be associated with increased odds of occurrence of various congenital anomalies, such as microcephaly, central nervous system anomalies (nonneural tube defects), club foot, oral clefts, and digestive system defects (13). Perinatal opioid exposure during the second and third trimesters is also associated with minor congenital malformations in the musculoskeletal system. This increased risk is shown to be dose-dependent (99). Moreover, perinatal opioid exposure or the sequelae of withdrawal symptoms may also be risk factors for developing laryngomalacia (02). Studies also suggest an increased probability of congenital cardiac malformations, but data are inconsistent (102; 13).

Time of onset of drug withdrawal symptoms following birth depends on when the mother took her last dose of the drug before 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 (51) (Table 1).

Table 1. Timing of Onset and Observation Time

Drug	Timing of onset of withdrawal symptoms	Observation time
Short-term opioids	36 to 72 hours after birth	72 hours
Long-term opioids	48 to 72 hours after birth (usually in the first 5 days) Can last for 8 to 79 days (average 30 days)	5 to 7 days
Heroin	12 to 24 hours after birth	72 hours
Methadone	48 to 72 hours after birth (may be delayed 5-7 days)	5 to 7 days
Buprenorphine	40 to 70 hours after birth	5 to 7 days
(43; 51; 64; 73)

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 (66). 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 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- or 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
(29; 45; 47; 93)

Table 2B. Evolution of Symptoms

Timing symptoms
Acute (first days and may last up to 1 to 2 weeks)	• Tremors • Seizures • Irritability • Feeding problems • Hyperthermia • Diarrhea, vomiting
Chronic (up to a few weeks to months)	• Hyperirritability • Sleep disturbances • Hyperphagia • Autonomic signs
(51)

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 one 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 (73). 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) that often persisted at discharge (78; 59; 60). Short subclinical electrographic seizures have also been seen in the acute and recovery phases of infants with neonatal opioid withdrawal syndrome (60). 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 the upregulation of sodium channels as a result of receptor instability (27). 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 (73).

With the increase in opioid use, polysubstance drug abuse has also increased (88; 101). The risk of neonatal abstinence syndrome increased 30% to 60% with co-exposure to antidepressants, benzodiazepines, and gabapentin. The use of SSRIs in the third semester, in addition to methadone or buprenorphine, has also been associated with more severe neonatal abstinence syndrome and longer hospitalizations (08). Atypical antipsychotics or nonbenzodiazepine hypnotics (eg, zolpidem) did not seem to impact (79). 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 (63).

Tobacco can also 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 fewer cigarettes per day (18). Likewise, cannabis exposure can modulate the apparition of neonatal abstinence syndrome symptoms and is associated with increased risks of neurodevelopmental impairments (85).

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 (43). Moreover, a study indicated that infants exposed to SSRIs in utero need increased delivery room resuscitation (91). 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 (91; 30). However, the absolute risk of severe neonatal outcomes, such as long-term NICU hospitalization (longer than 15 days), long-term ventilation treatment (longer than 5 hours), and seizures, was low. In-utero SSRI/SNRI exposure does not increase the risk of developing neonatal early-childhood seizures (100). Particular pharmacologic treatment is not needed except when associated with opioid exposure. Neonatal symptoms associated with SSRI exposure occur in a minority of cases and are self-limited. Evidence suggests that discontinuing clinically needed antidepressants in women near term is unwarranted when they have access to perinatal care providers, including NICU, and may put the mother at an unjustified perinatal risk as the risk of major postpartum depression is important (52). Gabapentin exposure also produces an atypical neonatal abstinence syndrome (45). 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 (29). These infants are also at increased risk for neonatal sepsis and jaundice (07).

A meta-analysis demonstrated higher odds of child maltreatment after neonatal abstinence syndrome. Neglect was the commonest type of maltreatment (69). 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 a 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 (69).

Neurodevelopmental difficulties following neonatal abstinence syndrome have been demonstrated in multiple studies. A meta-analysis of 16 studies revealed that children born to opioid-dependent mothers faced challenges in various areas of development, including general cognitive abilities, psychomotor development, language skills, and social-emotional development (57). At approximately 12 months, infants with pharmacologically treated neonatal opioid withdrawal syndrome have been shown to obtain lower scores on the Bayley Scales of Infant and Toddler Development (third edition) in all test domains (cognitive, receptive, and expressive language and fine and gross motor skills) compared to norms (12). Bayley-III scores in 18-month-old children also indicate they are at higher risk for language delays that may warrant referral for early intervention (22). More specifically, it has been shown that they have poorer receptive and expressive language outcomes at 4.5 years of age (50). Studies show worse neurocognitive performance among children up to 6 years of age with a history of neonatal abstinence syndrome (103). Children born to mothers under methadone maintenance treatment are at significant risk of impaired school readiness, as they often have challenges in multiple neurodevelopmental areas (57). The poorer neurodevelopmental outcomes in children with a history of neonatal opioid withdrawal syndrome persist in elementary school and in adolescence, and lower test scores are seen in high school (70; 103). Children with a history of prenatal opioid exposure also have higher hyperactivity and impulsivity, inattention, and combined ADHD symptom scores than nonexposed controls (82). Maternal tobacco use during pregnancy also increases the risk of ADHD. Polysubstance exposure has been shown to have an additive risk for ADHD (31).

A study linking health and educational outcome data showed that approximately 15% of children with a history of neonatal abstinence syndrome met the 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 (28).

The incidence of motor problems has been less studied than the cognitive and behavioral outcomes in children with previous neonatal abstinence syndrome. Benninger and colleagues reported an increased risk of cerebral palsy in children with intrauterine drug exposure, which is comparable to rates of cerebral palsy in other high-risk populations, such as those with intrauterine growth restriction, preterm birth, or congenital malformations (11). Studies also indicate a higher risk of nystagmus and strabismus in these children (33). These visual conditions are also often associated with subnormal visual acuity or impaired binocular vision (36).

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 (16). 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 opioids (77). Moreover, cerebral blood flow assessed with arterial spin labeling MRI has been shown to be increased in infants with neonatal abstinence syndrome. This finding supports how prenatal substance exposure affects brain development. Indeed, abnormal cerebral perfusion underlies many forms of neonatal brain injury because it reflects cellular metabolism and neural activity (10).

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 (84). 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 (90; 34). Most deaths occurred due to ill-defined or unknown causes, followed by external causes (including assaults and accidents) and congenital malformations or chromosomal abnormalities (90; 34). The mortality rate was higher in infants of mothers without medication for opioid use disorder than in infants of mothers who had medication for opioid use disorder during pregnancy (04). Also, the odds of mortality in opioid-exposed infants not diagnosed with neonatal abstinence syndrome were 72% greater than in the reference population (58).

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 the 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 the 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 a 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 remained 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, gastrointestinal, 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 (51). 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 (65).

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 (15; 48; 51).

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 (51).

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 (94; 95). Male infants have been reported to have a more severe neonatal abstinence syndrome expression (17). Also, preterm infants have less severe presentations, yet opioid-exposed infants do not seem to benefit from early-term delivery (32; 80).

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 the risk for substance use disorder. Validated screening tools available to providers include the 4Ps and 4Ps plus, NIDA quick screen, and CRAFFT (21).

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 to avoid the development of withdrawal in newborns may lead to mothers resorting to illicit drug use. 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 (14; 21). Furthermore, neonatal abstinence syndrome is not associated with maternal methadone dose (83). For more than 30 years, methadone was the most commonly used medication in opioid-addicted mothers during pregnancy. Buprenorphine has become the most commonly used first-line treatment option during pregnancy (55); it is associated with lower risks of neonatal abstinence syndrome, preterm birth, and low birth weight (86). Medically supervised withdrawal during pregnancy is associated with high relapse rates of 41% to 96% and worsened maternal outcomes (49). 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 (64; 85).

Diagnostic workup

Screening of the drug-exposed newborn. All infants should be evaluated for the potential risk of neonatal abstinence syndrome through a 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. 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 trimesters 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 the added benefit of being available at the time of birth (09; 45).

At-risk newborns should be monitored for withdrawal symptoms. Many standardized scoring tools have been developed to objectively quantify the severity of withdrawal symptoms (64). The Finnegan Neonatal Abstinence Scoring Tool (FNAST) is the most comprehensive and widely used tool in the United States (81; 71). 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 (29; 43). A Finnegan score of 8 or higher commonly requires an intervention (65). 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 (03). The Hopkins Assessment and Intervention tool describes domains of functioning 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 (93). Preterm infants with neonatal abstinence syndrome are more likely than term infants to have lower scores when measured with conventional scoring tools. Indeed, these tools do not account for the difference in the neonatal abstinence syndrome symptomatology experienced by infants of varying gestational ages.

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 (42).

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 suggests 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 (62).

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 (43; 51). 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 (93). 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 promoting bidirectional communication and dyadic synchrony (92; 93). 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 (41; 61; 97; 74). 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 (74). 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 (93).

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 (44). Studies of breastfeeding in neonatal abstinence syndrome show that there may be an association between breastfeeding and shorter length of stay (01). It has also been associated with a decreased need for initiation and duration of pharmacological treatment for infants with neonatal abstinence syndrome (19). Unless otherwise contraindicated, mothers on methadone or buprenorphine can breastfeed because the transfer of these drugs through breast milk is minimal and insufficient to impact the infant negatively. 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 (24; 65). However, women may require additional breastfeeding support related to infant latch and suck, milk transfer, and breast milk fortification or supplementation (104).

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 by evaluating an infant’s ability to eat more than 1 oz or breastfeed well, sleep undisturbed for more than an hour, and be consoled (74). In a cluster-randomized controlled trial including 1305 infants from 26 United States hospitals, use of the ‘’Eat Sleep Console’’ method decreased the time until infants with opioid withdrawal were ready for hospital discharge by a mean of 6.7 days compared with usual care. This approach also decreased the proportion of infants who received pharmacologic treatment by 32.5% (105).

Some studies suggest acupuncture can have a positive impact through the release of endogenous opioids (62).

Additionally, nonpharmacologic care of the mother is an important aspect to consider in treating 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 (45). Parents should be referred to appropriate medical and social health care providers who can provide 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 (43; 51). However, standardized approaches to the care of these infants have been shown to decrease the length of stay and the need for pharmacotherapy (37; 35).

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 infants not well controlled with an opioid alone, adjunctive drugs, such as clonidine or phenobarbital, are added (62).

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

Drug	Dosing	Action
Morphine	0.04 mg/kg/dose every 3 hours, increase by 0.02 mg/kg/dose if symptoms are not controlled and score is above 8 (maximum dose of 0.2 mg/kg/dose) Weaning: When the score is lower than 8, maintain dose for 48 to 72 hours and then wean 10% of the initial dose every 24 to 48 hours.	Full agonist µ opioid receptors
Methadone	0.05 to 0.1 mg/kg/dose every 6 to 12 hours Increase by 0.05 mg/kg/dose or increase frequency to every 4 hours, if symptoms are not controlled Weaning: 10% to 20% of total daily dose every 1 to 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 Weaning: Decrease daily dose by 10% once per day	Partial µ opioid agonist
Phenobarbital	An optional loading dose of 10 to 15 mg/kg intravenously or orally, followed by a maintenance dose of 2.5 mg/kg twice daily (maximum dose of 8 mg/kg/day) starting 12 to 24 hours after the loading dose Weaning: After stabilization, decrease daily dose by 10% to 20% every 24 to 48 hours	GABA agonist
Clonidine	Before 35 weeks: 2 mcg/kg/day divided in three to four doses per day Weaning: 0.25 mcg/kg every 6 hours After 35 weeks: 5 mcg/kg/day divided in four doses per day (can be increased by 1 mcg/kg/day, up to 12 mcg/kg/day) Weaning: Progressive weaning over 7 to 14 days to avoid noradrenergic rebound (decrease by 25% every 72 hours)	Central alpha-2 agonist
(43; 38; 54; 53; 56; 20)

Opioid therapy. When pharmacologic treatment is indicated, opiate treatment (morphine/methadone) is considered the preferred therapy (43; 72). Morphine is most commonly used as first-line therapy for neonatal abstinence syndrome (81; 96).

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 (23). 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 randomized controlled trial that compared buprenorphine and morphine revealed that treatment with buprenorphine was associated with a shorter duration of treatment and shorter length of stay than treatment with morphine (54). 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% (25). Also, a weaning rate of 25% shortened time to cessation.

Adjunct therapies. When symptoms are not controlled with opioids, 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 and as an adjunct when symptoms are uncontrolled on maximum doses of opioids. A study suggests that using 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 (67). Phenobarbital is the drug of choice if the infant has seizures (62). Oversedation is a potential adverse effect reported in infants treated with phenobarbital in addition to an opioid (106). Another concern with the use of phenobarbital is its potential effect on long-term neurodevelopment (26; 89).

Clonidine. Clonidine 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 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 (106). A study identified a significant decrease in length of stay when adding clonidine as an adjunct to morphine monotherapy (05).

Some centers wean adjunctive therapies before cessation of opioids, whereas others will wean the opioid first and discontinue the adjunct later (29).

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 (74). 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 (64). 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 (75). 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 (61), which itself has also been associated with decreased length of stay (01).

Data are limited to differentiate the effects on long-term outcomes due to prenatal drug exposure from the effects of opiates used for the 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, the overall health of the infant, and the postnatal caregiving environment were found to impact the child’s neurodevelopment (22).

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 (107). 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 (84; 70).

References

01: Abdel-Latif ME, Pinner J, Clews S, Cooke F, Lui K, Oei J. Effects of breast milk on the severity and outcome of neonatal abstinence syndrome among infants of drug-dependent mothers. Pediatrics 2006;117(6):e1163-9. PMID 16740817
02: Abraham EJ, Danis DO, Levi JR. Association between neonates with laryngomalacia and neonatal abstinence syndrome. Ann Otol Rhinol Laryngol 2022;131(9):946-53. PMID 34595938
03: Anbalagan S, Mendez MD. Neonatal abstinence syndrome. 2023 Jul 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing 2023. PMID 31855342
04: Austin AE, Di Bona V, Cox ME, Proescholdbell SK, Naumann RB. Differences in mortality among infants with neonatal opioid withdrawal syndrome. Am J Prev Med 2022;63(4):619-23. PMID 35489960
05: Bader MY, Zaghloul N, Repholz A, et al. A retrospective review following the addition of clonidine to a neonatal abstinence syndrome treatment algorithm. Front Pediatr 2021;9:632836. PMID 34164354
06: Bahwere P, Haumont D, Delange F. Congenital hypothyroidism and neonatal withdrawal syndrome. Euro J Pediatr 1996;155:937-8. PMID 8911892
07: Bailey BA, Shah DS, Boynewicz KL, Justice NA, Wood DL. Impact of in utero opioid exposure on newborn outcomes: beyond neonatal opioid withdrawal syndrome. J Matern Fetal Neonatal Med 2022;35(25):9383-90. PMID 35109759
08: Bakhireva LN, Sparks A, Herman M, Hund L, Ashley M, Salisbury A. Severity of neonatal opioid withdrawal syndrome with prenatal exposure to serotonin reuptake inhibitors. Pediatr Res 2022;91(4):867-73. PMID 34588611
09: Behnke M, Smith VC, Committee on Substance Abuse, Committee on Fetus and Newborn. Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 2013;131(3):e1009-24. PMID 23439891
10: Benninger KL, Peng J, Ho ML, et al. Cerebral perfusion and neurological examination characterise neonatal opioid withdrawal syndrome: a prospective cohort study. Arch Dis Child Fetal Neonatal Ed 2022a;107(4):414-20. PMID 34725106
11: Benninger KL, Purnell J, Conroy S, et al. Intrauterine drug exposure as a risk factor for cerebral palsy. Dev Med Child Neurol 2022b;64(4):453-61. PMID 34528707
12: Benninger KL, Richard C, Conroy S, et al. One-year neurodevelopmental outcomes after neonatal opioid withdrawal syndrome: a prospective cohort study. Perspect ASHA Spec Interest Groups. 2022c;7(4):1019-32. PMID 36211832
13: Bhatt P, Ampem-Darko C, Cudjoe GA, et al. Association between neonatal abstinence syndrome and congenital anomalies in the United States. Am J Perinatol 2022. PMID 36572036
14: Burns L, Mattick RP. Using population data to examine the prevalence and correlates of neonatal abstinence syndrome. Drug Alcohol Rev 2007;26(5):487-92. PMID 17701511
15: Cami J, Farre M. Drug addiction. N Engl J Med 2003;349:975-86. PMID 12954747
16: Caritis SN, Panigrahy A. Opioids affect the fetal brain: reframing the detoxification debate. Am J Obstet Gynecol 2019;221(6):602-8. PMID 31323217
17: Charles MK, Cooper WO, Jansson LM, Dudley J, Slaughter JC, Patrick SW. Male sex associated with increased risk for neonatal abstinence syndrome. Hosp Pediatr 2017;7(6):328-34. PMID 28465360
18: Choo RE, Huestis MA, Schroder JR, Shin AS, Jones HE. Neonatal abstinence syndrome in methadone-exposed infants is altered by the level of prenatal tobacco exposure. Drug Alcohol Depend 2004;75(3):253-60. PMID 15283946
19: Chu L, McGrath JM, Qiao J, et al. A meta-analysis of breastfeeding effects for infants with neonatal abstinence syndrome. Nurs Res 2022;71(1):54-65. PMID 34596065
20: CHU Sainte-Justine. Guide pratique des médicaments en néonatalogie CHU Sainte-Justine [Internet]. Quebec. [Cited 2023 July]. Available from: https://www.chusj.org/fr/soins-services/P/Pharmacie/Outils/Guide-Pratique/Medicaments. 2021.
21: Committee on Obstetric Practice. Committee opinion No. 711: opioid use and opioid use disorder in pregnancy. Obstet Gynecol 2017;130(2):e81-e94. PMID 28742676
22: Czynski AJ, Davis JM, Dansereau LM, et al. Neurodevelopmental outcomes of neonates randomized to morphine or methadone for treatment of neonatal abstinence syndrome. J Pediatr 2020;219:146-51. PMID 31987653
23: Davis JM, Shenberger J, Terrin N, et al. Comparison of safety and efficacy of methadone vs morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial. JAMA Pediatr 2018;172(8):741-8. PMID 29913015
24: Doerzbacher M, Chang YP. Supporting breastfeeding for women on opioid maintenance therapy: a systematic review. J Perinatol 2019;39(9):1159-64. PMID 31263203
25: Eudy-Byrne R, Zane N, Adeniyi-Jones SC, et al. Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome. Clin Transl Sci 2021;14(6):2171-83. PMID 34080312
26: Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. N Engl J Med 1990;322(6):364-9. PMID 2242106
27: Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets 2012;13(2):230-46. PMID 22204322
28: Fill MA, Miller AM, Wilkinson RH, et al. Educational disabilities among children born with neonatal abstinence syndrome. Pediatrics 2018;142(3):e20180562. PMID 30166364
29: Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis 1975;2(1-2):141-58. PMID 1163358
30: Fujioka I, Ohtsu H, Yonemoto N, Sase K, Murashima A. Association between prenatal exposure to antidepressants and neonatal morbidity: an analysis of real-world data from a nationwide claims database in Japan. J Affect Disord 2022;310:60-7. PMID 35490881
31: Garrison-Desany HM, Hong X, Maher BS, et al. Individual and combined association between prenatal polysubstance exposure and childhood risk of attention-deficit/hyperactivity disorder. JAMA Netw Open 2022;5(3):e221957. PMID 35275164
32: Gibson KS, Stark S, Kumar D, Bailit JL. The relationship between gestational age and the severity of neonatal abstinence syndrome. Addiction 2017;112(4):711-6. PMID 27886650
33: Gill AC, Oei J, Lewis NL, Younan N, Kennedy I, Lui K. Strabismus in infants of opiate-dependent mothers. Acta Paediatrica 2003;92(3):379-85. PMID 12725555
34: Grossarth S, Osmundson SS, Wiese AD, et al. Maternal opioid use disorder and the risk of postneonatal infant mortality. JAMA Pediatr 2023;177(7):675-83. PMID 37155175
35: Grossman MR, Berkwitt AK, Osborn RR, et al. An initiative to improve the quality of care of infants with neonatal abstinence syndrome. Pediatrics 2017;139(6). PMID 28562267
36: Gupta M, Mulvihill AO, Lascaratos G, Fleck BW, George ND. Nystagmus and reduced visual acuity secondary to drug exposure in utero: long-term follow-up. J Pediatr Ophthalmol Strabismus 2012;49(1):58-63. PMID 21417186
37: Hall ES, Wexelblatt SL, Crowley M, et al. A multicenter cohort study of treatments and hospital outcomes in neonatal abstinence syndrome. Pediatrics 2014;134(2):e527-34. PMID 25070317
38: Hall ES, Wexelblatt SL, Crowley M, et al. Implementation of a neonatal abstinence syndrome weaning protocol: a multicenter cohort study. Pediatrics 2015;136(4):e803-10. PMID 26371196
39: Hirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017. JAMA 2021;325(2):146-55. PMID 33433576
40: Hoegerman G, Schnoll S. Narcotic use in pregnancy. Clin Perinatol 1991;18:51-76. PMID 2040118
41: Howard MB, Schiff DM, Penwill N, et al. Impact of parental presence at infants' bedside on neonatal abstinence syndrome. Hosp Pediatr 2017;7(2):63-9. PMID 28137920
42: Hser Y, Lanza I, Li L, Kahn E. Maternal mental health and children's internalizing and externalizing behaviors: beyond mother's substance use disorder. [Abstract]. Drug Alcohol Dep 2014(140):e93.
43: Hudak ML, Tan RC, Committee on Drugs, Committee on Fetus and Newborn, American Academy of Pediatrics. Neonatal drug withdrawal. Pediatrics 2012;129(2):e540-60. PMID 22291123
44: Ip S, Chung M, Raman G, et al. Breastfeeding and maternal and infant health outcomes in developed countries. Evid Rep Technol Assess (Full Rep) 2007;(153):1-186. PMID 17764214
45: Jansson LM, Patrick SW. Neonatal abstinence syndrome. Pediatr Clin North Am 2019;66(2):353-67. PMID 30819342
46: Jilani SM, Jones HE, Grossman M, et al. Standardizing the clinical definition of opioid withdrawal in the neonate. J Pediatr 2022;243:33-9.e1.** PMID 34942181
47: Jilani SM, Jordan CJ, Jansson LM, Davis JM. Definitions of neonatal abstinence syndrome in clinical studies of mothers and infants: an expert literature review. J Perinatol 2021;41(6):1364-71. PMID 33514878
48: Johnson K, Gerada C, Greenough A. Treatment of neonatal abstinence syndrome. Arch Dis Child Fetal Neonatal Ed 2003a;88(1):F2-5. PMID 12496218
49: Jones HE, O’Grady KE, Malfi D, Tuten M. Methadone maintenance vs. methadone taper during pregnancy: maternal and neonatal outcomes. Am J Addict 2008;17(5):372-86. PMID 18770079
50: Kim HM, Bone RM, McNeill B, Lee SJ, Gillon G, Woodward LJ. Preschool language development of children born to women with an opioid use disorder. Children (Basel) 2021;8(4):268. PMID 8066299
51: Kocherlakota P. Neonatal abstinence syndrome. Pediatrics 2014;134(2):e547-61. PMID 25070299
52: Koren G, Matsui D, Einarson A, Knoppert D, Steiner M. Is maternal use of selective serotonin re- uptake inhibitors in the third trimester of pregnancy harmful to neonates? CMAJ 2005;172(11):1457-9. PMID 15911861
53: Kraft WK. Buprenorphine in neonatal abstinence syndrome. Clin Pharmacol Ther 2018;103(1):112-9. PMID 29105752
54: Kraft WK, Adeniyi-Jones SC, Chervoneva I, et al. Buprenorphine for the treatment of the neonatal abstinence syndrome. N Engl J Med 2017;376(24):2341-8. PMID 28468518
55: Krans EE. Neonatal outcomes after use of buprenorphine during pregnancy. New Engl J Med 2022;387(22):2085-6. PMID 36449426
56: Lacaze-Masmonteil T, O'Flaherty P. Managing infants born to mothers who have used opioids during pregnancy. Paediatr Child Health 2018;23(3):220-6. PMID 29769809
57: Lee SJ, Pritchard VE, Austin NC, Henderson JM, Woodward LJ. Health and neurodevelopment of children born to opioid-dependent mothers at school entry. J Dev Behav Pediatr 2020;41(1):48-57. PMID 31393318
58: Leyenaar JK, Schaefer AP, Wasserman JR, Moen EL, O’Malley AJ, Goodman DC. Infant mortality associated with prenatal opioid exposure. JAMA Pediatr 2021;175(7):706-14. PMID 33843963
59: Limjoco J, Zawadzki L, Belden M, Eickhoff J, Ikonomidou C. Amplitude-integrated EEG use in neonatal abstinence syndrome: a pilot study. J Matern Fetal Neonatal Med 2020;33(21):3565-70. PMID 30720377
60: Lust C, Vesoulis Z, Zempel J, et al. An amplitude-integrated eeg evaluation of neonatal opioid withdrawal syndrome. [Epub ahead of print.] Am J Perinatol 2022. PMID 35709730
61: MacMillan KDL, Rendon CP, Verma K, Riblet N, Washer DB, Volpe Holmes A. Association of rooming-in with outcomes for neonatal abstinence syndrome: a systematic review and meta-analysis. JAMA Pediatr 2018;172(4):345-51. PMID 29404599
62: Mangat AK, Schmölzer GM, Kraft WK. Pharmacological and non-pharmacological treatments for the neonatal abstinence syndrome (NAS). Semin Fetal Neonatal Med 2019;24(2):133-41. PMID 30745219
63: Mayes LC, Carroll KM. Neonatal withdrawal syndrome in infants exposed to cocaine and methadone. Subst Use Misuse 1996;31:241-53. PMID 8834011
64: McQueen K, Murphy-Oikonen J. Neonatal abstinence syndrome. N Engl J Med 2016;375(25):2468-79. PMID 28002715
65: McQueen K, Taylor C, Murphy-Oikonen J. Systematic review of newborn feeding method and outcomes related to neonatal abstinence syndrome. J Obstet Gynecol Neonatal Nurs 2019;48(4):398-407. PMID 31034790
66: Mensah NA, Madden EF, Qeadan F. Risk of feeding problems among infants with neonatal abstinence syndrome: a retrospective cohort study. Adv Neonatal Care 2021. [Epub ahead of print] PMID 34145169
67: Merhar SL, Ounpraseuth S, Devlin LA, et al. Phenobarbital and clonidine as secondary medications for neonatal opioid withdrawal syndrome. Pediatrics 2021;147(3):e2020017830. PMID 33632932
68: Newville J, Maxwell JR, Kitase Y, Robinson S, Jantzie LL. Perinatal opioid exposure primes the peripheral immune system toward hyperreactivity. Front Pediatr 2020;8:272. PMID 32670993
69: O'Donnell M, Nassar N, Leonard H, et al. Increasing prevalence of neonatal withdrawal syndrome: population study of maternal factors and child protection involvement. Pediatrics 2009;123(4):e614-21. PMID 19336352
70: Oei JL, Melhuish E, Uebel H, et al. Neonatal abstinence syndrome and high school performance. Pediatrics 2017;139(2). PMID 28093465
71: Oei JL, Wouldes T. Will simplifying the Finnegan neonatal abstinence scoring tool improve outcomes for infants with opioid exposure? JAMA Netw Open 2020;3(4):e202271. PMID 32267511
72: Osborn DA, Jeffrey HE, Cole M. Opiate for opiate withdrawal in newborn infants. Cochrane Database Syst Rev 2010;(10):CD002059. PMID 20927730
73: Palla MR, Khan G, Haghighat ZM, Bada H. EEG findings in infants with neonatal abstinence syndrome presenting with clinical seizures. Front Pediatr 2019;7:111. PMID 30984728
74: Patrick SW, Barfield WD, Poindexter BB. Neonatal opioid withdrawal syndrome. Pediatrics 2020;146(5):e2020029074. PMID 33106341
75: Patrick SW, Davis MM, Lehman CU, Cooper WO. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009-2012. J Perinatol 2015;35(8):650-5. PMID 26219703
76: Perlstein MA. Congenital morphinism: a rare cause of convulsions in the newborn. J Am Med Assoc 1947;135(10):633. PMID 20268632
77: Radhakrishnan R, Grecco G, Stolze K, et al. Neuroimaging in infants with prenatal opioid exposure: current evidence, recent developments and targets for future research. J Neuroradiol 2021;48(2):112-20. PMID 33065196
78: Rana D, Pollard L, Rowland J, Dhanireddy R, Pourcyrous M. Amplitude-integrated EEG in infants with neonatal abstinence syndrome. J Neonatal Perinatal Med 2019;12(4):391-7. PMID 31356218
79: Sanlorenzo LA, Stark AR, Patrick SW. Neonatal abstinence syndrome: an update. Curr Opin Pediatr 2018;30(2):182-6. PMID 29346142
80: Sanusi A, Gray M, Xue Y, et al. Delivery timing for the opioid-exposed infant. Am J Obstet Gynecol MFM 2022;4(6):100719. PMID 35977700
81: Sarkar S, Donn SM. Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol 2006;26(1):15-7. PMID 16355103
82: Schwartz AN, Reyes LM, Meschke LL, Kintziger KW. Prenatal opioid exposure and ADHD childhood symptoms: a meta-analysis. Children (Basel) 2021;8(2):106. PMID 33557208
83: Seligman NS, Almario CV, Hayes EJ, et al. Relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS). J Pediatr 2010;157:428-33. PMID 20472252
84: Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of Child and Family Health, et al. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 2012;129(1):e232-46. PMID 22201156
85: Stein Y, Hwang S, Liu CL, Diop H, Wymore E. The Association of Concomitant Maternal Marijuana Use on Health Outcomes for Opioid Exposed Newborns in Massachusetts, 2003-2009. J Pediatr 2020;218:238-42. PMID 31843217
86: Suarez EA, Huybrechts KF, Straub L, et al. Buprenorphine versus methadone for opioid use disorder in pregnancy. N Engl J Med 2022;387(22):2033-44. PMID 36449419
87: Sutter MB, Leeman L, Hsi A. Neonatal opioid withdrawal syndrome. Obstet Gynecol Clin North Am 2014;41(2):317-34. PMID 24845493
88: Tolia VN, Patrick SW, Bennett MM, et al. Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl J Med 2015;372(22):2118-26. PMID 25913111
89: Torolira D, Suchomelova L, Wasterlain CG, Niquet J. Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury. Ann Neurol 2017;82(1):115-20. PMID 28556259
90: Uebel H, Wright IM, Burns L, et al. Characteristics and causes of death in children with neonatal abstinence syndrome. J Paediatr Child Health 2020;56(12):1933-40. PMID 32815631
91: Ulbrich KA, Zumpf K, Ciolino JD, Shah M, Miller ES, Wisner KL. Acute delivery room resuscitation of neonates exposed to selective serotonin reuptake inhibitors. J Pediatr 2021;232:103-8. PMID 33453205
92: Velez M, Jansson LM. The opioid dependent mother and newborn dyad: non-pharmacologic care. J Addiction Med 2008;2(3):113-20. PMID 19727440
93: Velez ML, Jordan C, Jansson LM. Reconceptualizing non-pharmacologic approaches to neonatal abstinence syndrome (NAS) and neonatal opioid withdrawal syndrome (NOWS): a theoretical and evidence-based approach. Part II: The clinical application of nonpharmacologic care for NAS/NOWS. Neurotoxicol Teratol 2021;88:107032.** PMID 34600100
94: Wachman EM, Hayes MJ, Brown MS, et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 2013;309(17):1821-7. PMID 23632726
95: Wachman EM, Hayes MJ, Lester BM, et al. Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr 2014;165(3):472-8. PMID 24996986
96: Wachman EM, Schiff DM. Bringing attention to a need for a standardized treatment and weaning protocol for neonatal abstinence syndrome. Transl Pediatr 2016;5(1):12-5. PMID 26835401
97: Wachman EM, Schiff DM, Silverstein M. Neonatal abstinence syndrome: advances in diagnosis and treatment. JAMA 2018;319(13):1362-74. PMID 29614184
98: Wang J, Cosci F. Neonatal withdrawal syndrome following late in utero exposure to selective serotonin reuptake inhibitors: a systematic review and meta-analysis of observational studies. Psychother Psychosom 2021;90(5):299-307.** PMID 33971648
99: Wen X, Belviso N, Murray E, et al. Association of gestational opioid exposure and risk of major and minor congenital malformations. JAMA Netw Open 2021;4(4):e215708. PMID 33847750
100: Wiggs KK, Sujan AC, Rickert ME, et al. Maternal serotonergic antidepressant use in pregnancy and risk of seizures in children. Neurology 2022;98(23):e2329-36. PMID 35545445
101: Winkelman TNA, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW. Incidence and costs of neonatal abstinence syndrome among infants with medicaid: 2004-2014. Pediatrics 2018;141(4). PMID 29572288
102: Yazdy MM, Desai RJ, Brogly SB. Prescription opioids in pregnancy and birth outcomes: a review of the literature. J Pediatr Genet 2015;4(2):56-70. PMID 26998394
103: Yeoh SL, Eastwood J, Wright IM, et al. Cognitive and motor outcomes of children with prenatal opioid exposure: a systematic review and meta-analysis. JAMA Netw Open 2019;2(7):e197025. PMID 31298718
104: Yonke N, Jimenez EY, Leeman L, Leyva Y, Ortega A, Bakhireva LN. Breastfeeding motivators and barriers in women receiving medications for opioid use disorder. Breastfeed Med 2020;15(1):17-23. PMID 31692370
105: Young LW, Ounpraseuth ST, Merhar SL, et al. Eat, sleep, console approach or usual care for neonatal opioid withdrawal. N Engl J Med 2023;388(25):2326-37. PMID 37125831
106: Zankl A, Martin J, Davey JG, Osborn DA. Sedatives for opioid withdrawal in newborn infants. Cochrane Database Syst Rev 2021;5(5):CD002053. PMID 34002380
107: Zwicker JG, Miller SP, Grunau RE, et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine. J Pediatr 2016;172:81-7.e2. PMID 26763312

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Pouneh Amir Yazdani MD

Dr. Yazdani of CHU Sainte-Justine has no relevant financial relationships to disclose.
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Sophie Tremblay MD PhD

Dr. Tremblay of Université de Montréal has no relevant financial relationships to disclose.
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Elana Pinchefsky MDCM FRCPC MSc

Dr. Pinchefsky of Sainte-Justine University Hospital Center and University of Montreal has no relevant financial relationships to disclose.
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Editor

Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
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Former Authors

Michael V Johnston MD†
Gabrielle Arbour MD
Shelly-Ann Williams MD, Price Ward MD, Julie Ross MD, and Dilip M Purohit MD (original authors)

Patient Profile

Age range of presentation: 0 to1 month
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Neonatal opioid withdrawal syndrome

Associated Disorders

Neonatal drug withdrawal syndrome

Differential Diagnosis

Gastroesophageal reflux
Pain
Sepsis
Brain injury, eg, hypoxic-ischemic encephalopathy
Hyperthyroidism
- Hypoglycemia
- Hypocalcemia
- Immaturity
- Benign neonatal sleep myoclonus
- Seizures
- Dysmorphism/oromotor dysfunction
- Gastrointestinal disease
- Polycythemia

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Clinical Categories

General Child Neurology

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
(45)

Neonatal opioid withdrawal syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Timing of Onset and Observation Time

Table 2A. Symptomatology

Table 2B. Evolution of Symptoms

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Table 3. Differential Diagnosis of Neonatal Abstinence Syndrome

Diagnostic workup

Management

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

Outcomes

Special considerations

Pregnancy

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Rare brain embryonal tumors in infancy and early childhood

Pediatric-type diffuse high-grade gliomas (excluding diffuse midline gliomas)

Autosomal dominant hereditary ataxias

Megalencephaly

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