Neonatal abstinence syndrome (NAS): Clinical features and diagnosis

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 NAS is most commonly associated with in utero opioid exposure, withdrawal signs can also occur with prenatal exposure to other substances (eg, nicotine, alcohol, benzodiazepines, antidepressants). Additionally, concurrent exposure to these substances plus opioids can potentiate the severity of opioid-induced NAS. (See 'Impact of polysubstance exposure' below.)

The clinical features and evaluation of NAS will be reviewed here. Management and outcome of NAS is discussed in detail separately. (See "Neonatal abstinence syndrome (NAS): Management and outcome".)

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: 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 – NAS describes neonatal 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 (eg, methadone, buprenorphine) [3]. Characteristic clinical manifestations are discussed in detail below. (See 'Presenting features' below.)

●Neonatal opioid withdrawal syndrome (NOWS) – NOWS describes neonates with withdrawal specifically from in utero exposure to opioids alone. NOWS represents a subset of NAS [4]. However, 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. For this reason, we use the term NAS rather than NOWS throughout this topic. (See 'Impact of polysubstance exposure' below.)

●Iatrogenic narcotic withdrawal – Acute withdrawal can also occur in infants who are treated with opioids and other sedating medications in the neonatal period (eg, neonates receiving opioids to facilitate mechanical ventilation). Iatrogenic withdrawal is 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.

EPIDEMIOLOGY — NAS is a common health problem in newborns. Rates of NAS correlate with rates of opioid use disorder (OUD) among pregnant individuals in the community. In the United States, the reported incidence of NAS increased from 2.9 per 1000 births in 2009 to 7.3 per 1000 births in 2017 [5,6]. Since then, the incidence has declined slightly to 6.3 per 1000 births in both 2019 and 2020 [6]. The incidence varies substantially by state, ranging from a low of 1.3 per 1000 births in Hawaii to a high of 44 per 1000 births in West Virginia [5].

The use and misuse of illicit and licit substances by pregnant people, and thus risk for NAS, has increased since the early 2000s and is likely underreported [7,8]. The epidemiology of OUD among pregnant individuals is discussed in greater detail separately. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment", section on 'Pregnant women'.)

In the United States, some states have had success in reducing rates of NAS by adopting best practices for treatment of adults with OUD, optimizing prescription drug monitoring systems to discourage opioid overprescription, and diligently eliminating "pill mills." For example, in West Virginia, the incidence of NAS declined from a high of 56 per 1000 live births in 2017 to 41 per 1000 live births in 2021 [6]. While this demonstrates that some progress has been made in West Virginia, this incidence continues to represent the highest rate of NAS in the country, and it is nearly four times higher than the state's NAS rate before the height of the opioid epidemic.

Cannabis use during pregnancy and lactation has also increased related to increasing legalization across the United States and other regions [9-12].

In addition, people who use illicit drugs during pregnancy often use more than one substance (eg, they are more likely to concurrently smoke cigarettes and/or consume alcohol), which can also contribute to the severity of NAS manifestations [13-15].

Factors associated with prenatal stressors, including suboptimal treatment of substance use disorder, have also been associated with NAS. As an example, higher long-term unemployment and a shortage of mental health clinicians were associated with higher levels of NAS based on results from a 580 county-level study in eight states in the United States [16]. These data highlight the contribution of prenatal stressors to NAS expression. They also illustrate the need for efforts to comprehensively treat OUDs among childbearing people and to understand the social complexities related to opioid use and misuse during pregnancy and NAS. These issues are discussed in greater detail separately. (See "Substance use during pregnancy: Screening and prenatal care" and "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment" and "Opioid use disorder: Treatment overview".)

PATHOPHYSIOLOGY — The pathophysiology of NAS and factors that influence its severity are not completely understood. However, altered levels of neurotransmitters such as norepinephrine, dopamine, and serotonin are presumed to play a significant role in NAS related to opioids and other substances [17].

For neonates with prenatal opioid exposure, genetic variations of the mu-opioid receptor (OPRM1) and the catechol-o-methyltransferase (COMT; encodes an enzyme that metabolizes catecholamines) genes appear to affect the need for pharmacotherapy and length of stay [18]. These data are consistent with data from adult studies that also show polymorphisms in these genes and are associated with variability in adult opioid dependence [19]. Epigenetic modifications to the mu-opioid receptor (OPRM1) promoter have also been associated with NAS severity [20].

CLINICAL MANIFESTATIONS

Factors that impact presentation — The presentation of NAS is highly variable in terms of the timing of onset and in the types and severity of clinical manifestations. Reasons for this variability are likely multifactorial (table 1). The type of substance and how it was acquired (licit versus illicit) are important factors that impact the neonate's presentation. Other important factors include poor maternal health and well-being during the pregnancy (eg, poor medical/obstetrical care, maternal stress, violence, poverty, housing and/or food insecurity). These problems can affect both the parent/caregivers' ability to respond to the infant and the infant's NAS manifestations. Environmental factors include the location of the infant's care (ie, rooming-in with parent/caregiver versus care in the neonatal intensive care unit) and caregivers' ability to appropriately handle and respond to the infant [2,18,21-25]. (See "Substance use during pregnancy: Screening and prenatal care" and "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Care environment'.)

Of note, for infants born to individuals with opioid use disorder (OUD) who received pharmacologic treatment during pregnancy (eg, with buprenorphine or methadone), the dose of the OUD medication does not appear to impact the incidence or severity of NAS in the neonate [21,22,26].

NAS due to opioids

Presenting features — The characteristic signs of NAS reflect dysfunctional regulation in the central and autonomic nervous systems. The major domains of dysfunction include the following [27-29]:

●State control and attention – Sleep and wake cycle disturbances resulting in fragmented sleep with short sleep cycles and difficulty maintaining an alert state.

●Motor and tone control – Alterations in tone or movement characterized by hypertonicity, tremors, and jitteriness.

●Autonomic dysfunction – Sweating, sneezing, mottling, fever, tachypnea, nasal stuffiness, and frequent yawning.

●Sensory processing – Easy overstimulation, sensitivity, or hyperarousal resulting in irritability and crying (usually a high-pitched cry) with minimal stimuli.

Feeding difficulties and gastrointestinal symptoms, which are common in newborns with NAS, can be due to any of the above four domains. Feeding difficulties can include oral hypersensitivity and/or poor coordination of suck and swallow. Gastrointestinal problems can include gassiness, vomiting, and loose stools. All of these contribute to poor weight gain.

The presence and severity of these findings are the basis of assessment systems used in managing infants with NAS (table 2 and algorithm 1). (See 'NAS clinical scoring systems' below.)

Timing of onset — Timing of the onset of NAS manifestations varies depending upon the elimination half-life of the substance and timing of recent exposures. In infants exposed to heroin (short half-life), withdrawal signs often begin within 24 hours of birth, whereas withdrawal from longer-acting agents (eg, methadone, buprenorphine) can begin anywhere from 24 to 72 hours after birth [2,17]. In some cases, withdrawal may be delayed until five days of age or later [30]. If one week or longer has elapsed between the last parental opioid use and delivery of the infant, the risk of the neonate developing acute signs of withdrawal is low [2].

Other sequelae present at birth — In utero exposure to opioids (including prescribed medications to treat OUD) is associated with adverse neonatal outcomes such as intrauterine growth restriction, low birth weight, and small head circumference [31-34]. It is unclear if there is a direct causal relationship between opioids and these findings, or if they are driven by other factors (poor prenatal care, poverty, violence, housing and/or food insecurity). Adverse neonatal outcomes associated with opioid use are discussed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Complications from use' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Pregnancy outcome' and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy", section on 'Pregnancy outcome'.)

Impact of polysubstance exposure — Polysubstance exposure can alter the presentation of NAS. More severe and/or atypical opioid-induced neurobehavioral dysregulation may be seen in infants with concurrent exposure to other substances such as cocaine, nicotine, alcohol, benzodiazepines, selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs), xylazine, or gabapentin [35-42].

In a study analyzing data on >200,000 pregnancies in which the mother received prescription opioids within 45 days of delivery, rates of NAS were higher for infants whose mothers were also taking psychotropic medications (eg, benzodiazepines, gabapentin, antidepressants) compared with those taking an opioid alone [38].

Presentation in preterm infants — Compared with substance-exposed term newborns, preterm infants are less likely to develop clinically significant NAS manifestations, and the severity of NAS manifestations tends to diminish with decreasing GA [25,43].

Clinicians should be aware that the scoring systems used to assess NAS severity were developed and validated in term newborns, and they do not perform well in preterm neonates. (See 'NAS clinical scoring systems' below.)

Possible explanations of the reduced severity of NAS in preterm compared with term newborns include [8]:

●Reduced total in utero substance exposure

●Lower amounts of fat deposition of the substance

●Developmental immaturity of the preterm central nervous system

●Decreased mu receptor expression and sensitivity

●Limited ability to express motor signs of NAS

Other substances — Although NAS is most commonly seen in newborns with opioid exposure, other substances may present with similar findings of neurobehavioral dysregulation. In some of these cases, the substance does not cause a withdrawal syndrome per se, but rather the manifestations seen in the newborn represent direct effects of the substance.

Cannabis — Prenatal cannabis exposure can cause neurobehavioral dysregulation in the neonate [44,45]. Cannabis exposure in isolation is unlikely to result in significant withdrawal signs in the newborn. However, cannabis exposure can potentiate and prolong opioid-induced NAS in newborns exposed to both substances [46,47].

Prenatal cannabis exposure is also associated with long-term adverse neurobehavioral effects in childhood, adolescence, and early adulthood (eg, cognitive deficits, learning disabilities, high impulsivity, autism spectrum disorder) [48-50]. 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 — Newborn infants with prenatal cocaine exposure may exhibit neurobehavioral abnormalities which are most commonly noted between 48 and 72 hours of life [8,51,52]. In a prospective case-control study, infants known to be exposed only to cocaine compared with control infants were more likely to have central and autonomic neurologic manifestations, including [51]:

●Tremors

●High-pitched cry

●Irritability

●Excess sucking

●Hyper-alertness

●Episodes of either apnea or tachypnea

There appears to be a dose-response relationship, with increased exposure resulting in increased neonatal hyperactivity and inability to orient to the environment [53,54]. Other studies have reported that cocaine-exposed infants within the first week of life have an increased rate of abnormal auditory brainstem responses and transient abnormal electroencephalographic (EEG) changes compared with nonexposed infants [55,56]. Prenatal cocaine exposure is associated with structural deficits in the infant brain, which has been associated with functional connectivity and neurobehavioral disruptions [57-59].

The effects of cocaine use during pregnancy and at delivery are discussed in detail separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cocaine'.)

Alcohol — Infants chronically exposed to alcohol in utero can experience withdrawal symptoms after delivery characterized by tremors, hypertonia, restlessness, excessive mouthing movements, inconsolable crying, and reflex abnormalities [60,61].

Other direct effects of alcohol exposure in utero, referred to as fetal alcohol spectrum disorder (FASD), are well described. FASD is discussed in greater detail separately. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis".)

Benzodiazepines — Benzodiazepine-exposed newborns can manifest direct effects of the drug (ie, sedation) or withdrawal manifestations [38,62,63]. Signs of withdrawal may include irritability, hypertonicity, tachypnea, vigorous sucking, hyperactivity, vomiting, loose stools, and poor weight gain. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Benzodiazepines'.)

Nicotine — Nicotine-exposed infants can have alterations in tone and alertness, and a greater need for handling and poorer self-regulation than infants not exposed to nicotine [62-65]. It is not clear if this is a transient drug effect versus a true withdrawal phenomenon [66,67]. Infants exposed to both opioids and nicotine may have more severe NAS signs [68]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Postnatal'.)

Amphetamines — Amphetamines are addictive stimulants that can be misused or used as illicit drugs. Licit amphetamines include stimulants to treat attention-deficit hyperactivity disorder (ie, dextroamphetamine and amphetamine, methylphenidate). The most widely used illicit forms include methylenedioxymethamphetamine (MDMA; "ecstasy") and methamphetamine ("ice," "crystal").

It is unclear whether in utero exposure to amphetamines causes a withdrawal syndrome in the neonate. Some studies have reported manifestations including shrill cry, irritability, jerkiness, diaphoresis, and sneezing [69,70]. However, these reports included few patients, and most were exposed to other substances in utero in addition to amphetamines. Thus, it is unclear if these signs were attributable to amphetamine exposure. By contrast, one large prospective study found that these signs occurred with similar frequency in methamphetamine-exposed neonates and matched controls [71].

Other adverse effects of prenatal amphetamine exposure (eg, prematurity, fetal growth restriction, fetal death) are discussed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Amphetamines, including methamphetamine'.)

Others — Other substances for which in utero exposure may be associated with neurobehavioral abnormalities in the neonate include [38]:

●Antidepressants, particularly SSRIs and SNRIs. In utero exposure to SSRIs and SNRIs during the third trimester can result in a syndrome of poor neonatal adaptation which may manifest as agitation, restlessness, irritability, continuous crying, poor feeding, and jitteriness. This is discussed separately. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes".)

●Antipsychotics. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Antipsychotics'.)

●Gabapentin [40,41].

●Hypnotic benzodiazepine receptor agonists, which are sleep aids sometimes referred to as Z drugs (eg, eszopiclone, zaleplon, and zolpidem). (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Difficulty sleeping'.)

●Kratom, which is an herbal product used by some individuals for self-treatment of opioid withdrawal [72].

●Xylazine, which is an alpha-2 agonist sedative/analgesic agent used in veterinary medicine that has become a drug of abuse and is also sometimes found as an adulterant in heroin and illicit fentanyl. (See "Clonidine, xylazine, and related imidazoline poisoning", section on 'Xylazine'.)

In addition, exposure to one or more of these psychotropic medications in combination with an opioid can potentiate opioid withdrawal symptoms [38]. (See 'Impact of polysubstance exposure' above.)

EVALUATION

Maternal screening

●Screening for substance use – All pregnant individuals should be screened for substance use/misuse at multiple points during the pregnancy and at the time of delivery, ideally by confidential interview. Routine universal obstetrical screening for use and misuse of licit and/or illicit substances is the main way to identify pregnant people in need of treatment for substance use disorder and neonates at risk for NAS. Screening for substance use/misuse during pregnancy is discussed in detail separately. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use' and "Alcohol intake and pregnancy".).

●Screening for comorbid conditions – People with substance use/misuse should also be screened for comorbidities which can affect infant well-being, as they are at high risk for such conditions. These include sexually transmitted infections (syphilis, chlamydia, gonorrhea, human immunodeficiency virus [HIV]), mental health concerns (eg, depression), and violence exposure [2]. Screening for conditions associated with substance use/misuse during pregnancy is discussed in detail separately. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Prenatal care of individuals with substance use disorder'.)

Approach to newborn evaluation

Neonates with known exposure — The evaluation for neonates with known prenatal exposure to opioids or other substances that cause NAS includes all of the following:

●Routine NAS assessments – We assess for signs of NAS starting at birth and continuing every three to four hours throughout the entire birth hospitalization. At the author's center, we use a modified version of the Finnegan scoring system (table 2). Other centers may use the Eat, Sleep, Console approach (algorithm 1) [73]. These assessments are discussed in detail below. (See 'NAS clinical scoring systems' below.)

Neonates with signs of NAS should continue to undergo ongoing routine assessments of withdrawal severity, which informs the management approach. All neonates with substance exposure, regardless of whether they show clear withdrawal signs, benefit from nonpharmacologic measures, as discussed separately. (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Nonpharmacologic measures'.)

●Urine toxicology testing – Urine toxicology testing is routinely performed in substance-exposed neonates, as discussed below. (See 'Newborn drug testing' below.)

●Evaluation for other causes – Although the development of NAS signs (eg, irritability, poor sleep, jitteriness, hypertonicity, loose watery stools) in exposed neonates is likely related to withdrawal and supports the diagnosis of NAS, we also evaluate for other causes of these signs, if appropriate. (See 'Differential diagnosis' below.)

Examples include:

•For neonates with jitteriness, we perform point-of-care testing for blood glucose and ionized calcium to assess for hypoglycemia and hypocalcemia. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hypocalcemia".)

•For neonates with fevers, hypothermia, seizures, or other concerning signs of infection, we evaluate for sepsis and initiate empiric antibiotics. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

Neonates without a known exposure — NAS may be suspected in neonates born to mothers without known or confirmed substance use if the presentation is consistent with withdrawal (ie, irritability, poor sleep, jitteriness, hypertonicity, loose watery stools). In these cases, the evaluation includes all of the following:

●NAS assessments – The severity of the neonate's withdrawal signs are assessed using a standardized tool. At the author's center, we use a modified version of the Finnegan scoring system (table 2). Other centers may use the Eat, Sleep, Console approach (algorithm 1) [73]. These assessments are discussed below. (See 'NAS clinical scoring systems' below.)

Unless an alternate etiology is identified, we continue NAS assessments throughout the birth hospitalization.

●Screen birth parent – the birth parent is screened for substance use/misuse, ideally via confidential interview. Urine drug testing may also be used. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use'.)

●Toxicology testing for the newborn – We send neonatal specimens for toxicology testing when the diagnosis of NAS is suspected. Infrequently, neonatal testing may confirm the diagnosis of prenatal substance exposure in symptomatic infants with negative maternal screening. (See 'Newborn drug testing' below.)

●Evaluate for other causes – Evaluation for other causes includes the following initial laboratory tests (see 'Differential diagnosis' below):

•Hematocrit, to evaluate for polycythemia. (See "Neonatal polycythemia", section on 'Diagnosis'.)

•Serum glucose and calcium, to assess for hypoglycemia and hypocalcemia. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hypocalcemia".)

•For neonates with fevers, hypothermia, seizures, or other concerning signs of infection, we evaluate for sepsis and initiate empiric antibiotics. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

•For neonates with clinical signs of hypothyroidism (ie, hypotonia, large tongue, large anterior fontanelle), we obtain thyroid function studies. (See "Clinical features and detection of congenital hypothyroidism".)

NAS clinical scoring systems — Substance-exposed newborns should have routine ongoing assessments of NAS signs using a standardized assessment tool [2].

NAS assessment tools provide a semiobjective and standardized assessment of the severity of the patient's withdrawal signs [2,74-76]. The two most commonly used approaches are the modified Finnegan scoring system (table 2) and the Eat, Sleep, Console approach (algorithm 1). The choice between them is center-dependent. Every center caring for substance-exposed newborns should adopt a protocol that incorporates routine NAS assessments by trained staff to guide management decisions since this has been shown to decrease the duration of opioid therapy and length of hospital stay [2,73,77,78].

Finnegan scoring system — Most centers using this tool use a modified version. An example of a modified Finnegan NAS scoring tool is shown in the table (table 2). It evaluates 18 different signs of withdrawal, with scores ranging from 0 to 36. Scores >8 reflect clinically significant withdrawal signs. (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Threshold for treatment'.)

The Finnegan score is used to assess the severity of neonatal withdrawal and to initiate, adjust, and wean pharmacologic therapy. Newborns managed with this approach should also receive nonpharmacologic measures, as discussed separately. (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Nonpharmacologic measures'.)

Assessment begins at birth (or ideally before with prenatal teaching) for all opioid- and other substance–exposed newborns. 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.

Eat, sleep, console — The Eat, Sleep, Console approach is a functional assessment of withdrawal severity that has been adopted at many centers [2,75,76,79-81]. This approach assesses NAS signs by asking three simple questions (algorithm 1):

●Does the newborn take >10 minutes to coordinate feeding or breastfeed for <10 minutes or feed <10 mL (or an age-appropriate duration and volume) due to NAS?

●Does the newborn sleep <1 hour due to NAS?

●Does the newborn take >10 minutes to console or cannot stay consoled for at least 10 minutes due to NAS?

If the answer to any of these questions is yes, care is escalated, focusing initially on parent/caregiver involvement and nonpharmacologic interventions. If two consecutive assessments yield yes answers to any question, pharmacologic therapy is generally warranted (after joint discussion with the care team). (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Threshold for treatment'.)

Advantages and disadvantages of each approach — Both assessment tools have advantages and disadvantages. A limitation that they share is that they fail to capture the individual newborn's neurophysiologic processes underlying the behaviors being scored. For example, both approaches assess for feeding difficulty, but neither approach considers the reason for the difficulty, which can vary widely from infant to infant and in the same infant over time. Feeding difficulty in newborns with NAS can be due to oral hypersensitivity, suck and swallow dysfunction, tremors/hypertonia, and/or poor positioning. Since different strategies are used to address each of these issues, the intervention for a newborn with feeding difficulty should optimally be tailored to the underlying problem. In addition, overemphasizing the details of the score (eg, the number of ounces fed or hours slept) misses an opportunity to help parents/caregivers gain a full understanding of the newborn's strengths and weaknesses so they can develop specific strategies to address NAS symptoms and optimize functioning of the dyad (ie, both the newborn and their parent/caregiver).

●Finnegan score – An advantage of the Finnegan score is that it assesses a broad array of withdrawal signs, which can facilitate teaching parents/caregivers how to comfort and support their newborn in the context of their specific withdrawal manifestations. In addition, because the Finnegan system has been a standard part of NAS management for decades, there is longer experience with this approach, and there are ample data on long-term outcomes for infants managed with this approach.

Limitations of the Finnegan score are the large number of elements that need to be scored and the subjective nature of some elements [82].

●Eat, Sleep, Console - The advantages of the Eat, Sleep, Console approach are its simplicity and emphasis on parental/caregiver involvement and nonpharmacologic measures. In addition, the newborn does not need to be moved, undressed, or examined to make this assessment. As discussed below, the available studies suggest that Eat, Sleep, Console is associated with shorter hospital stay and less use of opioid therapy compared with the Finnegan score approach.

However, it is unclear whether reducing use of opioid therapy is the optimal goal when managing newborns with acute withdrawal. As this is a relatively new approach, there are few data on the long-term outcomes for newborns managed with this approach. The impact on long-term neurodevelopmental outcomes is not known. Another limitation is that nonpharmacologic care in the Eat, Sleep, Console approach tends to be a one-size-fits-all "bundle" rather than tailoring interventions to address the individual signs of NAS.

●Comparative data – Most studies suggest that the Eat, Sleep, Console approach is associated with lower use of opioid therapy and shorter duration of hospitalization compared with the Finnegan system [73,79-81,83]. The two approaches were directly compared in the ESC-NOW trial, a cluster-randomized trial involving 1305 opioid-exposed newborns managed at 26 hospitals (including academic centers and community hospitals) [73]. Patients managed at centers randomly assigned to the Eat, Sleep, Console approach were less likely to require opioid therapy during the birth hospitalization compared with those managed at centers using the Finnegan scoring system (20 versus 52 percent, respectively; relative risk 0.38, 95% CI 0.30-0.47). Patients in the Eat, Sleep, Console group also had a shorter mean duration of hospitalization (8 versus 14 days, mean difference 6.2 days, 95% CI 4.6 to 7.7 days). Rates of in-hospital complications and subsequent urgent care or rehospitalization within three months were similar between groups.

The findings of the ESC-NOW trial highlight the short-term advantages of the Eat, Sleep, Console approach. However, 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 with the Finnegan system, despite recommendations to do so [27]. Ultimately, assessing long-term outcomes of newborns managed with the Eat, Sleep, Console approach will be important to better understand its impact.

Newborn drug testing — Practice regarding drug testing for neonates with prenatal substance exposure varies among institutions. Although detection of an opioid (or other substance) in a specimen from the newborn is not required to make the diagnosis of NAS, it can be helpful to confirm the diagnosis when uncertain or to document it. Drug testing may also detect polysubstance exposure. However, given testing limitations, a negative test in the newborn does not exclude NAS.

Neonatal testing can be done on an infant's first void, meconium, or umbilical cord blood. Each test has clinical advantages and limitations [2,8,24]:

●Urine – Urine drug testing is the most commonly used method since it is relatively easy to obtain and results from urine testing are rapid. However, urine testing has the lowest sensitivity (highest false-negative rate) of the three testing methods since it only detects recent exposure in most cases (table 3) [84]. Thus, negative urine drug testing results do not rule out earlier exposures. Similarly, positive results may indicate one-time maternal use rather than a substance use disorder. Furthermore, urine toxicology testing does not detect prenatal alcohol exposure.

●Meconium – Although results from meconium testing may take longer than a urine toxicology test, meconium analysis is sensitive and specific for substances that are excreted into the hepatobiliary system (eg, metabolites of heroin, cocaine, and cannabinoids) or intestinal tract [85]. Meconium analysis reflects exposures in the second and third trimesters. However, collection of appropriate meconium samples can be challenging, as meconium may be passed in utero or be contaminated with transitional stools. The delayed passage of meconium may result in a delayed diagnosis of substance exposure. In addition, this test may not be available on-site at birth hospitals, and results from outside reference laboratories are often not received in time to inform management decisions during the initial postpartum period.

●Umbilical cord blood and tissue – Testing of umbilical cord blood and tissue by using drug class-specific immunoassays appears to be a promising method of testing and is easier to collect than meconium [86,87]. However, it is not widely available and its utility in medical management is limited because it does not quantify maternal use nor reflect periods of drug abstinence closer to delivery [88,89].

Although positive drug test results in the newborn indicate that the infant was exposed to the substance, they cannot be used to diagnose substance use disorder in the parent. Urine tests reflect recent parental use but cannot quantify it.

Additional testing

●Perinatal infections – Infants born to mothers with substance use disorder are at increased risk of congenital or perinatally acquired infections. Testing for the following infections is often warranted in substance-exposed neonates, depending on the maternal history and results of testing during pregnancy. If the birth mother was not previously tested for these infections, both the newborn and mother should be tested.

•Hepatitis B and C (see "Hepatitis viruses and the newborn: Clinical manifestations and treatment", section on 'Hepatitis B' and "Vertical transmission of hepatitis C virus", section on 'Diagnosis')

•Syphilis (see "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on 'Evaluation and diagnosis')

•HIV (see "Diagnostic testing for HIV infection in infants and children younger than 18 months")

●Congenital malformations – Substance-exposed neonates may have a slightly increased risk of congenital malformations [90]. Thus, all affected infants should be evaluated for malformations with a thorough physical examination. The need for additional evaluation (eg, echocardiogram, head ultrasound) is determined by the physical examination findings. (See "Congenital anomalies: Causes", section on 'Drug exposure' and "Congenital anomalies: Approach to evaluation".)

Studies have reported increased rates of various congenital malformations (including cardiac defects, neural tube defects, cleft lip/palate, and club foot) in substance-exposed neonates; however, these findings have not been consistent across all studies [90-96]. The exception is the association between prenatal opioid exposure and cleft lip/palate, which has been reported in multiple observational studies [90-92,97].

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

●Diagnostic criteria – We use an approach suggested by a panel of maternal and child health experts to make a presumptive diagnosis of NAS, which requires both of the following [4]:

•Prenatal exposure to opioids, cannabis, or illicit substances, with or without other psychotropic substances, based on a positive maternal screen for substance use (either by history or by urine drug testing).

•≥2 of the following characteristic signs of substance withdrawal in the newborn:

-Excessive crying or irritability

-Fragmented sleep (<2 hours at a time after feeding)

-Tremors (jitteriness with or without being disturbed)

-Increased tone

-Gastrointestinal dysfunction (eg, hyperphagia, poor feeding, feeding intolerance, loose/watery stools)

A positive drug test in the newborn helps to confirm the diagnosis of NAS but is not required to make the diagnosis. A negative test in the newborn does not exclude NAS. (See 'Newborn drug testing' above.)

●Substance-exposed neonates without signs of NAS — For newborns with prenatal substance exposure, the approach to monitoring and nonpharmacologic support is the same regardless of whether the newborn meets the criteria above, since even infants without signs of NAS remain at risk for later development of NAS. Supportive care measures for substance-exposed newborns is discussed in detail separately. (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Measures for all substance-exposed dyads'.)

●Threshold for treatment – The more clinically relevant criteria are those used to define the treatment threshold, which is discussed separately. (See "Neonatal abstinence syndrome (NAS): Management and outcome", section on 'Threshold for treatment'.)

REPORTING REQUIREMENTS — Clinicians must be aware of the legal requirements needed for consent and for reporting when a diagnosis of prenatal substance exposure is made. Health care providers should be aware of local requirements for reporting substance use; decisions to report should be made in conjunction with social services providers based on the mother's/caregiver's available support/treatment structure and not on the presence of substance use alone [98]. Each birth institution should adopt a policy that complies with local laws and avoids discriminatory practices [8].

In the United States, the Child Abuse Prevention and Treatment Act requires health care professionals to facilitate referral of infants with prenatal substance use exposure and their caregivers to community-based, family support programs known as Plans of Safe Care. These programs address the health and other needs of the infant and the substance use disorder treatment needs of the affected caregiver and others in the family [99,100].

DIFFERENTIAL DIAGNOSIS — The clinical manifestations of NAS (irritability, jitteriness, seizures, fever, feeding difficulty, poor weight gain) are nonspecific and can be seen in many other neonatal conditions, including sepsis, meningitis, intraventricular hemorrhage, metabolic derangements (hypoglycemia, hypocalcemia), inborn errors of metabolism, congenital heart disease, and hyperthyroidism. The key feature that differentiates NAS from these conditions is prenatal exposure to a culprit substance. However, the following concerning clinical findings in the newborn should not be attributed solely to withdrawal without performing an appropriate evaluation for other potential causes:

●Seizures – Neonates with seizures should undergo thorough diagnostic evaluation, as seizures can be a manifestation of a serious condition (eg, sepsis, meningitis, intraventricular hemorrhage, severe hypoglycemia). This is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

●Jitteriness and tremors – These are common signs of neonatal hypoglycemia or hypocalcemia, which can readily be identified by blood glucose and calcium level. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Neonatal hypocalcemia".)

●Fever and irritability – Fever and irritability in a newborn with NAS should prompt evaluation and empiric therapy for sepsis, as discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

Infectious illnesses are more common among substance-using/misusing populations, especially people who inject drugs. Therefore, substance-exposed infants are at increased risk for perinatally acquired infections, as discussed above. (See 'Additional testing' above.)

●Irritability and poor weight gain – Irritability and poor weight gain can be seen in many neonatal conditions (eg, viral infections, congenital heart disease, hyperthyroidism, inborn errors of metabolism). These are discussed in detail separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and "Identifying newborns with critical congenital heart disease" and "Evaluation and management of neonatal Graves disease" and "Inborn errors of metabolism: Identifying the specific disorder".)

●Feeding difficulty – Feeding difficulty can be associated with anatomic or functional abnormalities. The approach to evaluating newborns with oral feeding difficulties is discussed elsewhere. (See "Neonatal oral feeding difficulties due to sucking and swallowing disorders", section on 'Diagnostic evaluation'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Fetal alcohol syndrome (The Basics)" and "Patient education: Alcohol and drug use in pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions –NAS describes neonatal withdrawal from in utero exposure to licit and illicit substances, including (but not limited to) opioids. Neonatal opioid withdrawal syndrome (NOWS) is a subset of NAS that describes neonates with signs of withdrawal specifically from in utero opioid exposure. (See 'Terminology' above.)

●Clinical manifestations – Characteristic signs of NAS include (see 'Clinical manifestations' above):

•Sleep and wake cycle disturbances resulting in fragmented sleep with short sleep cycles and difficulty maintaining an alert state.

•Alterations in tone or movement, including hypertonicity, tremors, and jitteriness.

•Autonomic dysfunction manifesting as sweating, sneezing, mottling, fever, tachypnea, nasal stuffiness, and frequent yawning.

•Easy overstimulation and sensitivity, resulting in irritability and crying (usually a high-pitched cry) with minimal stimuli.

•Gastrointestinal signs (gassiness, vomiting, loose stools), feeding difficulties, and poor weight gain.

●Polysubstance exposure – Opioid-exposed infants with concurrent exposure to other substances often have more severe or atypical NAS signs. (See 'Impact of polysubstance exposure' above.)

●Preterm infants – Preterm infants have a lower incidence of NAS, but it is unclear if this is due to factors related to prematurity or to the inaccuracy of scoring systems to reflect NAS in preterm infants. (See 'Presentation in preterm infants' above.)

●Evaluation – For neonates with known prenatal substance exposure and those with signs of NAS but without a known exposure, we perform the following evaluation:

•Routine NAS scoring – NAS signs are assessed with a standardized abstinence scoring system (table 2 and algorithm 1). For newborns with a known exposure, NAS scoring starts at birth and continues every four hours throughout the birth hospitalization. For neonates with suspected but uncertain exposure, NAS scoring should be started as soon as the possibility of NAS is raised. (See 'NAS clinical scoring systems' above.)

•Newborn drug testing –The approach to testing varies among institutions. Urine drug testing is the most commonly used method since it is relatively easy to obtain and results are rapidly available. Testing can also be performed on meconium or umbilical cord blood. A positive drug test in the newborn supports the diagnosis of NAS but is not required to make the diagnosis; a negative test does not exclude NAS. (See 'Newborn drug testing' above.)

•Screening the birth parent for substance use/misuse – For newborns with signs of NAS but without a known exposure, we screen (or rescreen) the birth parent for substance use/misuse by confidential interview. Urine drug testing may also be used in some cases. (See "Substance use during pregnancy: Screening and prenatal care", section on 'Screening for substance use'.)

•Evaluation for other causes – We also evaluate for other potential causes of NAS manifestations. For example, in newborns with jitteriness, we check the blood glucose to assess for hypoglycemia; for newborns with fevers, seizures, or other concerning signs of infection, we evaluate for sepsis and start empiric antibiotics. (See 'Differential diagnosis' above and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

●Diagnosis – NAS is a clinical diagnosis that requires both of the following (see 'Diagnosis' above):

•Prenatal exposure to opioids, cannabis, or illicit substances, with or without other psychotropic substances, based on a positive maternal screen for substance use (either by history or by urine drug testing).

•≥2 of the following characteristic signs of substance withdrawal:

-Excessive crying or irritability

-Fragmented sleep (<2 hours at a time after feeding)

-Tremors (jitteriness with or without being disturbed)

-Increased tone

-Gastrointestinal dysfunction (eg, hyperphagia, poor feeding, feeding intolerance, loose/watery stools)

●Differential diagnosis – The clinical manifestations of NAS (irritability, jitteriness, seizures, fever, feeding difficulty, poor weight gain) are nonspecific and can be seen in many other neonatal conditions, including sepsis, meningitis, intraventricular hemorrhage, metabolic derangements (hypoglycemia, hypocalcemia), inborn errors of metabolism, congenital heart disease, and hyperthyroidism. (See 'Differential diagnosis' above.)