Neonatal abstinence syndrome

INTRODUCTION — An infant born to a person with a substance use disorder is at risk for withdrawal, commonly referred to as neonatal abstinence syndrome (NAS). NAS is a variable, complex, and incompletely understood spectrum of signs of neonatal neurobehavioral dysregulation.

Although most commonly associated with opioid exposure, other substances have been associated with an abstinence syndrome, including nicotine. Additionally, other substances, such as cigarettes, benzodiazepines, and selective serotonin reuptake inhibitors (SSRIs), can potentiate the severity of opioid-induced NAS.

The clinical manifestations, diagnosis, and management of NAS will be reviewed here. Opioid use during pregnancy and neonatal exposure to other substances are reviewed separately. (See "Infants with prenatal substance use exposure" and "Substance use during pregnancy: Screening and prenatal care" and "Overview of management of opioid use disorder during pregnancy".)

TERMINOLOGY

NAS versus NOWS — NAS describes neonates who are at-risk for poly-substance exposure, including opioids. NAS has been used interchangeably by some with the term neonatal opioid withdrawal syndrome (NOWS), which is used to describe opioid-only withdrawal symptoms [1,2]. The term NAS will be used here to encompass both opioid/polysubstance and opioid-only exposure.

Opioids — The term opioid refers to natural and synthetic substances with morphine-like activities that activate mu-opioid receptors in the central nervous system and gastrointestinal tract. Opiate refers to a subclass of opioids consisting of alkaloid compounds extracted or derived from opium that include morphine, codeine, and semisynthetic derivatives such as heroin, methadone, fentanyl, hydromorphone, and buprenorphine. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis".)

EPIDEMIOLOGY — In the United States, the reported prevalence of NAS increased from 4.0 per 1000 birth hospitalizations in 2010 to 7.3 per 1000 birth hospitalizations in 2017 [3]. The rate of NAS per 1,000 newborn hospitalizations varies amongst states, and is available for each state from the Healthcare Cost and Utilization Project database.

NAS, defined by signs of opioid withdrawal, is associated with the antenatal exposure to illicit opioids (eg, heroin), misuse of licit opioids (eg, oxycodone, fentanyl), or exposure to medications used to treat maternal opioid use disorder (methadone or buprenorphine) [4,5]. NAS also may be precipitated by exposure to products from the plant Mitragyna speciosa, commonly known as kratom, a substance that can cause similar effects to opioids and has been used by some people as a recreational drug or to treat certain conditions, including pain [6]. The management of pregnant people with opioid use disorder is discussed separately. (See "Substance use during pregnancy: Screening and prenatal care" and "Overview of management of opioid use disorder during pregnancy" and "Methadone and buprenorphine pharmacotherapy of opioid use disorder during pregnancy".)

Among infants with prenatal exposure to opioids, the reported rate of NAS requiring pharmacotherapy ranges from 42 to 94 percent [7-12]. Prescription opioid use during pregnancy is associated with neonatal complications [13]. Antenatal cumulative prescription exposures, type of opioid used, tobacco use, and selective serotonin reuptake inhibitor (SSRI) use may increase the risk of NAS. There is no conclusive available evidence that there is a relationship between maternal methadone dose and NAS severity [14]. Higher long-term unemployment and shortage of mental-health clinicians were also associated with higher levels of NAS based on results from a 580 county-level study in eight states in the United States [15]. These data highlight the need for efforts to comprehensively treat opioid use disorders among childbearing people and to understand the social complexities related to opioid use and misuse during pregnancy and NAS. (See "Substance use during pregnancy: Screening and prenatal care" and "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Approach to treating opioid use disorder".)

PATHOPHYSIOLOGY — The pathophysiology of NAS and factors that influence its severity are not completely understood. However, altered levels of neurotransmitters such as norepinephrine, dopamine, and serotonin are presumed to play a significant role [16].

Genetic variations of the mu-opioid receptor (OPRM1) and the catechol-o-methyltransferase (COMT; encodes an enzyme that metabolizes catecholamines) genes appear to affect the need for pharmacotherapy and length of stay in neonates with prenatal opioid exposure [17]. These data are consistent with data from adult studies that also show polymorphisms in these genes are associated with variability in adult opioid dependence [18]. Epigenetic modifications to the mu-opioid receptor (OPRM1) promoter have also been associated with NAS severity [19].

CLINICAL MANIFESTATIONS

Clinical findings — The characteristic signs of NAS occurs after chronic in utero exposure to opioids and reflect dysfunction in any of four domains: state control and attention, motor and tone control, sensory integration, and autonomic functioning [20]. The presence and severity of these findings are the basis of scoring systems used in making management decisions in infants with NAS (form 1) (see 'Assessment and management protocols' below).

The major domains of dysfunction resulting in signs and symptoms in the infant with NAS are:

●Sleep and wake cycle disturbances manifested by fragmented sleep with short sleep cycles and difficulty maintaining an alert state.

●Alterations in tone or movement manifested by hypertonicity, tremors, jitteriness.

●Autonomic dysfunction manifested by sweating, sneezing, mottling, fever, nasal stuffiness, and frequent yawning.

●Easy overstimulation, sensitivity, or hyperarousal resulting in irritability and crying with any stimuli. Infants may have difficulties with feeding (suck-swallow incoordination and oral hypersensitivities resulting in poor weight gain, respiration (tachypnea) and gastrointestinal problems (gassiness, vomiting, loose stools).

Other findings in infants with NAS may include:

●Birth weight <10^th percentile for gestational age (GA) due to intrauterine growth restriction [21,22]. (See "Infants with fetal (intrauterine) growth restriction".)

●Cardiac birth defects; however, data are inconsistent [23,24].

Although a prospective cohort study reported an association between chronic opioid exposure and decreased head circumference in offspring [25], the validity of the findings is uncertain based on methodologic concerns about study design [26]. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Etiology'.)

Timing of the onset of NAS — Timing of the onset of NAS symptoms varies depending upon the recent history of exposures and the half-life of substance elimination. In infants exposed to heroin (short half-life), withdrawal signs often begin within 24 hours of birth, whereas withdrawal from longer-acting methadone or buprenorphine usually begins anywhere from 24 to 72 hours after birth [2,16,27]. However, for any opioids, withdrawal may be delayed until five days of age or later [28]. Therefore, the length of hospital stay can be tailored if the specific agent is known: observation for infants for at least three days with exposure to immediate-release opioids, four to seven days with exposure to buprenorphine and sustained-release opioids, and five to seven days with exposure to methadone [2]. However, more commonly, the precise details of the exposure are uncertain or there are multiple exposures. In such circumstances, the infant should be observed in the hospital for a minimum of four to five days to avoid the onset of NAS after hospital discharge. In all cases, scheduled pediatric follow-up care should be firmly in place prior to hospital discharge.

If one week or longer has elapsed between the last parental opioid use and delivery of the infant, the risk of acute signs of neonatal withdrawal is low [2]. However, parents/caretakers should be informed of the possibility of late-onset NAS and be instructed to seek medical attention if signs of NAS appear after hospital discharge [28].

Other variations in presentation — NAS presentation is widely variable in timing of onset and in the types and severity of signs displayed. The mechanisms that underlie the signs are likely to be multifactorial and unique to each pregnancy.

This variability is poorly understood, but is likely due to myriad factors, which include [2,29-31]:

●Parental exposures – Substances used; concurrent use of prescribed medications such as benzodiazepines [32], SSRIs [33], and gabapentin [34], which produces an atypical NAS in opioid-exposed infants; timing of exposures during gestation; polysubstance (including alcohol and nicotine) use; and frequency, type, and dose of opioid.

●Parental/caregiver factors – Nutrition, infections, stress, and comorbid psychiatric conditions.

●Placental opioid metabolism.

●Genetics and epigenetics. (See 'Pathophysiology' above.)

●Infant factors – Infant sex, preterm birth, gestational age, comorbid infections, rate of substance metabolism and excretion, other concomitant medical conditions, and medications.

●Environmental factors – Ability of the parent/caregiver and other handlers to understand and respond to infant cueing appropriately; physical environment (ie, neonatal intensive care unit [NICU] versus newborn nursery, rooming in).

Exposure to violence, stress, poor prenatal care, or prenatal infections may also influence NAS expression as NAS often occurs in the context of an infant who has been compromised by other adverse intrauterine conditions.

Preterm infants — Preterm infants have a lower incidence of NAS as compared with term infants [35]. NAS symptom severity diminishes as GA decreases [8,31]. However, scoring systems were designed to be used for term infants and may not accurately reflect NAS signs in preterm infants, a group in whom NAS has not been well described. Possible explanations of the reduced symptomatology in preterm compared with term infants include [36]:

●Developmental immaturity of the preterm central nervous system

●Decreased receptor development and sensitivity

●Limited ability to express the signs of motor dysfunction

●Reduced total substance exposure during the intrauterine period

●Lower amounts of fat deposition of substance

DIAGNOSIS — NAS is defined and diagnosed by the cardinal signs of opioid withdrawal rather than the need for pharmacotherapy [37].

Clinical diagnosis — The clinical diagnosis of prenatal opioid exposure is based upon a history (or suspected history) of parental opioid use disorder, positive parental or infant urine toxicology screening for opioids, and/or neonatal findings that are consistent with NAS. (See 'Clinical manifestations' above.)

Although opioid exposure identified as a positive toxicology screening in either a parental or neonatal specimen is useful to confirm the diagnosis of NAS, there are challenges in obtaining accurate results in an opioid-exposed infant. As a result, false-negative results can occur in neonatal screening tests. Screening for parental substance use disorder is discussed separately. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use'.)

Neonatal testing — Although testing in the neonate to detect the presence of opioids can be performed in a variety of biological specimens (eg, urine, hair, umbilical cord blood, and meconium), each of these tests has clinical limitations [2,30]. Although information about prenatal exposures is better obtained by providing maternal written consent for discussion with treatment providers, neonatal testing may be useful for a clinician faced with an infant displaying signs of NAS whose mother denies any substance use.

Specific infant tests for the detection of substance exposure include [2]:

●Urine – Urine screening of the newborn has a low sensitivity (high false-negative rate) because for most substances only infants with recent exposure will have a positive test.

●Hair – Testing of neonatal hair is challenging because of difficulties in quantifying the small amount of substance and the slow growth of hair in the fetus/neonate, and because this practice is culturally unacceptable to some parents. Hair testing utility in medical management is limited.

●Meconium – Meconium analysis is sensitive and specific for substances (including opioids) that are excreted either in the hepatobiliary system or amniotic fluid via fetal renal excretion [7,38]. However, testing is not typically available on-site at birth hospitals, and results from outside reference laboratories are often not available for days to weeks. Meconium must be collected before the specimen is contaminated by transitional, human milk, or formula stools. In some cases, meconium is passed in utero making collection impossible, and in other cases, it may take several days for the passage of meconium, thereby delaying the diagnosis. In addition, analysis of meconium for substances reflects exposures during the second and third trimesters when meconium forms, and therefore may not reflect periods of abstinence closer to delivery.

●Umbilical cord – Testing of umbilical cord tissue by using class-specific immunoassays appears to be a promising method of testing [39]. In the United States, testing is commercially available, but its utility in medical management is limited [40,41].

Of note, meconium and umbilical cord assays have limited or no utility for people in substance use disorder treatment, as they do not reflect periods of abstinence closer to term because meconium and umbilical cord testing reflects exposures in the second and third trimesters.

Legal requirements — Clinicians must be aware of the legal requirements for reporting infants affected by prenatal substance exposures, and each birth institution should adopt a policy that complies with local laws and avoids discriminatory practices. In the United States, the Child Abuse Prevention and Treatment Act requires health care professionals to facilitate community-based, family support programs known as Plans of Safe Care. These programs address the health and other needs of the infant and the substance use disorder treatment needs of the affected caregiver and others involved in the care of the infant [42]. Both websites provide a list for each state's reporting requirements and available plans of care.

DIFFERENTIAL DIAGNOSIS — Because other neonatal problems may have similar features to NAS, clinical signs should not be attributed solely to withdrawal without appropriate assessment and diagnostic tests to differentiate the following diseases from NAS (see 'Further evaluation' below) :

●Seizures:

•Hypocalcemia – Risk factors associated with early neonatal hypocalcemia include prematurity, intrauterine growth restriction (IUGR), birth asphyxia, and parental diabetes. A serum calcium measurement differentiates NAS from hypocalcemia. (See "Neonatal hypocalcemia", section on 'Early hypocalcemia'.)

•Hypoglycemia – Risk factors associated with neonatal hypoglycemia include prematurity, large for gestational age (LGA), parental diabetes, and polycythemia. Measurement of glucose differentiates NAS from hypoglycemia. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Screening'.)

•Hypoxic-ischemic encephalopathy (HIE) – Patients with HIE generally have a history of birth or prenatal asphyxia, which differentiates them from infants with NAS. In addition to seizures, other overlapping symptoms with NAS include irritability and hyperreflexia. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Markers of acute hypoxia-ischemia'.)

●Fever and irritability:

•Sepsis – Infectious illnesses are more common among substance-using/misusing populations, especially injection substance users. Therefore, substance-exposed infants are at increased risk for neonatal infections. While awaiting blood culture results, empiric antibiotics should be considered in patients in whom there is an increased risk of bacterial sepsis (eg, parental fever, premature rupture of membranes, or chorioamnionitis), which is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

●Hyperthyroidism – Generally neonatal hyperthyroidism occurs in infants born to parents with hyperthyroidism. Neonatal thyroid function studies differentiate this condition from NAS. (See "Evaluation and management of neonatal Graves disease".)

•Poor feeding may occur in all of the above conditions as well as in infants with polycythemia. In addition, infants with polycythemia may also have a mottled skin appearance. Risk factors for neonatal polycythemia include LGA, parental diabetes, and delayed cord clamping. Measurement of hematocrit differentiates this condition from NAS. (See "Neonatal polycythemia", section on 'Diagnosis'.)

FURTHER EVALUATION — Further evaluation focuses on differentiating NAS from other disorders and detecting comorbidities.

As discussed above, infants affected by NAS may have findings that are observed in other neonatal conditions. In patients in whom it is uncertain whether the signs are due to opioid withdrawal (ie, no clinical suspicion or evidence of parental substance use disorder), further evaluation is needed to differentiate NAS from other disorders. (See 'Differential diagnosis' above and "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use'.)

Initial laboratory testing in these patients includes a complete blood count, and measurements of serum glucose and calcium, which may distinguish NAS from hypoglycemia, hypocalcemia, and polycythemia. In addition, an elevated or markedly decreased white blood cell count may be indicative of systemic infection.

Additional tests are obtained if the clinical conditions are suggestive of neonatal hyperthyroidism (thyroid function studies) or sepsis (blood cultures and possible empiric antibiotic therapy). (See 'Differential diagnosis' above.)

Comorbidities of NAS may include maternal sexually transmitted infection (syphilis, chlamydia, gonorrhea, hepatitis C, and human immunodeficiency virus [HIV]) [2]. Also common in people with substance use disorder is psychiatric comorbidity, particularly depression and violence exposure, both of which can affect infant well-being. Screening for these conditions should be considered in parents with infants who have NAS. (See "Infants with prenatal substance use exposure" and "Infants with prenatal substance use exposure", section on 'Diagnosis'.)

MANAGEMENT APPROACH

Multidisciplinary team — The optimal care of the parent/caregiver-infant dyad is provided by a nonjudgmental multidisciplinary team that is well versed in the management of parental substance use disorder and NAS [43]. Healthcare and social service providers should collaborate in the care of these infants and their parents during the birth hospital stay and determine appropriate postdischarge disposition and follow-up care. Every nursery should adopt a standardized protocol for assessing and managing neonates at risk for NAS [43-46].

At our center, the management approach discussed in the following section is used by our multi-disciplinary team, which includes obstetricians, mental health therapists, psychiatrists, pediatricians, nurses, and social workers.

Goals — Our main goals of therapy are to promote infant and parental regulation and to minimize the signs of NAS expression in the infant by optimizing handling and the environment and only using pharmacotherapy when necessary.

Our management approach includes supportive nonpharmacologic care in all dyads (parent/infant pairs) affected by parental substance use disorders, and pharmacologic therapy in some infants who have more severe NAS expression [2]. The decision to initiate pharmacologic therapy is based on the severity of signs, which is determined by an abstinence scoring system, and an inadequate response to appropriate, individualized, and maximal nonpharmacologic measures.

Assessment and management protocols — NAS assessment should start at birth for all opioid- and other substance-exposed newborns, and ongoing assessment should be performed every three to four hours for the infant's entire birth hospitalization [43]. In every center caring for infants with NAS, an abstinence scoring system should be adopted, as it provides a semi-objective and standardized assessment of the severity of the patient's withdrawal signs [2]. Several abstinence scoring methods (eg, Lipsitz tool, Finnegan Neonatal Abstinence Scoring System and modified versions, and the Neonatal Withdrawal Inventory) based upon the clinical manifestations of NAS have been developed and verified for clinical use. These are used to initiate, adjust, and wean pharmacologic therapy based on the severity of neonatal withdrawal findings. Evaluation and management protocols using these scoring systems by trained staff have been shown to decrease the duration of opioid exposure and length of hospital stay [47,48]. In our center, we use a modified version of the Finnegan scoring system (form 1).

It is important to note that there is a lack of evidence to support the use of one scoring/treatment tool or one management strategy over another [49,50].

●The Finnegan scoring system, the most widely adapted scoring system, and modified versions of this tool are designed for use in term infants, but a major limitation of its use is nonapplicability to preterm (<37 weeks gestation) and older (>30 days) infants [2]. A second concern is the subjective nature of the scales used [51].

●Other assessment tools have been developed including the Eat, Sleep, Console (ESC) assessment approach that evaluates the neonates' ability to eat ≥1 oz or breastfeed well, sleep undisturbed ≥1 hour, and be consoled within 10 minutes [2,45,46,52-54]. This approach emphasizes maternal involvement with a goal of reducing opioid therapy and length of birth hospitalization and has been reported to reduce length of stay and use of postnatal opioid therapy [52-54]. However, high-quality evidence supporting its use and longer-term effects on the infant and parent are lacking as the use of this tool has only been reported as part of quality improvement initiatives without determination of short- or long-term risk. It is unclear that reported improved outcomes (eg, length of birth hospitalization and amount of medication received for the treatment of NAS) are reflective of more optimal care of the NAS affected infant and consideration for his development, and/or are due to the approach itself or better adherence to nonpharmacologic care [2]. Further study and validation of its safety and effectiveness are required prior to adopting this tool for routine use for infants with NAS.

To improve the evaluation of research efforts across studies, a consensus and evidence-based core outcome (NOWS-COS: neonatal opioid withdrawal syndrome core outcome set) has been developed by a multidisciplinary group of experts [49]. Although this tool will need to be clinically validated, it is hoped that its implementation will reduce heterogeneity and facilitate comparison of results across future studies, thereby improving the quality of care for affected infants.

NONPHARMACOLOGIC CARE — Nonpharmacologic care should begin at birth for all substance-exposed infants, be inclusive of the parent/caregiver, and continue throughout the neonate's hospitalization and beyond, regardless of the need for pharmacotherapy and the clinical status of the infant. Nonpharmacologic interventions, when appropriately applied can avoid or reduce the amount of pharmacologic therapy, but are not an alternative to pharmacotherapy when it is needed. It entails an individualized assessment of the infant's and parent's functioning, the environment to identify specific triggers for dysregulation in the dyad, and adaptations to the environment and handling to minimize physiologic and neurobehavioral signs and promote dyadic regulation [20].

General care measures — In our center, nonpharmacologic care measures include the following [2,20]:

●Individualizing the care of the infant, based on behavioral observations, with the goal of promoting organization, physiologic stability, and competence. For example, if an infant has difficulty with hypertonicity or tremors, using positioning (side-lying C position) and swaddling to reduce the motoric hyperactivity will allow the infant to organize his/her behaviors to become calm and better able to interact with care providers. Excessive irritability may be overcome with gentle vertical rocking.

●Recognizing signs and triggers of physiologic behavioral disorganization (see 'Clinical manifestations' above). Intervention with nonpharmacologic techniques tailored to the infant's expression of NAS may prevent the development of more overtly disorganized behaviors.

●Identification of sensory or other environmental input as potential sources of dysregulation for the infant and the provision of interventions to ameliorate their effects. Alterations to the environment to minimize dysregulation related to sensory input should be specific to the identified triggers for dysregulation in each infant. For example, an infant who becomes disorganized (ie, hypertonic or irritable) with eye contact may require feeding or handling by a caregiver who avoids eye contact during that activity. Likewise, an infant who is easily overstimulated by sound can be cared for in a quiet room.

●Support of the infant's efforts to become stable, organized, and competent by identifying techniques that ameliorate symptomatology specific to each infant. For example, a hypertonic or jittery infant will be better able to function if swaddled or provided containment holding with the hands held.

●Oral hypersensitives, when identified, can affect the infant's ability to feed and be difficult to address. Pacifier use, if tolerated, may be beneficial.

●Small, frequent feedings, or breastfeeding when appropriate. (See 'Feeding' below.)

●Assessment of parental functioning and interaction with the infant and adaptations to handling of the infant to minimize dysregulation and promote dyadic synchrony [55]. Teaching the parent/caregiver what the infant is sensitive to and assisting in finding techniques to minimize that sensitivity and the infant's dysregulation can help the parent/caregiver to provide contingent responses to the infant and thereby minimize the NAS expression. Helping the parent/caregiver to provide contingent responses to the infant and thereby minimize the NAS expression. Helping the mother/caregiver with their own self-regulation and helping them to understand the feelings that they have surrounding their infant's functioning can help them to be more appropriately responsive to the infant.

Environment — The physical environment of the opioid-exposed dyad is an important component of NAS management. Rooming-in (ie, the colocation of parental and infant care after delivery and beyond), has been shown to reduce NAS severity [2,56,57] and is the preferred inpatient model of care for NAS. Neonatal intensive care unit (NICU) care, while necessary for some NAS-affected infants due to comorbid conditions or very severe expression, is generally not optimal, as the intensive care environment can be overstimulating for many sensitive opioid-exposed infants. In addition, adaptations to the environment to optimize care for the parent/caregiver (for example, for those who have experienced violence) may also be necessary. (See "Infants with prenatal substance use exposure".)

Skin care — The best approach to prevent skin excoriation due to excessive rubbing in hypertonic infants is to swaddle the infant, thereby reducing trauma to the skin. Topical barrier creams used to treat diaper dermatitis should be applied early, at the first signs of skin irritation, to affected areas to protect the skin and prevent further damage. (See "Diaper dermatitis".)

Feeding — Human milk feeding can be successful in some people with opioid use disorder, and formula feeding should not be the default feeding for infants with NAS [2,58-60]. Each institution should have a protocol for breastfeeding for people with substance use disorder. (See "Infants with prenatal substance use exposure", section on 'Breastfeeding'.)

●Challenges to breastfeeding – Challenges to breastfeeding for people with substance use disorder include [61,62]:

•Difficulties with positioning and feeding the infant due to the symptoms of NAS

•Difficulties ensuring adequate milk intake

•Lengthy hospital stays that may result in separation of the infant and parent

•Requirements of substance use disorder treatment centers

•Lack of support and education

•Trauma exposure

Infants with NAS are at increased risk of poor weight gain and growth during the neonatal period [63]. Their intake and weight gain should be monitored closely regardless of feeding method.  

●Criteria for supporting breastfeeding – Breastfeeding generally can be supported in people who meet all of the following criteria:

•Provide consent to discuss progress in treatment and plans for postpartum treatment with a substance use disorder treatment counselor, and the counselor endorses that they have been able to achieve and maintain sobriety prenatally.

•Plan to continue in substance use disorder treatment in the postpartum period. People on a stable methadone or buprenorphine regimen should be encouraged to breastfeed, as discussed below.

•Have been abstinent from illicit or licit substances for 90 days prior to delivery and demonstrated the ability to maintain sobriety in an outpatient setting.

•Have a negative parental urine toxicology testing at delivery except for prescribed medications.

•Received consistent prenatal care.

•Do not have medical contraindication to breastfeeding (such as HIV) (table 1). While not an absolute contraindication, people who are positive for hepatitis C with cracked or bleeding nipples should abstain from breastfeeding. (See "Breastfeeding: Parental education and support", section on 'Contraindications to breastfeeding'.)

•Are not taking a medication that is unsafe during lactation.

Breastfeeding by methadone-maintained people appears to be safe, and may reduce the severity of NAS and the need for pharmacologic intervention [64-67]. Concentrations of methadone are low in human milk (range 21 to 462 ng/mL) and appear not to be related to the parent's dose of methadone [64]. The low concentrations of methadone in human milk are unlikely to produce a substantial effect on the infant's display of NAS, and other factors associated with breastfeeding may be responsible for the reduced severity of NAS in breastfed infants of methadone-maintained people. Infants should be monitored closely and treated appropriately with pharmacologic therapy if indicated.

Buprenorphine is excreted in low concentrations into breast milk and appears to be safe for the infant of a breastfeeding mother maintained on buprenorphine [68,69].

●Reasons to discourage breastfeeding – Breastfeeding generally should be discouraged in people for whom any of the following are true:

•Did not receive prenatal care.

•Relapsed into illicit substance use or licit substance misuse (including cannabis) in the 30-day period prior to delivery.

•Are not willing to engage in substance use disorder treatment or who are engaged in treatment but are not willing to provide consent for contact with the counselor.

•Positive parental urine toxicology testing for substances of use/misuse at delivery, indicating active substance use/misuse.

•Do not have confirmed plans for postpartum substance use disorder treatment or pediatric care.

•Demonstrate behavioral qualities or other indicators of active substance use.

●Individualized decision – Recommendations regarding the suitability of breastfeeding should be individualized for people with any of the following (if possible, by a multidisciplinary team consisting of perinatal and substance use disorder treatment providers):

•Relapsed to illicit substance use or licit substance misuse in the 90- to 30-day period prior to delivery, but who maintained abstinence within the 30 days prior to delivery.

•Concomitant use of other prescription (ie, psychotropic) medications.

•Engaged in prenatal care and/or substance use disorder treatment during or after the second trimester.

•Attained sobriety only in an inpatient setting.

PHARMACOLOGIC THERAPY — Pharmacologic intervention is aimed at the short-term improvement of clinical symptomatology.

Indications — Pharmacologic therapy is initiated for infants who, despite adequate and individualized nonpharmacologic care, display significant signs of NAS as defined by predetermined criteria based on an abstinence scoring system (generally when the infant has two scores ≥8) (form 1).

Choice of initial agent — Although no optimal treatment has been established in clinical trials, opioid therapy is the preferred initial treatment for NAS compared to other drug classes (eg, sedatives) based on limited data that report opioid therapy is associated with shorter duration of hospital stay and decrease need for an additional drug [2,47,70-72]. The preferred opioid formulations are morphine or methadone, and the selection is dependent on clinician choice. In our center, we use an oral solution of morphine sulfate. We do not use nonopioid pharmacologic agents (ie, phenobarbital and clonidine) as initial therapy but add them as a second agent, if necessary, based on limited observation data [70,73-75].

The following different opioids have been used in treating NAS [2]:

●Morphine – Morphine is a short-acting opioid. It is the preferred agent for treating NAS at our center.

●Methadone – Methadone is a long-acting opioid. It is a reasonable alternative to morphine and is used as the first-line agent at some centers. Limited observational data reported that methadone minimally reduced treatment duration and length of birth hospitalization compared with morphine after adjusting for confounding factors and when using a hybrid weight- and symptom-based scoring paradigm [76,77].

●Buprenorphine – Buprenorphine appears to be an effective treatment for NAS [78,79]; however its use in neonates is limited because it has a high ethanol content (30 percent) and sublingual administration is challenging [2]. If an ethanol-free formulation is developed, this agent may play a more central role in managing NAS in the future.

Agents that are no longer used to treat NAS include tincture of opium (also referred to as diluted opium tincture and DTO) and paregoric-containing anhydrous morphine (0.4 mg/mL), also referred to as camphorated tincture of opium [2].

There is a paucity of data directly comparing different pharmacologic interventions as initial therapy for NAS. A 2020 systematic review identified 16 trials that included 1110 infants [70]. The following findings were noted:

●In a single trial (n=80 infants) comparing morphine with supportive care alone, morphine increased duration of hospitalization and treatment, but reduced the days to regain birthweight.

●Use of an opioid agent was more effective in reducing NAS scores than a sedative agent such as phenobarbital (six trials, 458 infants).

●In trials comparing morphine with methadone (2 trials, 147 infants), both agents had similar rates of treatment failure, breastfeeding success, and duration of hospitalization.

●In trials comparing morphine with buprenorphine, (3 trials, 113 infants), both agents had similar rates of treatment failure. However, hospitalization duration was shorter in the buprenorphine group.

●Data were insufficient to determine the effectiveness of clonidine for NAS treatment (1 trial, 31 infants).

In a network meta-analysis using both direct and indirect comparisons from 18 trials (n=1072 infants) evaluating six agents (morphine, methadone, buprenorphine, DTO, clonidine, phenobarbital), morphine and methadone were the agents associated with lowest rates of treatment failure, though the differences were not statistically significant [73]. Buprenorphine was associated with the shortest duration of hospitalization.

Dosing — In our center, the dosing of morphine sulfate (our preferred opioid) is determined by the overall presence and severity of signs as opposed to a weight-based protocol [80,81]. The infant's response to therapy is monitored using the abstinence scoring system. For patients with persistent significant clinical signs, the dose of opioid therapy is increased (form 1). In other institutions, medication (morphine or methadone) is given on an mg/kg basis both as an initial dose and incremental dose based on symptoms (table 2) [30,36].

Addition of second agent, if necessary — A second medication is used in infants with severe NAS that is not adequately controlled with the use of a single agent. However, data are limited on the optimal choice of a second agent. In our center, the preferred second-line medication is clonidine, which is consistent with the AAP guidelines, because of concerns regarding the adverse effects of phenobarbital including oversedation, the high alcohol content of phenobarbital solutions, difficulties in weaning phenobarbital among substance-exposed infants, and the potential long-term effects of prolonged exposure to phenobarbital on neurodevelopment based on animal data [2,30,82-84]. However, other centers may use phenobarbital as the initial second-line agent. We consider phenobarbital as the second-line medication for opioid and benzodiazepine or for some polysubstance-exposed infants.

●Clonidine – Clonidine has been shown to be effective as an adjunctive medication to opioid therapy for the treatment of NAS. Clonidine can be started at an initial oral dose of 0.75 mcg/kg every three hours in infants on maximal morphine dose and increased to 1 mcg/kg every three hours if necessary.

In a clinical trial of 80 neonates with intrauterine exposure to methadone or heroin, the addition of oral clonidine (1 mcg/kg every four hours) versus placebo to standard opioid therapy decreased the duration of pharmacologic therapy (11 versus 15 days) [85]. Higher doses of opioid therapy also were needed in the placebo group. There were no significant short-term complications (eg, hypertension, hypotension, bradycardia, or oxygen desaturations) in either group. However, there were three deaths in the clonidine group (myocarditis, sudden infant death syndrome [SIDS], and homicide).

●Phenobarbital – Phenobarbital is also used as a second-line medication and may be effective in polysubstance-exposed infants, particularly those who are also exposed to barbiturates and/or benzodiazepines. In one study, the combined use of opioid and phenobarbital therapy compared with opioid therapy alone reduced the length of hospital stay and duration of symptoms [86]. Despite its widespread use for treating seizures and NAS, a safety profile has not been adequately established and alcohol content is a concern [87]. (See "Infants with prenatal substance use exposure".)

•For infants with significant withdrawal symptomatology, an oral loading dose of 10 mg/kg (up to 20 mg/kg based on severity of symptoms) is followed by a maintenance dose of 2.5 mg/kg given twice daily in 12 to 24 hours after the administration of the loading dose. Once the patient is stable and symptoms are controlled, weaning can be accomplished by decreasing the daily dose by 20 percent once per week.

•For some infants, particularly those exposed to benzodiazepines and opioids, a one-time loading dose of 10 or 5 mg/kg in conjunction with opioid therapy with morphine sulfate may be sufficient.

•Limited data from a multisite study evaluating the effects of pharmacologic treatment (morphine versus methadone) for NAS on neurodevelopmental outcome found no significant differences between the two treatment groups for most outcomes evaluated in primary analyses. However, in post-hoc analyses, infants who received adjunctive phenobarbital had lower Bayley scale scores and more behavioral problems on the Child Behavioral Check List (CBCL) at 18 months [88].

Data are limited in comparing the efficacy of these two agents as adjunctive therapy in reducing the duration of morphine therapy. In a retrospective multicenter study of 563 infants with NOWS treated with morphine, approximately one-third of infants received a second medication; 72 received phenobarbital and 108 received clonidine [74]. After adjusting for multiple covariates, length of stay was shorter for infants treated with phenobarbital compared with the clonidine group (-10.26±1.5 days, 95% CI -13.21 to -7.31 days) as well as length of morphine treatment (-7.51±1.4, 95% CI -10.27 to -4.75). More infants were discharged home on phenobarbital than clonidine (78 versus 29 percent). However, there were no data after discharge regarding length of continued therapy or developmental outcome, which remains a concern with continued phenobarbital therapy.

Avoidance of naloxone — Naloxone should not be used in the management of NAS because it may precipitate rapid withdrawal symptoms [2,89].

Discontinuation of pharmacologic therapy — Once the patient responds to therapy with a decrease in the number and/or severity of signs of NAS based on ongoing assessment using the abstinence scoring system, drug therapy is weaned. For infants requiring more than one medication, morphine is weaned off first.

In our center, we wean oral morphine sulfate by 0.02 mg every 24 hours for scores that are ≤8. The infant is discharged home when they have been totally weaned off morphine for at least 24 hours.

Occasionally infants will require a re-escalation in treatment once weaning have begun. In this case, oral morphine sulfate is increased by half of the initial escalation dosing (form 1). For infants that have failed weaning at least once, infants are observed for 48 hours off medications prior to discharge.

DISCHARGE CRITERIA — The length of hospitalization should be sufficient to detect the development of signs of NAS recognizing that in a subset of infants, the presentation of significant NAS symptoms can be delayed. In our hospital, we use a minimum stay of four days, as it is challenging to determine if exposure is limited to only short-acting opioids such as heroin especially in parents who are not participating in a substance use disorder treatment program, for whom there is a more thorough understanding of prenatal exposures. If the infant was managed with pharmacologic therapy, the infant can be discharged if clinically stable for at least 24 hours after medication has been discontinued. We do not discharge infants on any medications for the treatment of NAS for many reasons, including the difficulty weaning these medications on an outpatient basis and the challenges of the postpartum period for many parents with OUD.

Families of infants who are opioid exposed are disproportionately at risk for socioeconomic and social challenges [2]. The immediate postnatal period is often a stressful period for both mother and infant, and also a critical time for dyadic functioning. Therefore, discharge planning should be thoughtful and sensitive to the needs of the dyad. Discharge planning for substance-exposed infants should include an evaluation of parental functioning and mental health needs, ongoing support for substance use disorder treatment, and assessment of the home environment and support systems, with particular attention to any issues with domestic violence and instability [2]. Parents should be educated about sudden infant death syndrome (SIDS), sleeping positions/safe sleep, postnatal exposures, the importance of ongoing substance use disorder treatment (and mental health care if warranted), signs of infection, and how and when to access pediatric care and advice if needed. Pediatric care should be identified prior to discharge, and mothers/caregivers should be aware of how to access pediatric help should the infant develop any signs of withdrawal. A referral to an early intervention program may be initiated as substance-exposed infants are at risk for developmental alterations [2].

Post-discharge follow-up — Early pediatric follow-up within 48 hours should be arranged prior to hospital discharge in the event that the infant requires re-evaluation for NAS symptoms, or has inadequate weight gain/feeding problems [2]. Pediatric providers should be aware of the potential need for ophthalmologic evaluation for the identification of nystagmus, strabismus, or other refractive errors, and for neurodevelopmental assessment [16].

LONG-TERM OUTCOME — It has been difficult to ascertain the long-term effects of prenatal opioid exposure on the developmental outcome of affected children because of confounding variables (including prenatal tobacco exposure [90]) and small sample sizes of published studies [91,92]. These include prenatal (eg, other substance exposures including tobacco smoke, prematurity, low birth weight, intrauterine growth restriction [IUGR], etc) and postnatal factors (eg, NAS pharmacotherapy, continued maternal substance use/misuse, violence exposure, and socioeconomic and educational level). Most of the evidence is observational in nature and results are mixed, and thus the long-term direct effects of prenatal opioid exposure remains inconclusive. Nevertheless, there appears to be a complex developmental vulnerability in opioid-exposed children, which in part is likely due to potential confounding factors [91-94].

In the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study of 96 children, a randomized trial of opioid-agonist pharmacotherapy during pregnancy, no differences in growth and neurodevelopmental outcome at 36 months were reported between children with either prenatal buprenorphine versus methadone exposures or those who received NAS pharmacotherapy versus those with no medication therapy for NAS [95].

In contrast, several observational studies have reported an association between prenatal opioid exposure and negative impact on neurodevelopmental and psychological outcomes in children (eg, lower intelligence quotient scores, educational disability), maltreatment, and trauma during childhood [91,96-103]. A systematic review of the literature reported an association between a diagnosis of NAS and future child maltreatment, mental health diagnosis, visual problems, and poor school performance [93]. However, causation is not suggested due to multiple factors.

SUMMARY AND RECOMMENDATIONS

●Terminology – A newborn infant born to a parent taking, using, or misusing opioids and/or other substances is at risk for withdrawal, commonly referred to as neonatal abstinence syndrome (NAS). In the United States, opioids to which infants are exposed prenatally include illicit opioids (eg, heroin), licit opioids that are used or misused (eg, oxycodone, fentanyl), medications used to treat maternal opioid use disorder (methadone, buprenorphine), or kratom. (See 'Opioids' above and 'Epidemiology' above.)

●Clinical manifestations – The signs of NAS are due to dysfunction of autonomic regulation, state control capacities, and sensory and motor functioning. They include sleep/wake disturbances, alterations in tone or movement (eg, tremor and hypertonicity), autonomic disturbances (fever, yawning, sweating, nasal stuffiness, vomiting, and loose stool), hypersensitivity to ordinary stimuli with irritability/crying, gastrointestinal difficulties (vomiting, diarrhea), tachypnea, poor feeding, and poor weight gain (form 1). (See 'Clinical manifestations' above.)

●Presentation – The clinical presentation of NAS varies according to individualized factors, including the specific opioid (eg, half-life), timing of the most recent maternal substance use before delivery, parental factors (eg, nutrition, stress, comorbid conditions, and metabolism), genetic predisposition, epigenetic factors, infant factors (eg, gestational age, comorbid infections, other concomitant medical conditions, and rate of substance metabolism and excretion), environmental factors, and placental opioid metabolism transfer. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of prenatal opioid exposure is clinically based upon a history (or suspected history) of parental substance use disorder, treatment with medications for opioid use disorder (methadone, buprenorphine), positive parental screening for substance use/misuse, positive parent or infant urine toxicology screening for opioids or other substances, and/or neonatal findings that are consistent with NAS. Although a positive opioid identification in either a parent or neonatal specimen is useful to confirm the diagnosis of NAS, false-negative results often occur in neonatal screening tests for NAS. (See 'Diagnosis' above.)

●Differential diagnosis – Other neonatal conditions have similar features to NAS. These include sepsis, hypocalcemia, hypoglycemia, hyperthyroidism, polycythemia, and encephalopathy. Careful clinical assessment and diagnostic tests (eg, parental screening for opioid and other substance exposures, complete blood count and blood cultures for sepsis, or serum blood glucose level for hypoglycemia) can help to differentiate NAS from these disorders. The dyad should also be evaluated and treated for comorbid conditions including other substance use, sexually transmitted infections, maternal psychiatric comorbidities, and trauma exposure. All parents/caregivers identified as having a substance use disorder should be provided with appropriate referrals to ongoing substance use disorder treatment and psychiatric care for the treatment of comorbidities as necessary. (See 'Differential diagnosis' above and 'Further evaluation' above and "Substance use during pregnancy: Screening and prenatal care".)

●Management – In our center, infants with NAS are managed by a multidisciplinary team. Management includes the following (see 'Management approach' above):

•Nonpharmacologic care – The mainstay of care for the infant affected by NAS is nonpharmacologic care, which is initiated ideally prenatally with maternal teaching, continued at birth and throughout the infant's hospitalization. It entails individualized assessment and intervention of the infant's and parent's functioning and the environment to promote parent and infant regulation and synchrony. (See 'Nonpharmacologic care' above.)

•Scoring NAS symptoms – In our center, NAS symptoms are assessed using a modified and symptom-based version of the Finnegan scoring system (form 1). (See 'Assessment and management protocols' above.)

•Pharmacologic therapy – For infants with significant NAS symptoms that exceed a predetermined threshold (two scores ≥8) (form 1) despite optimal nonpharmacologic care, we suggest pharmacologic therapy (Grade 2B). We suggest morphine or methadone rather than other agents (Grade 2C). (See 'Indications' above and 'Choice of initial agent' above.)

Add-on medication may be necessary if the infant's symptoms are not adequately controlled on single-medication therapy. In such cases, we suggest clonidine rather than phenobarbital (Grade 2C) because the risk of the adverse effects is lower with clonidine. (See 'Addition of second agent, if necessary' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lori A Sielski, MD, who contributed to an earlier version of this topic review.