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Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes

Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes
Literature review current through: Jan 2024.
This topic last updated: Jul 24, 2023.

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 management and outcome of neonates with prenatal substance exposure and NAS will be reviewed here. Clinical features and evaluation of infants with prenatal substance exposure and NAS is discussed in detail separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis".)

Other related topics are discussed separately:

(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: Impact on pregnancy and the neonate".)

(See "Alcohol intake and pregnancy".)

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

DEFINITIONS AND TERMINOLOGY — NAS is a clinical diagnosis based on the development of consistent manifestations in an infant with prenatal substance exposure.

Terminology continues to evolve for infants prenatally exposed to substances. For this discussion, we use the following terms:

Neonatal abstinence syndrome – NAS describes neonates with withdrawal from in utero exposure to licit and illicit substances, including (but not limited to) opioids [1,2]. NAS 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 (methadone or buprenorphine) [3,4]. Characteristic signs are discussed in detail separately. (See 'Managing individual manifestations' below.)

Neonatal opioid withdrawal syndrome (NOWS) – NOWS describes neonates with withdrawal from in utero opioids only. NOWS is a subset of NAS [5]. However, it can be difficult to distinguish whether manifestations are due to withdrawal from opioids versus other substances (ie, nicotine, psychotropic medications), and thus NAS is used in this topic.

Iatrogenic NAS – Iatrogenic NAS refers to NAS occurring due to the therapeutic application of opioids for analgesia and sedation in infants; iatrogenic NAS will not be discussed here.

Opioid – 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 – 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, clinical features, health consequences, screening, and assessment".)

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

GOALS OF CARE FOR THE SUBSTANCE-EXPOSED DYAD — Main goals of care are to promote infant and parental/caregiver connection and to minimize the signs of NAS [2]. Optimal care for infants with NAS involves both the infant and the parent/caregiver, as well as a nonjudgmental multidisciplinary team that is well versed in the management of substance use disorder and NAS [6]. Care teams may include obstetricians, mental health therapists, psychiatrists, pediatricians, nurses, social workers and subspecialty providers such as occupational or physical therapists.

Care is comprised of comprehensive assessment of infant and maternal functioning to promote healthy caregiver-infant communication and interaction [7]. Parental/caregiver appreciation and understanding of the infant's unique NAS expression and modification of handling and the environment to reduce the NAS-associated dysregulation are the mainstays of nonpharmacologic care, which is critical to the infant's recovery [8]. A comprehensive multidisciplinary program has been shown to reduce overall utilization of pharmacologic therapy [9]. Healthcare and social service providers collaborate in the care of these infants and their parents/caregivers during the birth hospital stay and determine appropriate postdischarge disposition and follow-up care.

MEASURES FOR ALL SUBSTANCE-EXPOSED DYADS

Newborn care

Ongoing assessment — Ongoing and standardized assessment of NAS manifestations is necessary for management of substance-exposed neonates [6,10]. Neonatal abstinence scoring systems provide a semiobjective and standardized assessment of the severity of the patient's withdrawal signs [2,6,11-13]. Every center caring for infants with NAS should adopt an abstinence scoring system, as 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 [14,15].

Commonly used assessment tools include the following:

The Finnegan scoring system – The Finnegan and modified versions are the most widely adapted scoring system (form 1). The Finnegan system is used to assess the severity of neonatal withdrawal findings and to initiate, adjust, and wean pharmacologic therapy. It should be used conjunction with non-pharmacologic care, regardless of the need or not for pharmacotherapy for NAS. (See 'Managing individual manifestations' below and 'Optimizing the care environment' below and 'Feeding' below.)

Assessment begins at birth (or ideally before with prenatal teaching) for all opioid- and other substance–exposed newborns [6]. Ongoing assessment is performed every three to four hours throughout the infant's birth hospitalization, and for as long as the infant has signs of dysregulation. In general, infants with any substance exposure should be hospitalized for four to five days for ongoing assessment [10]. A limitation of the Finnegan system is the subjective nature of the scales [16].

Eat, Sleep, Console – The Eat, Sleep, Console approach evaluates the neonate’s ability to eat ≥1 oz or breastfeed well, sleep undisturbed ≥1 hour, and be consoled within 10 minutes, and guides opioid therapy for those not meeting those criteria [2,12,13,17-19]. This approach also incorporates nonpharmacologic management and emphasizes maternal involvement. Although some studies, including a randomized trial, suggest that the Eat, Sleep, Console approach reduces opioid therapy and length of birth hospitalization compared with other approaches (in particular the Finnegan system) [17-20], the impact on developmental and health outcomes is unknown; it is uncertain whether omitting individual assessment of specific signs of NAS is an appropriate developmental approach. Moreover, it is uncertain whether reductions in opioid needs or hospital stay are the optimal goals for the neonate and the family. Nevertheless, because of the potential value of reducing opioid administration, and the lack of evident harm, many institutions have adopted the Eat, Sleep, Console approach.

In a cluster-randomized trial in which institutions transitioned at randomly assigned time points from usual care that included the Finnegan scoring system to the Eat, Sleep, Console approach for managing NAS, the 603 infants treated with the Eat, Sleep, Console approach had a lower rate of opioid use (52 versus 20 percent, RR 0.38, 95% CI 0.30-0.47) and a shorter mean time to hospital discharge (8 versus 14 days, RR 0.56, 95% CI 0.49-0.64) than the 702 infants treated with usual care [20]. Among other criteria, infants had to be off opioids for at least 48 hours prior to discharge. Rates of in-hospital complications and subsequent urgent care or re-hospitalization within three months were similar between groups. Although these results are promising, certain issues reduce confidence in the findings. In addition to concerns about optimal outcomes discussed above, it is uncertain how much the difference in short-term outcomes was related to incorporation of nonpharmacologic care, which is an integrated component of the Eat, Sleep, Console approach, but is not routinely implemented, despite recommendations to do so [7], with the Finnegan system.

To improve the evaluation of research efforts across studies, a consensus and evidence-based core outcome (neonatal opioid withdrawal syndrome core outcome set [NOWS-COS]) has been developed by a multidisciplinary group of experts [21]. 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.

Managing individual manifestations — Care for each infant should be individualized based on their presentation. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Clinical manifestations of NAS'.)

Some signs with potential interventions include:

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

Irritability – Excessive irritability may be overcome with gentle vertical rocking.

Oral hypersensitivities – Oral hypersensitivities can affect the infant'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 infants. The best intervention is to swaddle the infant, thereby reducing trauma to the skin.

Other manifestations related to sensory or environmental input – Sensory or environmental input may cause dysregulation. 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. Understanding the capabilities of each infant to manage internal (hunger, fatigue) and external (sound, touch, movement) stimuli is key to mitigating dysregulation that these stimuli might cause.

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

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 infant are discussed elsewhere. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Maternal screening' and "Substance use during pregnancy: Screening and prenatal care" 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 maternal depression and 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 [22]. 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 infant'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 infant's behavioral and physiological organization/self-regulation [7].

Teaching the mother/caregiver what the infant is sensitive to and assisting in finding techniques to minimize that sensitivity and the infant's dysregulation can help the mother/caregiver to provide appropriate responses to the infant. (See 'Managing individual manifestations' 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' below.)

Ongoing assessment – During the birth hospitalization, we continually assess the mother/caregiver’s ability to identify and respond appropriately to the infant's behavioral cues. We facilitate understanding of the infant's strengths and challenges, optimize handling and response to the infant, and modify the infant's environment to support their optimal functioning [23]. 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.

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 [24,25].

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

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.

Optimizing the care environment — 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 infant self-regulation. Rooming-in (ie, parent/caregiver and child in the same room throughout the birth hospitalization) has been shown to reduce NAS severity and is the preferred inpatient model of care for NAS [2,26,27].

Neonatal intensive care unit 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 substance-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 "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis".)

Feeding

Deciding on method — Formula feeding should not be the default feeding method for infants with NAS, since breastfeeding can be successful in some people with substance use disorder [2,28-30]. Breast milk and breastfeeding have a large potential benefit, particularly for infants 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 1). 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 HIV (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 or buprenorphine as part of a treatment program appears to be safe for the infant, as concentrations of methadone and buprenorphine are low in human milk, regardless of dose [31-33]. Additionally, breastfeeding while on methadone or buprenorphine maintenance therapy has been associated with reduced need for pharmacologic intervention in the infant [31,34-38]. Breastfed infants exposed to methadone have also been reported to have a lower incidence of NAS requiring pharmacotherapy than opioid-exposed infants who were not breastfed [36]. Reasons for this observation are uncertain. The low concentrations of methadone and buprenorphine in human milk are unlikely to produce a substantial effect on the infant's NAS manifestations, and other factors associated with breastfeeding may be responsible for the reduced severity of NAS in breastfed infants of people on maintenance opioid therapy. The safety of medications for opioid use disorder in breastfeeding is discussed in detail separately. (See "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders", section on 'Medications for substance use disorders'.)

Our approach is consistent with guidelines that promote safe breastfeeding practices for infants of mothers/caregivers with substance use disorder [28]. Each institution should have a protocol for breastfeeding for people with substance use disorder. Unfortunately, there have been legal decisions that have implicated ingestion of breast milk from a mother/caregiver with substance use disorder as a cause of neonatal death, without supporting scientific data [39].

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 [40,41]:

Difficulties with positioning and feeding the infant due to the manifestations of NAS

Difficulties ensuring adequate milk intake

Lengthy hospital stays that may result in separation of the infant 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 [42]. 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 [29,43]. The following substances and breast milk are discussed in detail separately:

Opioids – Breastfeeding by people using methadone or buprenorphine as part of a treatment program appears to be safe for the infant, as concentrations of methadone and buprenorphine are low in human milk, regardless of dose [31-33]. (See "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Breastfeeding'.)

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 [44]. 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)' and "Breastfeeding: Parental education and support", section on 'Maternal cannabis use'.)

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 levels [45]. Newborns metabolize alcohol at approximately half the rate of adults [46]. Breastfeeding from alcohol-consuming mothers/caregivers appears to decrease neonatal milk intake and alters neonatal sleep-wake cycles [47-49]. (See "Maternal nutrition during lactation", section on 'Alcohol'.)

PHARMACOTHERAPY FOR INFANTS WITH SEVERE NAS

Threshold for treatment — The main goal of pharmacologic therapy is the short-term improvement of NAS manifestations. In general, pharmacologic therapy is warranted for infants whose withdrawal signs compromise their ability to regulate movements or autonomic function, to feed, or to interact with caregivers, despite adequate and individualized nonpharmacologic care. Using an abstinence scoring system can help clinicians identify neonates who meet this threshold (eg, two consecutive scores >8, an hour apart, on the Finnegan scoring system) (form 1). (See 'Ongoing assessment' above.)

Treatment of opioid-exposed infants

Choice and dosing of initial agent — Neonates with known exposure to opioids are treated for opioid withdrawal regardless of any other substance exposures. Although no optimal treatment has been established in clinical trials, we suggest opioid therapy (ie, morphine, methadone) for treatment of NAS in neonates with exposure to opioids rather than other drug classes (eg, sedatives). Opioids are effective in reducing signs of NAS. In our center, we use an oral solution of morphine sulfate:

Morphine administration – We start with oral morphine sulfate at a dose that ranges from 0.04 to 0.2 mg, depending on the severity of NAS manifestations (form 1) [50,51]. After the first dose of morphine, we reassess with the Finnegan score in one hour and adjust additional doses based on the presence and severity of manifestations. Our aim is to achieve Finnegan scores ≤8. Once we have reached a morphine dose which allows for Finnegan scores ≤8, we give that dose every three to four hours. If the infant again scores >8 twice, an hour apart, we escalate the morphine dose further until the infant scores ≤8.

Dosing practice varies. We use this presentation-based dosing schedule for morphine rather than a fixed, weight-based dose because we feel that it provides better control of NAS signs and allows for easier titration of the short-acting medication (ie, oral morphine). In other institutions, medication (morphine or methadone) is given on a mg/kg basis both as an initial dose and incremental dose based on signs (table 2) [52,53].

Methadone, a long-acting opioid, is a reasonable alternative to morphine and is used as the first-line agent at some centers.

Although buprenorphine can reduce NAS manifestations [54,55], its use in neonates is limited by the high ethanol content (30 percent) and challenges with sublingual administration [2].

Opioids reduce manifestations of NAS. The practice of using oral opioids, mainly morphine or methadone, as initial treatment for NAS rather than other non-opioid agents is supported by clinical trials and meta-analyses that suggest superior control [2,14,56-58]. In a meta-analysis of six randomized trials (458 infants with NAS), treatment failure, defined as persistent signs requiring additional medication for treatment, was less common with opioid therapy than phenobarbital (15 versus 30 percent; relative risk [RR] 0.51, 95% CI 0.35-0.74) [56]. Among trials that evaluated hospitalization duration, seizure incidence, or neurodevelopmental outcomes, results were similar for opioids and phenobarbital. Two trials in the meta-analysis suggested lower rates of treatment failure with opioids versus benzodiazepines as well. In a separate network meta-analysis using both direct and indirect comparisons from 18 trials (1072 infants) evaluating six agents (morphine, methadone, buprenorphine, tincture of opium, clonidine, phenobarbital), morphine and methadone were the agents associated with the lowest rates of treatment failure (ie, need for an additional agent) although the differences were not statistically significant [58].

Among opioids, control of NAS signs with morphine and methadone is largely comparable although methadone has been associated with shorter hospitalization in some but not all studies. We use morphine rather than methadone because methadone's long duration of action makes it difficult to titrate dosing. In a meta-analysis of two trials including 147 infants with NAS, morphine and methadone resulted in similar rates of treatment failure (ie, persistent signs requiring additional medications) and breastfeeding success as well as similar durations of hospitalization [56]. However, limited observational data suggested that methadone was associated with shorter treatment duration and length of birth hospitalization compared with morphine, after adjusting for confounding factors and when using a hybrid weight- and manifestation-based scoring paradigm [59,60]. Data on other outcomes with morphine versus methadone are limited. One multisite trial of 118 neonates born to mothers on opioid substitution therapy found no differences in short- or long-term neurodevelopmental outcomes with morphine versus methadone for NAS therapy [61].

Trials also suggest that buprenorphine results in similar rates of treatment failure and shorter hospitalization duration than morphine [56,58]. However, as discussed above, practical limitations preclude routine use of buprenorphine.

Additional agent for suboptimal response — For infants with severe NAS that is not adequately controlled (ie, Finnegan scores not ≤8) despite a high opioid dose (ie, morphine 0.2 mg every three hours), we suggest a second medication. For those infants who have known exposure to other substances, we have a lower threshold to start a second medication since opioids alone are less likely to be sufficient. For most infants, we prefer clonidine as the adjunctive agent based on limited observational data [56,58,62,63]. Exceptions include infants exposed to benzodiazepines in addition to opioids, in whom we instead use phenobarbital.

The general preference for clonidine is consistent with American Academy of Pediatrics guidelines and related to concerns regarding adverse effects of phenobarbital. These include 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 [2,52,64-66]. However, other centers may use phenobarbital as the initial second-line agent.

ClonidineClonidine 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) [67]. 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).

PhenobarbitalPhenobarbital 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 NAS signs [68]. 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 [69]. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis".)

For infants with significant withdrawal signs, an oral loading dose of 10 mg/kg (up to 20 mg/kg based on severity of manifestations) is followed by a maintenance dose of 2.5 mg/kg given twice daily starting 12 to 24 hours after the administration of the loading dose. Once the patient is stable and signs of NAS 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 5 or 10 mg/kg in conjunction with opioid therapy with morphine sulfate may be sufficient.

Limited data from post-hoc analyses of a multisite study evaluating the effects of pharmacologic treatment for NAS on neurodevelopmental outcome found that infants who received adjunctive phenobarbital had lower Bayley scale scores and more behavioral problems on the Child Behavioral Check List at 18 months [61].

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 NAS treated with morphine, approximately one-third of infants received a second medication; 72 received phenobarbital, and 108 received clonidine [62]. After adjusting for multiple covariates, length of stay was shorter for infants 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, 95% CI -10.3 to -4.8). 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.

Medications not to use — Naloxone should not be used in the management of NAS, because it may precipitate rapid withdrawal [2,70].

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].

Weaning 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 once Finnegan scores are ≤8 for at least 48 hours. Occasionally infants will require a re-escalation in treatment once weaning has begun. In this case, oral morphine sulfate is increased by half of the initial escalation dosing (form 1).

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/caregivers with substance use disorder.

LENGTH OF HOSPITALIZATION

For infants receiving pharmacologic therapy – The infant may be discharged home when they have been totally weaned off all medications for at least 24 hours. Infants who have failed weaning at least once should be observed for 48 hours off medications prior to discharge.

For infants not receiving pharmacologic therapy – For infants 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 infants in the hospital for a minimum of four to five days, to reduce the chance that an infant will develop signs of withdrawal after discharge. This is because the clinical presentation of NAS is variable, and in some infants 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 "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis", section on 'Timing of onset'.)

However, 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 [10].

DISCHARGE PLANNING AND FOLLOW-UP — The immediate postnatal period is often a stressful period for both mother/caregiver and infant 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 infants 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 infants 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 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]. Follow-up care includes the following:

Continued support for the mother/caregiver, including a treatment program for substance use disorder that will accept the infant 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 infant.

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 infant 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 [71].

LONG-TERM OUTCOMES — When considering clinical sequelae for the infant 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 [72].

Psychosocial comorbidities — People with substance use during pregnancy often have other stressors (eg, trauma/violence exposure, poor prenatal care, poverty) or illnesses (eg, psychiatric comorbidities, infections) during pregnancy or after delivery that may negatively impact their infant. These factors may contribute to the observed increased risk for child maltreatment among in utero substance-exposed infants compared with non–substance-exposed peers [73-75]. 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. However, intervention and referral should occur in the absence of pejorative/punitive attitudes.

Effects of specific substances

Opioids — 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 and small sample sizes of published studies [76,77]. These confounding variables include prenatal (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, and socioeconomic and educational level) [78]. Most of the evidence is observational in nature and results are mixed, and thus the long-term direct effects of prenatal opioid exposure remain inconclusive. Nevertheless, there appears to be a complex developmental vulnerability in substance-exposed children [76,77,79,80].

Specifically, several observational studies have reported an association between prenatal opioid exposure and negative neurodevelopmental and psychological outcomes in children (eg, lower intelligence quotient scores, educational disability), maltreatment, and trauma during childhood [73,76,81-87]. A systematic review similarly reported an association between NAS and future child maltreatment, mental health diagnosis, visual problems, and poor school performance [79]. However, given the observational nature of the data, causation cannot be established.

Furthermore, not all observational data suggest worse outcomes. Particularly, prenatal exposure to buprenorphine or methadone was associated with growth and neurodevelopmental outcomes within the normal range at 36 months in one follow-up study of a randomized trial of opioid-agonist pharmacotherapy during pregnancy [88].

Cannabis — There is increasing evidence that perinatal cannabis use adversely impacts the neurodevelopment and growth of the developing fetus and infant, including persistent changes in higher-level cognition and psychological well-being [89-91]. However, data are often confounded by other factors and determining the direct effect of only cannabis is challenging [91,92]. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)

Autism A population-based study of 508,025 live births based on link data from birth registry and health administrative databases reported an increased incidence of autism for offspring of mothers who used cannabis during pregnancy compared with non-exposed children (4 versus 2.42 per 1000 person years [adjusted hazard ratio 1.51, 95% CI 1.17-1.96]) [93]. There was also a trend towards an increase in intellectual disability and learning disorders for exposed children, but these findings did not reach statistical significance. Limitations of this observational study included reliance on self-reported use of cannabis during pregnancy and the diagnosis of autism in the offspring, as well as an exclusion rate of 25 percent. Nevertheless, these results support our approach of advising people not to use cannabis during pregnancy.

Other areas of impairment – Several studies have reported impaired neurodevelopmental outcome, particularly in areas of sustained attention, visuospatial function, hyperactivity, and problem solving [91,94-103]. It should be noted that most of these studies were performed at a time when cannabis was much less potent, and the negative effects of prenatal exposures may be more pronounced with greater potency of the drug over the last two decades [90].

Other substances

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):

A systematic review of studies that evaluated the effects of prenatal cocaine exposure in children greater than six years of age reported that after controlling for confounding variables, prenatal cocaine exposure was associated with impairments in sustained attention and behavioral self-regulation among school-aged children [104].

Subsequent studies have also demonstrated that cocaine exposure affects short- and long-term neurodevelopment from infancy through adolescence:

-At one month of age, affected infants have poorer arousal and behavioral regulation and higher excitability [105].

-In older children, several studies have reported subtle language and cognitive delays, increased symptoms of attention deficit hyperactivity disorder (ADHD), poor auditory attention skills, and reduced short-term verbal memory [106-108].

-In adolescents, prenatal cocaine exposure has been reported to result in poor perceptual organization, visuospatial information processing, attention, executive function, and behavioral organization, and language delays [109,110].

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 [111-115].

There are numerous reports that suggest that prenatal amphetamine exposure is associated with cognitive problems, including learning and memory difficulties [111,112,116,117] and persistent motor delays [118], as well as neuroimaging findings of structural brain abnormalities, particularly in the striatum [119]. 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 infants with heavy prenatal exposure [120].

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 3, 5, and 7.5 years of age [114]. 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: 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. Infants whose mothers consume alcohol during pregnancy can have chronic nonreversible sequelae.

Fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD) are terms used to describe the range of effects, including lifelong consequences, that can occur in an individual who was prenatally exposed to alcohol.

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".)

Phencyclidine – Phencyclidine hydrochloride (PCP, or "angel dust") can act both as a central nervous system stimulant and depressant. There are limited data on the effect of prenatal PCP exposure on offspring.

SUMMARY AND RECOMMENDATIONS

Terminology – Neonatal abstinence syndrome (NAS) describes neonates with in utero exposure to licit and illicit substances, including opioids. Neonatal opioid withdrawal syndrome (NOWS) is a subset of NAS that describes neonates who have features of withdrawal from in utero opioids exposure specifically. (See 'Definitions and terminology' above.)

Care for all substance-exposed newborns – Our main goals of care are to promote infant and parental/caregiver connection and to minimize the manifestations of NAS. Nonpharmacologic care is critical to the infant's recovery. (See 'Goals of care for the substance-exposed dyad' above.)

System for ongoing assessment – We start assessment for signs associated with NAS at birth for all opioid- and other substance–exposed newborns. We perform ongoing assessment every three to four hours throughout the infant's birth hospitalization (form 1) in conjunction with nonpharmacologic management. Abstinence scoring systems are a semiobjective and standardized way to assess the severity of neonatal withdrawal findings, which inform management. (See 'Ongoing assessment' above.)

Managing individual manifestations – Care for each infant should be individualized based on their presentation and focus on a calm, quiet environment. Excessive irritability can be addressed with gentle vertical rocking. Special positioning (side-lying C position) and swaddling may help calm infants with hypertonicity or tremors. Infants should room-in with parents/caregivers (rather than stay in a separate nursery) when possible. (See 'Optimizing the care environment' 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 infant's unique signs of withdrawal. (See 'Maternal care' 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 or buprenorphine 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 1). (See 'Deciding on method' above.)

Pharmacotherapy for infants with severe NAS – Pharmacotherapy is generally required for infants with severe NAS (eg, two scores ≥8 on the Finnegan scoring system) despite adequate and individualized nonpharmacologic care. (See 'Threshold for treatment' above.)

Our suggested approach is as follows:

First line treatment for most neonates with severe NAS – For infants with in utero exposure to opioids with or without other substances, we suggest oral opioid (ie, morphine, methadone) therapy rather than sedatives (Grade 2C). We typically initiate oral morphine sulfate and adjust the dose based on the severity of NAS manifestations using the abstinence scoring system (form 1). Opioid therapy is associated with a decreased need for additional medications compared with other interventions. (See 'Choice and dosing of initial agent' above.)

Additional agent for suboptimal response – Adjunctive therapy is necessary for infants whose NAS is not adequately controlled (eg, Finnegan scores not ≤8) with maximal opioid dosing.

In most cases when adjunctive therapy is used, we suggest clonidine rather than phenobarbital (Grade 2C). The main exceptions are infants exposed to benzodiazepines in addition to opioids, in whom we favor phenobarbital. We start clonidine at 0.75 mcg/kg orally every three hours and increase to 1 mcg/kg every three hours if necessary. (See 'Additional agent for suboptimal response' above.)

Weaning therapy – Once the patient responds to therapy with a decrease in the number and/or severity of signs of NAS based on ongoing assessment (eg, Finnegan scores ≤8 for at least 48 hours (form 1)), we wean drug therapy, starting with the opioid. We wean oral morphine sulfate by 0.02 mg every 24 hours. (See 'Weaning therapy' above.)

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

Long-term outcomes – Exposure to both opioids and cannabis is associated with negative neurodevelopmental and psychological outcomes. However, it is challenging to assess long-term outcomes, as it is difficult to determine the relative contribution of prenatal substance exposure versus the effects of maternal and neonatal comorbidities. (See 'Long-term outcomes' above.)

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

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Topic 5016 Version 88.0

References

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