Neonatal abstinence syndrome (NAS): Management and outcome

INTRODUCTION — 

A neonate born to a person with opioid use disorder is at risk for withdrawal, commonly referred to as neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS). NAS and NOWS represent a variable, complex, and incompletely understood spectrum of signs of neonatal neurobehavioral dysregulation.

Although NAS is most commonly associated with in-utero opioid exposure, similar neurobehavioral dysregulation can also be seen in newborns with prenatal exposure to other substances (eg, benzodiazepines, antidepressants, nicotine, alcohol). Additionally, concurrent exposure to these substances and opioids can potentiate the severity of withdrawal. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Impact of polysubstance exposure'.)

The management and outcome of neonates with prenatal substance exposure and NAS will be reviewed here. The clinical features and evaluation of NAS are discussed in detail separately. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis".)

Other related topics include:

●(See "Substance use during pregnancy: Screening and prenatal care".)

●(See "Opioid use disorder: Overview of treatment during pregnancy".)

●(See "Cigarette and tobacco products in pregnancy: Screening and impact on pregnancy and the neonate".)

●(See "Alcohol intake and pregnancy".)

●(See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy".)

TERMINOLOGY — 

The following terms are used in this topic:

●NAS versus NOWS – Neonatal abstinence syndrome (NAS) refers to neonatal withdrawal from in utero exposure to licit and illicit substances, including (but not limited to) opioids, whereas neonatal opioid withdrawal syndrome (NOWS) refers to withdrawal specifically from in utero exposure to opioids [1-3]. In clinical practice, these two terms are often used interchangeably.

NAS has traditionally been the term used in the literature to describe the syndrome since it is a broader term describing neonatal withdrawal from opioid and nonopioid exposures (eg, benzodiazepines). NOWS is a more recent term that has been adopted by many institutions, professional societies (including the American Academy of Pediatrics) [2], and governmental agencies (including the United States Food and Drug Administration) [4]. Some experts prefer the term NOWS over NAS because the former emphasizes that the disorder represents a withdrawal phenomenon (as opposed to abstinence) and because contemporary evidence suggests that the growth of neonatal drug withdrawal since the early 2000s has been primarily from in utero opioid exposure (alone or in combination with other substances) [2].

In many cases, opioid-exposed neonates are also exposed to other substances (eg, nicotine, alcohol, antidepressants, other psychotropic medications) and it can be difficult to clearly establish whether withdrawal signs are purely due to opioid withdrawal. In addition, the precise nature of the prenatal substance exposure may be uncertain in some cases. For these reasons, we will use the term NAS rather than NOWS throughout this topic. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Impact of polysubstance exposure'.)

NAS and NOWS can be associated with 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 (eg, methadone, buprenorphine) [5]. The characteristic clinical manifestations are discussed in detail separately. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Presenting features'.)

●Iatrogenic narcotic withdrawal – Acute withdrawal can also occur in newborns who are treated with opioids and other sedating medications in the neonatal period (eg, neonates receiving opioids to facilitate mechanical ventilation). Iatrogenic withdrawal in this setting is discussed separately. (See "Management and prevention of pain in neonates", section on 'Mechanical ventilation'.)

●Opioid versus opiate – The term opioid refers to natural and synthetic substances that activate mu-opioid receptors. Opiates are a subclass of opioids consisting of alkaloid compounds that occur naturally in the opium poppy, including morphine and codeine.

●Substance-exposed dyad – The substance-exposed dyad refers to the simultaneous consideration of the newborn and their mother/parent/caregiver who used a substance or substances during pregnancy.

GOALS OF MULTIDISCIPLINARY CARE — 

The main goals of care for the substance-exposed dyad are to [2]:

●Promote newborn and parental/caregiver connection

●Minimize the signs of NAS

Optimal care for the substance-exposed dyad requires a dedicated nonjudgmental multidisciplinary team that is well versed in the management of substance use disorder (SUD) and NAS. The multidisciplinary team consists of obstetricians, neonatologists, pediatricians, nurses, SUD counselors, psychiatrists, social workers, and other subspecialty providers such as occupational, physical therapists, and feeding specialists.

An effective program requires coordination and consistency in the care approach throughout pregnancy, during the birth hospitalization, and in the outpatient setting following discharge. (See 'Discharge planning and follow-up' below.)

Close follow-up prior to and after delivery is crucial. For some dyads, a dedicated outpatient supervised housing program may be helpful both before and after delivery.

During the birth hospitalization, care for the dyad includes regular assessments of newborn and maternal functioning to promote bonding and healthy parent/caregiver-newborn interaction [6]. The care team should help the parents/caregivers understand of their newborn's unique NAS expression and develop strategies to reduce NAS-associated dysregulation. These are the mainstays of nonpharmacologic care, which are critical to the newborn's recovery [7]. (See 'Nonpharmacologic measures' below.)

A comprehensive multidisciplinary program has been shown to reduce overall utilization of pharmacologic therapy [8]. Healthcare and social service providers collaborate in the care of these newborns and their parents/caregivers during the birth hospital stay and determine appropriate postdischarge disposition and follow-up care.

CARE ENVIRONMENT — 

Rooming-in (ie, parent/caregiver and child in the same room throughout the birth hospitalization) is the preferred model of inpatient care for NAS [2]. The physical environment of the substance-exposed dyad is an important component of NAS management. The environment should be modified to support both maternal and newborn self-regulation. Rooming-in has been shown to reduce NAS severity [2,9,10].

Special adaptations of the care environment may be needed in some cases to meet the unique needs of the dyad (eg, mothers who have experienced intimate partner violence, which requires a trauma-informed approach). (See "Intimate partner violence: Intervention and patient management", section on 'Caring for the patient with a history of trauma'.)

Neonatal intensive care unit (NICU) care is occasionally necessary for the most severely affected newborns. However, the NICU environment is generally not optimal for substance-exposed newborns as it can be overstimulating.

Our approach is consistent with guidelines from the American Academy of Pediatrics (AAP) which encourage rooming-in as the preferred model of care for newborns with NAS and discourage NICU admission unless medically necessary [2]. In a retrospective study that included 434 newborns who were managed before the AAP guidelines and 390 newborns who were managed in the two years after publication of the guidelines, rates of NICU admission for NAS declined from 79 percent to 47 percent [11].

MEASURES FOR ALL SUBSTANCE-EXPOSED DYADS

Newborn care

Routine assessment of NAS signs — Substance-exposed newborns should have routine ongoing assessment of NAS signs using a standardized assessment tool [2,12]. At the author's center, we use a modified version of the Finnegan scoring system (table 1), which provides a semi-objective and standardized assessment of withdrawal severity. Other centers may use the Eat, Sleep, Console approach (algorithm 1). Each approach has advantages and disadvantages, as discussed separately. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'NAS clinical scoring systems'.)

Nonpharmacologic measures — Nonpharmacologic measures should be provided for all substance-exposed neonates, regardless of whether they are demonstrating clinical signs of withdrawal. Optimally, nonpharmacologic measures are tailored to the newborn's specific NAS manifestations.

●General measures – Examples of nonpharmacologic measures include:

•Holding by the parent/caregiver

•Skin-to-skin contact

•Safe swaddling

•Frequent small breast or bottle feedings (see 'Feeding' below)

•Non-nutritive sucking

•Maintaining a quiet, low-stimulation environment (see 'Care environment' above)

Some of these interventions are also used to provide comfort in newborns undergoing painful procedures, as discussed separately. (See "Management and prevention of pain in neonates", section on 'Nonpharmacologic measures'.)

●Measures for specific NAS signs – Interventions that may be particularly helpful for specific NAS manifestations include:

•Hypertonicity, jitteriness, tremors – For a neonate with hypertonicity or tremors, using positioning (side-lying C position) and swaddling may allow the newborn to organize their behaviors to become calm and better able to interact with care providers. A hypertonic or jittery newborn may be better able to function if swaddled or provided containment holding with the hands held.

•Irritability/crying – Excessive irritability and/or crying may be overcome with gentle, vertical rocking.

•Oral hypersensitivities – Oral hypersensitivities can affect the neonate's ability to feed and be difficult to address. Pacifier use, if tolerated, may be beneficial. Small, frequent feedings are helpful, as is breastfeeding when appropriate. (See 'Feeding' below.)

•Loose stools – Stools can be loose and frequent, which can lead to diaper dermatitis. 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".)

•Skin irritation – Skin excoriation may occur due to excessive rubbing in hypertonic newborns. The best intervention is to swaddle the newborn, thereby reducing trauma to the skin.

•Other manifestations related to sensory or environmental input – Sensory or environmental input may cause dysregulation in the newborn. For example, a newborn 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, a newborn who is easily overstimulated by sound or visual stimulation can be cared for in a quiet dimly lit room. Understanding the capabilities of each newborn to manage internal stimuli (hunger, fatigue) and external stimuli (sound, touch, movement) is key to finding successful strategies to mitigate the newborn's dysregulation.

The AAP's guidelines on management of NAS/NOWS emphasize that nonpharmacologic measures should be the first-line interventions for all newborns with NAS and that this should be considered a principal foundation of care [2]. In a retrospective study that included 434 newborns who were managed over a two-year period before the AAP guidelines and 390 newborns who were managed in the two years after publication of the guidelines, rates of pharmacologic therapy for NAS declined from 59 percent to 50 percent [11].

Acupuncture has been investigated as a possible adjunctive therapy for NAS, but there is insufficient evidence to support its use [13].

Feeding

Deciding on method — Formula feeding should not be the default feeding method for newborns with NAS, since breastfeeding can be successful in some people with substance use disorder [2,14-16]. Breast milk and breastfeeding have a large potential benefit, particularly for newborns and their mothers/caregivers affected by substance use disorder. Thus, mothers/caregivers who are able to safely breastfeed should be encouraged to do so. In particular, we highly encourage breastfeeding for those who are stably in a substance use disorder treatment program, who are able to demonstrate abstinence from illicit substance use, and who have adequate prenatal care.

Formula is appropriate for those who have a contraindication to breastfeeding (table 2). These include people who are actively using/misusing substances at the time of delivery. Active use can be reflected by positive toxicology testing, behaviors concerning for substance use during the birth hospitalization, and known relapse within the prior 30 days. We discourage mothers/caregivers from using cannabis if they wish to breastfeed. Other relevant contraindications include use of medications that are not safe during lactation (and cannot be stopped during breastfeeding) and human immunodeficiency virus (in resource-abundant settings).

Otherwise, we individualize the decision to breastfeed and consider several factors to assess the safety of breastfeeding. These factors should be considered as a whole and in discussion with the mother/caregiver and the multidisciplinary team. These include:

●Consistency of prenatal care – A longer period of consistent prenatal care during the pregnancy is more favorable for safe breastfeeding.

●Length of abstinence from substance use/misuse – A longer period of abstinence is more favorable for safe breastfeeding. For instance, people who have been abstinent for 90 days prior to delivery and have demonstrated the ability to maintain sobriety in the outpatient setting may be more likely to breastfeed safely (ie, less likely to relapse). In contrast, we discourage breastfeeding for people who relapsed into substance use/misuse in the 30 days prior to delivery. Ongoing use of substances can result in ongoing exposure to a breastfeeding infant and potential toxicity. (See "Breastfeeding: Parental education and support" and "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)

●Participation in a substance use disorder treatment program – Participation for as long as possible throughout the pregnancy is favorable for safe breastfeeding. However, participation in a treatment program during or after the second trimester is more favorable for safe breastfeeding than no participation. Participation can be confirmed with the treatment program, with appropriate consent. Plans to continue in substance use disorder treatment after pregnancy should also be discussed and confirmed.

Breastfeeding by people using methadone, buprenorphine, or buprenorphine-naloxone as part of an opioid use disorder (OUD) treatment program appears to be safe for the infant. Concentrations of methadone and buprenorphine are low in human milk, as discussed below. (See 'Specific substances and breast milk' below.)

Our approach is consistent with guidelines that promote safe breastfeeding practices for newborns of mothers/caregivers with substance use disorder [17]. Each institution should have a protocol for breastfeeding for people with substance use disorder.

Challenges to breastfeeding — Mothers/caregivers with substance use disorder should be supported in their desire to breastfeed if they are able to do so safely, as they face challenges to breastfeeding. These include [18,19]:

●Difficulties with positioning and feeding the newborn due to the manifestations of NAS

●Difficulties ensuring adequate milk intake

●Difficulty meeting the caloric needs of the newborn, since newborns with NAS have higher caloric expenditures compared with healthy newborns

●Lengthy hospital stays that may result in separation of the newborn and mother/caregiver

●Potential restrictions of substance use disorder treatment centers (eg, there may be a lack of breastfeeding support, some treatment centers may not allow breastfeeding)

●Lack of support and education

●Trauma exposure

A lactation specialist familiar with NAS can provide the support these dyads need to help them to breastfeed successfully.

Monitoring growth and nutrition — Infants with NAS are at increased risk of poor weight gain and growth during the neonatal period [20]. Thus, their intake and weight gain should be monitored closely. (See "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation".)

Specific substances and breast milk — Although it is known that many substances are excreted into breast milk, data are limited for specific drugs regarding their concentration within breast milk and their effects on the infant [15,21]. The following substances and breast milk are discussed in detail separately:

●Opioids – Breastfeeding by people using methadone, buprenorphine, or buprenorphine-naloxone as part of an OUD treatment program appears to be safe for the infant, as concentrations of methadone and buprenorphine are low in human milk, regardless of dose [22-25]. Additionally, breastfeeding while on methadone or buprenorphine maintenance therapy has been associated with reduced need for pharmacologic intervention in the infant [22,26-30]. Reasons for this observation are uncertain. The low concentrations of methadone and buprenorphine in human milk are unlikely to substantially effect the newborn's NAS manifestations. Other factors associated with breastfeeding may be responsible for the reduced severity of NAS in breastfed infants.

The safety of medications for opioid use disorder in breastfeeding is discussed in detail separately. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Breastfeeding' and "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders", section on 'Medications for substance use disorders'.)

●Cannabis – We concur with the recommendation in the American Academy of Pediatrics Clinical Report that pregnant and breastfeeding people be advised not to use cannabis, based on the available data on potential adverse effects on fetal growth and child development [31]. (See "Breastfeeding: Parental education and support", section on 'Maternal cannabis use'.)

For pregnant and postpartum people who are unable to stop cannabis use, referral for further intervention and treatment should be offered. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)

●Alcohol – The amount of alcohol in breastmilk is approximately 5 to 6 percent of the weight-adjusted maternal dose and is similar to maternal blood alcohol levels [32]. Newborns metabolize alcohol at approximately half the rate of adults [33]. (See "Breastfeeding: Parental education and support", section on 'Maternal alcohol use'.)

Breastfeeding from alcohol-consuming mothers/caregivers appears to decrease neonatal milk intake and alters neonatal sleep-wake cycles [34-36]. (See "Maternal nutrition during lactation", section on 'Alcohol'.)

Maternal care — Optimal care for the mother/caregiver includes:

●Identification of polysubstance use – Polysubstance use is identified through maternal screening, ideally performed via confidential interview, or may be discovered/confirmed on maternal urine toxicology screening. Polysubstance exposure and its effects on the newborn are discussed elsewhere. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Impact of polysubstance exposure' and "Substance use during pregnancy: Overview of selected drugs".)

●Careful evaluation of the mother/caregiver's history – Comorbidities in people with substance use disorder are common and may include depression, anxiety, intimate partner violence victimization, and housing and employment instability. These are discussed in detail elsewhere. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Prenatal care of individuals with substance use disorder' and "Intimate partner violence: Diagnosis and screening" and "Unipolar major depression during pregnancy: Epidemiology, clinical features, assessment, and diagnosis".)

For mother/caregivers with a history of sexual trauma, additional attention to the environment is needed [37]. For example, unknown caregivers at night, "tethering" to the bed with IVs, exposed breasts or body parts, or the sight/scent of blood in the genital area may cause psychologic trauma or flashbacks for people who have experienced abuse. These issues can be addressed with confidential discussion and environmental modification. People who have experienced trauma should be referred at the earliest opportunity for care by an experienced psychiatric provider.

●Maternal education and support – Engaging the mother/caregiver early, ideally during pregnancy, so that they understand the newborn's behavior can establish better understanding of NAS. It is important to provide education and therapy to promote maternal self-regulation and the mother/caregiver's ability to support the newborn's behavioral and physiological organization/self-regulation [6].

Teaching the mother/caregiver what the newborn is sensitive to and assisting in finding techniques to minimize that sensitivity and the newborn's dysregulation can help the mother/caregiver to provide appropriate responses to the newborn. (See 'Nonpharmacologic measures' above.)

In addition, mothers/caregivers with substance use disorder are actively supported if they desire and are able to safely breastfeed. (See 'Deciding on method' above.)

●Ongoing assessment – During the birth hospitalization, we continually assess the mother/caregiver's ability to identify and respond appropriately to the newborn's behavioral cues. We facilitate understanding of the newborn's strengths and challenges, optimize handling and response to the infant, and modify the infant's environment to support their optimal functioning [38]. Helping the mother/caregiver with their own self-regulation and helping them to understand the feelings that they have surrounding their newborn's functioning can help them to be more appropriately responsive to the newborn.

●Maternal substance use disorder treatment – Mother/caregiver and neonatal outcomes are improved when mothers/caregivers are cared for in an integrated perinatal program that provides substance use disorder counseling and treatment (with medication if needed) with comprehensive prenatal and postnatal care [39,40].

●Identification of supports – Identification of familial and community supports for maternal engagement in treatment and health care for mother/caregiver and the newborn.

It is important that the mother/caregiver be treated in a nonjudgmental fashion by all care providers and that the use of pejorative language (eg, addict, methadone baby, NAS baby) and attitudes be avoided. Maintenance of the mother/caregiver's confidentiality as a person who uses substances is also important.

PHARMACOTHERAPY FOR NEWBORNS WITH SEVERE NAS

Threshold for treatment — The main goal of pharmacologic therapy is to reduce functional limitations caused by acute NAS manifestations. In general, pharmacologic therapy is warranted for newborns whose withdrawal signs compromise their ability to feed, interact with caregivers, or regulate movements or autonomic function, despite adequate and individualized nonpharmacologic care.

Different thresholds are used depending on the scoring system used (see "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'NAS clinical scoring systems'):

●When using the modified Finnegan NAS score (table 1) – Pharmacologic intervention is warranted if the newborn has two consecutive scores >8 or a single score >12 despite optimizing nonpharmacologic measures.

●When using the Eat, Sleep, Console approach (algorithm 1) – Pharmacologic therapy is generally warranted (after joint discussion with the care team) if despite optimizing nonpharmacologic measures, two consecutive assessments yield yes answers to any question.

Initial therapy (opioids) — For neonates requiring pharmacologic therapy for NAS, we suggest oral opioid therapy (eg, morphine, methadone) rather than other drug classes (eg, sedatives). Neonates with polysubstance exposure are treated in the same manner as those with opioid-only exposure except that the threshold for starting a second agent is somewhat lower for these newborns since an opioid alone may not be sufficient. (See 'Adjunctive therapy for refractory NAS' below.)

Our approach to therapy and medication dosing (table 3) are as follows:

●Morphine – At the author's center, oral morphine is the preferred first-line agent for treatment of NAS. Dosing is as follows:

•Weight-based dosing – Initial weight-based dosing for morphine in term neonates with NAS is 0.03 to 0.05 mg/kg per dose given orally every three to four hours (table 3) [41]. The lower end of this dose range (0.03 mg/kg) is appropriate for newborns with moderate NAS signs (eg, Finnegan score 9 to 15), whereas the higher end (0.05 mg/kg) is appropriate for those with more severe signs (eg, Finnegan score >20). Higher initial doses are occasionally required for newborns with very severe NAS manifestations.

•Fixed dosing based on NAS score – Alternatively, some centers provide oral morphine in term newborns with NAS using fixed doses determined solely by the Finnegan score. For example, newborns with Finnegan scores in the range of 9 to 12 start at a dose of 0.04 mg, those with scores of 13 to 16 start at 0.08 mg, those with scores of 17 to 20 start at 0.12 mg, those with scores of 21 to 24 start at 0.16 mg, and those with scores ≥25 start at 0.2 mg [42]. In all cases, the medication is given orally every three to four hours.

Regardless of which dosing regimen is used, the newborn's response to morphine should be frequently assessed. If the newborn's NAS signs are not adequately controlled, the dose can be increased as needed (usual increment 0.03 to 0.05 mg/kg; maximum dose 0.2 mg/kg per dose) (table 3).

●Other opioids – Other opioids used for the treatment of NAS include:

•Methadone – Methadone, a long-acting opioid, is a reasonable alternative to morphine and is used as the first-line agent at some centers [43]. Dosing is summarized in the table (table 3). However, methadone's long duration of action makes it difficult to titrate dosing.

•Buprenorphine – Buprenorphine is effective for reducing NAS manifestations [44,45]; however, its use in neonates is limited by the high ethanol content (30 percent) and challenges with sublingual administration [2].

Evidence supporting use of opioids for NAS — Opioids reduce manifestations of NAS. The practice of using oral opioids (morphine [preferred] or methadone) as initial treatment for NAS is supported by clinical trials and meta-analyses that suggest superior control of NAS signs and better safety profile when compared with nonopioid agents [2,46-51].  

●Morphine versus methadone – Among opioids, the efficacy of morphine and methadone in controlling NAS symptoms are largely comparable, although methadone has been associated with shorter hospitalization in some studies. However, we prefer morphine because it is easier to titrate the dose, as discussed above. (See 'Initial therapy (opioids)' above.)

•In a meta-analysis of two trials including 147 newborns with NAS, morphine and methadone resulted in similar rates of treatment failure (ie, persistent signs requiring additional medications), duration of hospitalization, and breastfeeding success [47]. In contrast, a large observational study including 7667 newborns with NAS found that methadone was associated with a shorter length of birth hospitalization compared with morphine after adjusting for confounding factors [52].

•Few trials have evaluated neurodevelopment outcomes after use of these opioids. In one multicenter trial including 118 newborns born to mothers on opioid substitution therapy, morphine and methadone resulted in similar short- and long-term neurodevelopmental outcomes [50].

●Morphine versus buprenorphine – In meta-analyses of randomized trials, buprenorphine resulted in similar rates of treatment failure and shorter duration of hospitalization than morphine [47,49]. However, its high ethanol content (30 percent) and challenges with sublingual administration are disadvantages compared with other opioids, as discussed above. (See 'Initial therapy (opioids)' above.)

●Opioids versus sedatives – Trials comparing opioids with sedatives (eg, phenobarbital, benzodiazepines) for NAS have generally found opioids had lower rates of treatment failure, with mixed results on other outcomes.

•In a meta-analysis of randomized trials, treatment failure (defined as persistent signs requiring additional medication for treatment) occurred less commonly with opioids (eg, morphine, methadone) compared with phenobarbital (15 versus 30 percent; relative risk [RR] 0.51, 95% CI 0.35-0.74; six trials, 458 newborns) [47]. Hospitalization duration, seizure incidence, or neurodevelopmental outcomes, results were similar for opioids and phenobarbital. Two trials comparing opioids with benzodiazepines also found lower rates of treatment failure in neonates treated with opioids.

•In a network meta-analysis using both direct and indirect comparisons from 18 trials (1072 newborns) evaluating six agents (morphine, methadone, buprenorphine, diluted tincture of opium, clonidine, phenobarbital), morphine and methadone had the lowest rates of treatment failure (defined as a need for an additional agent), although the differences were not statistically significant [49].

In the multicenter trial described above (118 opioid-exposed neonates), newborns discharged on phenobarbital had poorer developmental and behavioral outcomes at 18 months compared with those who did not receive phenobarbital at discharge [50].

●Opioids versus clonidine – Trials directly comparing opioids to clonidine as monotherapy for newborns with NAS are limited. When clonidine is used as monotherapy, adjunctive pharmacotherapy is often required. Clonidine can be used as an adjunctive medication to opioid therapy for refractory NAS, as discussed below. (See 'Adjunctive therapy for refractory NAS' below.)

•In a randomized trial evaluating clonidine as monotherapy for NOWS in 120 opioid-exposed newborns, clonidine resulted in similar lengths of pharmacologic treatment compared with morphine [51]. However, newborns in the clonidine group required higher rates of adjunctive therapy with other agents including phenobarbital, which is associated with an increased risk of adverse neurodevelopmental outcomes [50]. Further studies evaluating the safety and efficacy of clonidine are necessary to determine its use as initial therapy for NAS.

Adjunctive therapy for refractory NAS

●Threshold for starting a second agent – For newborns with severe NAS that is not adequately controlled (eg, Finnegan scores persistently >8) despite maximal opioid dose, we suggest adding a second agent. For newborns with known polysubstance exposure, we have a lower threshold for starting a second medication since an opioid alone is less likely to be sufficient.

●Choice of adjunctive agent – For most newborns, we prefer clonidine as the adjunctive agent based on limited observational data [47,49,53,54]. Exceptions include newborns with prenatal exposure to both opioids and benzodiazepines, for whom we instead use phenobarbital.

The general preference for clonidine over phenobarbital is largely based on concerns regarding the safety of phenobarbital. These include the risk of oversedation, the high alcohol content of phenobarbital solutions, difficulties in weaning phenobarbital among substance-exposed newborns, and the potential long-term effects on neurodevelopment [2,50,55,56]. Our approach is consistent with guidelines of the American Academy of Pediatrics [2]. However, other centers may use phenobarbital as the initial second-line agent.

●Dosing and efficacy

•Clonidine – Clonidine can be started at an initial dose of 0.5 to 1 mcg/kg given orally every four to six hours. If NAS signs are not adequately controlled, the dose can be increased in increments of 0.25 to 0.5 mcg/kg (maximum dose 12 mcg/kg per day) [57].

Clonidine has been shown to be effective as an adjunctive medication to opioid therapy for the treatment of NAS. 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) [58]. 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 newborns, particularly those who were also exposed to barbiturates and/or benzodiazepines.

For some newborns, particularly those exposed to both opioids and benzodiazepines, a one-time low dose of oral phenobarbital (5 to 10 mg/kg) in conjunction with ongoing morphine therapy may be sufficient. However, for newborns with significant withdrawal signs, a higher loading oral dose is given (10 to 20 mg/kg, depending on severity of manifestations), which is followed by a maintenance dose of 5 mg/kg per day in two divided doses given orally every 12 hours (first dose given 12 hours after the loading dose).

Some studies have found that adding phenobarbital to opioid therapy was associated with longer length of hospital stay, whereas other studies have not detected a difference in length of stay for newborns treated with phenobarbital versus morphine alone [59,60].

Despite the widespread use of phenobarbital for treating seizures in NAS, a safety profile has not been adequately established and alcohol content is a concern [61].

In addition, the long-term impact of phenobarbital on neurodevelopment remains a concern, as discussed above. (See 'Evidence supporting use of opioids for NAS' above.)

●Comparative data – Data directly comparing clonidine versus phenobarbital as adjunctive therapy in newborns with NAS are limited. In a retrospective, multicenter study of 563 newborns with NAS treated with morphine, approximately one-third of newborns received a second medication; 108 received clonidine and 72 received phenobarbital [53]. After adjusting for other factors, length of stay was shorter for newborns treated with phenobarbital compared with the clonidine group (-10.3 days, 95% CI -13.2 to -7.3 days) as well as length of morphine treatment (-7.5 days, 95% CI -10.3 to -4.8). More newborns 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.

Weaning therapy — Once the patient responds to therapy with a decrease in the severity of signs of NAS (eg, Finnegan scores are ≤8 for 48 hours), drug therapy should be weaned. Our general approach to weaning is as follows (table 3):

●For newborns requiring more than one medication, the opioid (morphine or methadone) is weaned off first.

●Morphine can be weaned by 10 to 20 percent every 24 to 48 hours and discontinued when the total daily dose is ≤0.04 mg/kg.

●Methadone can be weaned by 10 to 20 percent every 24 to 48 hours and discontinued when the total daily dose is ≤0.05 mg/kg.

●Occasionally, the newborn may require dose re-escalation during weaning (eg, if NAS signs are consistently above treatment levels). If this occurs, the dose should be increased to the last effective dose, weaning should be held for 24 hours, and then resumed once the newborn is stable.

●Once the newborn has been successfully weaned from the opioid, any second-line medications can be weaned.

●Clonidine can be weaned by 10 to 20 percent every other day and discontinued when the total daily dose is <1 mcg/kg.

●Phenobarbital can be weaned by 10 to 20 percent every other day and discontinued when the total daily dose is <1 mg/kg.

We do not discharge newborns on any medications for the treatment of NAS. (See 'Duration of hospitalization' below.)

Medications to avoid — Naloxone should not be used in the management of NAS, because it may precipitate rapid withdrawal [2,62].

Agents that are no longer used to treat NAS include a diluted version of tincture of opium and paregoric-containing anhydrous morphine, also referred to as camphorated tincture of opium [2].

DURATION OF HOSPITALIZATION

●For newborns receiving pharmacologic therapy – The newborn may be discharged home when they have been successfully weaned off all NAS medications for at least 24 hours. Newborns who have failed weaning at least once should be observed for 48 hours off medications prior to discharge.

We do not discharge newborns on any NAS medications for many reasons, including the difficulty weaning these medications in the outpatient setting and the challenges of the postpartum period for many parents/caregivers with substance use disorder.

●For newborns not receiving pharmacologic therapy – For newborns with prenatal substance use exposure, the length of hospitalization should be sufficient to detect the development of signs of NAS. In our hospital, we observe newborns in the hospital for a minimum of four to five days, to reduce the chance that a newborn will develop signs of withdrawal after discharge. This is because the clinical presentation of NAS is variable, and in some newborns the presentation of significant NAS signs can be delayed. In addition, the precise details of the exposure are often uncertain, or there are multiple exposures. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Timing of onset'.)

Parents/caregivers 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.

DISCHARGE PLANNING AND FOLLOW-UP — 

The immediate postnatal period is often a stressful period for both mother/caregiver and newborn and is also a critical time for dyadic functioning. Therefore, pediatric follow-up within 48 hours should be arranged prior to hospital discharge. Families of newborns who are opioid exposed are also disproportionately at risk for socioeconomic and social challenges, so discharge planning should be thoughtful and sensitive to the needs of the dyad [2].

Discharge planning for substance-exposed newborns should include an evaluation of parental/caregiver 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/caregivers 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 newborn develop any signs of withdrawal. A referral to an early intervention program may be initiated as substance-exposed newborns are at risk for developmental alterations [2]. Follow-up care includes the following:

●Continued support for the mother/caregiver, including a treatment program for substance use disorder that will accept the newborn and provide medication for opioid use disorder if warranted, psychiatric care when needed, and postpartum obstetric care including contraceptive care if desired by the mother/caregiver.

●Safe housing and case management for the mother/caregiver and newborn.

●Pediatric care provided by a knowledgeable provider. This pediatric care is instituted prior to hospital discharge and accessible by the mother/caregiver in the event that the newborn is difficult to care for, develops any signs of late onset of withdrawal or illness, or has inadequate weight gain/feeding problems [2]. Pediatric care should include frequent appointments and developmental assessment to identify, and if needed, to manage any ongoing neurodevelopmental concerns for the child. 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 [63].

LONG-TERM OUTCOMES — 

When considering clinical sequelae for the newborn related to in utero substance exposures, it is difficult to determine the relative contribution of prenatal substance exposure versus the effects of maternal and neonatal comorbidities and confounding psychosocial factors [64].

Confounding psychosocial factors — People with substance use during pregnancy often have other stressors (eg, trauma/violence exposure, poor prenatal care, poverty, food and/or housing insecurity) and/or conditions (eg, psychiatric comorbidities, infections) during and after pregnancy that may negatively impact their newborn. These factors may contribute to the observed increased risk for neurodevelopmental delays and child maltreatment among substance-exposed newborns compared with nonsubstance-exposed peers [65-67]. As a result, additional support is frequently required from medical providers and community-based services to help parents/caregivers and families care for their child while coping with ongoing comorbidities. Intervention and referral should occur in a nonjudgmental and nonpunitive manner.

Effects of specific substances

Opioids — It has been difficult to ascertain the long-term effects of prenatal opioid exposure on childhood neurodevelopment because there are numerous confounding prenatal factors (eg, other substance exposures including tobacco smoke, prematurity, low birth weight, intrauterine growth restriction) and postnatal factors (eg, NAS pharmacotherapy, continued maternal substance use/misuse, violence exposure, socioeconomic factors, parental/caregiver educational level) [68-70]. The available observational studies have yielded variable conclusions, and thus the long-term direct effects of prenatal opioid exposure remain uncertain. Nevertheless, there appears to be a complex developmental vulnerability in substance-exposed children [68,69,71,72].

Several observational studies have reported associations between prenatal opioid exposure and the following outcomes in childhood [65,68,71,73-80]:

●Neurodevelopmental impairments (eg, intellectual disability, learning disabilities, motor deficits) (see "Intellectual disability (ID) in children: Evaluation for a cause", section on 'Nongenetic causes')

●Mental health disorders (attention deficit hyperactivity disorder [ADHD], autism spectrum disorder, behavioral and emotional disorders) (see "Attention deficit hyperactivity disorder in adults: Epidemiology, clinical features, assessment, and diagnosis" and "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis")

●Maltreatment and trauma (see "Child abuse: Epidemiology, mechanisms, and types of abusive head trauma in infants and children", section on 'Risk factors')

However, not all studies suggest worse outcomes. For example, in follow-up of a randomized trial comparing buprenorphine and methadone for treatment of opioid use disorder during pregnancy, neurodevelopmental outcomes of the offspring at age 36 months were within the normal range [81].

Cannabis — Prenatal cannabis exposure is associated with long-term adverse neurobehavioral effects in childhood, adolescence, and early adulthood (eg, cognitive deficits, learning disabilities, high impulsivity, autism spectrum disorder) [82-84]. This issue and other adverse effects of prenatal cannabis exposure (eg, preterm birth, low birth weight, and possible risk of congenital anomalies) are discussed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Neonatal and pediatric outcomes'.)

Cocaine — It has been difficult to ascertain whether there are direct long-term effects of prenatal cocaine on neurobehavioral development. Research in this area has been hampered by the difficulty in controlling confounding variables (ie, postnatal psychosocial factors, prenatal exposure to other substances) and in accounting for the indirect effect of cocaine on biological variables (ie, prematurity, fetal growth restriction).

Several studies have demonstrated that prenatal cocaine exposure is associated with increased risk of long-term neurodevelopmental abnormalities in childhood and adolescence, including the following [85-91]:

●Easy excitability

●Poor behavioral self-regulation

●Difficulty sustaining attention (eg, ADHD)

●Language delay

●Learning disabilities

●Poor short-term memory

●Poor executive function

Other substances

●Amphetamines – Amphetamines are addictive stimulants that can be misused or used as illicit drugs. Data are insufficient to determine the effects of prenatal amphetamine exposure on neurodevelopmental outcomes.

In addition, these effects may be confounded by other factors, including another substance exposure, socioeconomic factors, and adversity after birth [92-96].

There are numerous reports that suggest that prenatal amphetamine exposure is associated with cognitive problems, including learning and memory difficulties [92,93,97,98] and persistent motor delays [99], as well as neuroimaging findings of structural brain abnormalities, particularly in the striatum [100]. Impact may be dependent on the degree of exposure, as one prospective study, which controlled for confounding factors, reported that motor and mental impairment were only observed in newborns with heavy prenatal exposure [101].

However, a longitudinal study of 339 children, including 171 individuals who were exposed prenatally to methamphetamine, did not observe any behavioral problems related to prenatal methamphetamine exposure at three, five, and seven and a half years of age [95]. Rather, behavioral issues were associated with caregiver psychological symptoms and the quality of the home.

●Nicotine – Although tobacco use is not considered a substance use disorder in pregnancy, the negative neonatal impact of prenatal maternal cigarette smoking is well established and is discussed separately. (See "Cigarette and tobacco products in pregnancy: Screening and impact on pregnancy and the neonate", section on 'Adverse outcomes' and "Secondhand smoke exposure: Effects in children", section on 'Fetal growth and neurologic development'.)

●Alcohol – Alcohol freely crosses the placenta and is known to be teratogenic. Newborns whose mothers consume alcohol during pregnancy can have chronic nonreversible sequelae. The range of effects of prenatal alcohol exposure is referred to as fetal alcohol spectrum disorder (FASD). The clinical manifestations, diagnosis, and management of FASD are discussed separately. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Fetal alcohol spectrum disorder: Management and prognosis".)

SUMMARY AND RECOMMENDATIONS

●Care for all substance-exposed newborns – The main goals of care for substance-exposed neonates are to promote newborn and parental/caregiver connection and to minimize the manifestations of NAS. Optimal care for the substance-exposed dyad requires a dedicated, nonjudgmental multidisciplinary team that is well versed in the management of substance use disorder and NAS. Rooming-in (ie, parent/caregiver and child in the same room throughout the birth hospitalization) is the preferred model of inpatient care for NAS. (See 'Goals of multidisciplinary care' above and 'Care environment' above.)

•NAS symptom assessment – Substance-exposed newborns should have routine ongoing assessment of NAS signs using a standardized assessment tool (eg, the Finnegan scoring system (table 1) or the Eat, Sleep, Console approach (algorithm 1)). Assessments begin at birth and continue throughout the birth hospitalization. These tools are discussed separately. (See "Neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'NAS clinical scoring systems'.)

•Nonpharmacologic measures – Nonpharmacologic measures should be provided for all substance-exposed neonates, regardless of whether they are demonstrating clinical signs of withdrawal and regardless of the assessment tool used. Examples of nonpharmacologic measures include holding by the parent/caregiver, skin-to-skin contact, safe swaddling, non-nutritive sucking, and maintaining a quiet, low-stimulation environment. Optimally, nonpharmacologic measures are tailored to the newborn's specific NAS manifestations. When possible, newborns should room-in with parents/caregivers (rather than stay in a separate nursery). (See 'Nonpharmacologic measures' above and 'Care environment' above.)

•Feeding – We encourage mothers/caregivers who are able to safely breastfeed to do so. These include individuals who have had consistent prenatal care, have been abstinent from substance use for at least a month, and are participating in a substance use treatment program; those taking methadone, buprenorphine, or buprenorphine-naloxone as part of a treatment program can breastfeed safely. Formula is appropriate for those who are actively using illicit substances or have another contraindication to breastfeeding (table 2). (See 'Deciding on method' above.)

●Maternal care – Optimal mother/caregiver care is provided in a nonjudgmental manner. Care includes ongoing assessment and support of a person in substance use disorder treatment, as well as screening for associated comorbidities (ie, depression, anxiety, intimate partner violence, and employment or housing instability). Mothers/caregivers should be engaged in ongoing education about caring for their newborn's unique signs of withdrawal. (See 'Maternal care' above.)

●Pharmacotherapy for newborns with severe NAS – Pharmacotherapy is generally required for newborns with severe NAS despite adequate and individualized nonpharmacologic care. The threshold for treatment differs depending on the NAS assessment tool used (for the modified Finnegan scoring system, the threshold is two consecutive scores >8 or a single score >12 (table 1)). (See 'Threshold for treatment' above.)

Our suggested approach is as follows:

•First line treatment for most neonates with severe NAS – For newborns with severe NAS, we suggest oral opioid therapy (morphine or methadone) rather than sedatives or other types of medication (Grade 2C). Dosing guidance for morphine and methadone for the treatment of NAS are provided in the table (table 3). (See 'Initial therapy (opioids)' above.)

•Adjuvant therapy for refractory NAS – For most newborns with severe NAS that is not adequately controlled (ie, Finnegan scores persistently >8) despite a maximal opioid dose, we suggest adjunctive therapy with clonidine (Grade 2C). The exception is the newborn exposed to both opioids and benzodiazepines, for whom we suggest phenobarbital (Grade 2C). Dosing guidance for these agents is provided in the table (table 3). (See 'Adjunctive therapy for refractory NAS' above.)

•Weaning therapy – Once the patient responds to therapy with a decrease in NAS severity (eg, Finnegan scores ≤8 for 48 hours), drug therapy should be weaned, starting with the opioid (table 3). (See 'Weaning therapy' above.)

●Length of hospitalization – In our center, we observe newborns in the hospital for a minimum of four to five days. For newborns receiving pharmacologic therapy, the newborn may be discharged home when they have been successfully weaned off all NAS medications for at least 24 hours. Pediatric follow-up should occur within 48 hours of discharge. (See 'Duration of hospitalization' above and 'Discharge planning and follow-up' above.)

●Long-term outcomes – Prenatal exposures to opioids, cannabis, and other substances can be associated with negative long-term neurodevelopmental outcomes during childhood and adolescence. However, it is challenging to establish the relative contribution of prenatal substance exposure in these outcomes as there are often other confounding psychosocial factors (maternal psychiatric comorbidities, poor prenatal care, trauma/violence exposure, poverty, food and/or housing insecurity). (See 'Long-term outcomes' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Lori A Sielski, MD, who contributed to earlier versions of this topic review.