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Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis

Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis
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.

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

Other related topics are discussed separately, including:

(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 clinical manifestations in an infant with prenatal substance exposure. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

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

NAS – 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 clinical manifestations are discussed in detail below. (See 'Presenting features' 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 signs 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 includes 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".)

EPIDEMIOLOGY — NAS is a common issue in newborns. In the United States, the reported prevalence of NAS increased from 4.0 per 1000 birth hospitalizations in 2010 to 7.3 per 1000 birth hospitalizations in 2017 [6]. The specific rate of NAS varies across states, and in some states, the rate has decreased; data for each state are available from the Healthcare Cost and Utilization Project database.

The use and misuse of illicit and licit substances by pregnant people, and thus risk for NAS, has increased and is likely under reported [7,8]. In particular, the incidence of opioid use disorder (OUD) has increased in the United States, including among pregnant women, with a concomitant increase in NAS [6]. Cannabis use during pregnancy and lactation has also increased in the United States related to increasing legalization in the country [9-12].

Additionally, many pregnant and postpartum people use more than one substance [13-22]. In particular, people who use illicit drugs during pregnancy are more likely to concurrently smoke cigarettes and consume alcohol, which can also contribute to NAS manifestations. (See "Substance use during pregnancy: Screening and prenatal care".)

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 [23]. 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. (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 [24].

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 [25]. 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 [26]. Epigenetic modifications to the mu-opioid receptor (OPRM1) promoter have also been associated with NAS severity [27].

CLINICAL MANIFESTATIONS OF NAS

Factors that affect presentation — NAS presentation is widely variable in timing of onset and in the types and severity of signs displayed. This variability is likely multifactorial (table 1) and is unique to each pregnancy. Maternal use of licit and illicit substances can affect presentation of NAS. Of note, studies have reported no association between the dose of medications to treat maternal opioid use disorder (OUD) (ie, buprenorphine, methadone) and NAS outcomes [28-30]. Factors which can cause poor maternal health and well-being during the pregnancy (eg, poor medical/obstetrical care, maternal stress, violence, poverty) 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 [2,25,29-33]. (See "Substance use during pregnancy: Screening and prenatal care" and "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Optimizing the care environment'.)

Presentations by substance

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 [34-36]:

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, nasal stuffiness, and frequent yawning.

Sensory processing – Easy overstimulation, sensitivity, or hyperarousal resulting in irritability and crying (usually a high-pitched cry) with any stimuli. Infants may have tachypnea, gastrointestinal problems (gassiness, vomiting, loose stools), difficulties with feeding (suck-swallow incoordination), and oral hypersensitivities resulting in poor weight gain.

The presence and severity of these findings are the basis of assessment systems used in making management decisions in infants with NAS (form 1). (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Ongoing assessment'.)

Timing of onset — Timing of the onset of NAS manifestations varies depending upon the recent history of exposures and the half-life of substance elimination. In infants exposed to heroin (short half-life), withdrawal signs often begin within 24 hours of birth, whereas withdrawal from longer-acting methadone or buprenorphine usually begins anywhere from 24 to 72 hours after birth [2,24,37]. For any opioids, withdrawal may be delayed until five days of age or later [38]. If one week or longer has elapsed between the last parental opioid use and delivery of the infant, the risk of acute signs of neonatal withdrawal is low [2].

Other sequelae present at birth — Studies have demonstrated an association between exposure to opioids (including medications to treat opioid use disorder) and smaller head circumference and intrauterine growth restriction with low birth weight, although whether the relation is direct or driven by other factors is uncertain [39-42]. (See "Infants with fetal (intrauterine) growth restriction" and "Microcephaly in infants and children: Etiology and evaluation", section on 'Etiology'.)

In addition, multiple obstetric complications of opioid use during pregnancy can affect the fetus. These are discussed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Complications from use'.)

Impact of polysubstance exposure — Polysubstance exposure can alter the presentation of NAS. Infants also exposed to cocaine, nicotine, or serotonin receptor inhibitors may have more severe opioid-induced neurobehavioral dysregulation [43-46]. Although data are limited, concurrent exposure to benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), or gabapentin can produce an atypical NAS in opioid-exposed infants [47-50].

As an example, in one case series of 19 neonates prenatally exposed to both opioids and gabapentin, 15 demonstrated similar behaviors of wandering eye movements while awake, tongue thrusting, back arching, and continuous extremity movements [49].

Presentation in preterm infants — Preterm infants have a lower incidence of NAS compared with term infants [51]. NAS manifestations severity diminishes as GA decreases [14,33]. However, scoring systems may not accurately reflect NAS signs in preterm infants, as they were designed to be used for term infants. Possible explanations of the reduced severity in preterm compared with term infants include [8]:

Developmental immaturity of the preterm central nervous system

Decreased receptor development and sensitivity

Limited ability to express the signs of motor dysfunction

Reduced total substance exposure during the intrauterine period

Lower amounts of fat deposition of substance

Cannabis — Prenatal cannabis exposure has been associated with neurobehavioral dysregulation in the neonate as well as variable adverse effects in childhood, adolescence, and early adulthood (eg, cognitive deficits, high impulsivity) [52,53].

Although there are no data on a direct teratologic effect of prenatal cannabis exposure, indirect evidence has been reported showing an increased rate of congenital anomalies (cardiac and central nervous defects and Down syndrome) in areas with increased cannabis use during pregnancy (eg, Colorado) [54].

Negative effects of prenatal cannabis exposure on preterm birth, birth weight, and likelihood of transfer to the neonatal intensive care unit (NICU) are discussed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)

Cocaine — Newborn infants with prenatal cocaine exposure may exhibit neurobehavioral abnormalities which are most commonly noted between 48 and 72 hours of life [8,55-57]. 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 [55]:

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 [58,59]. 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 [60,61]. Prenatal cocaine exposure is associated with structural deficits in the infant brain, which has been associated with functional connectivity and neurobehavioral disruptions [62-64].

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'.)

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 amphetamine exposure in utero causes withdrawal in the neonate. When reported, manifestations include shrill cry, irritability, jerkiness, diaphoresis, and sneezing [65,66]. However, such reports are limited by the inability to separate the effect of amphetamine alone from the effect of other substances used in utero and by the small number of reported patients. Furthermore, one large prospective study found no increase in neonatal withdrawal manifestations between methamphetamine-exposed neonates and matched controls [67].

Reported negative effects of prenatal amphetamine exposure on the fetus include prematurity and fetal growth restriction as well as fetal and neonatal death [68-75]. The risk of congenital anomalies with prenatal amphetamine exposure is uncertain [76-78]. These effects are discussed in detail separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Amphetamines, including methamphetamine'.)

Other substances — Although neonatal neurobehavioral dysregulation is most commonly associated with opioid exposure, other substances may present with similar findings [79-85]. These include:

Alcohol – Infants with fetal alcohol syndrome can experience withdrawals characterized by tremors, hypertonia, restlessness, excessive mouthing movements, inconsolable crying, and reflex abnormalities [86]. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis" and "Natural fertility and impact of lifestyle factors", section on 'Lifestyle effects on established pregnancy'.)

Benzodiazepines – Benzodiazepine-exposed infants can experience intoxication and withdrawal manifestations [87,88]. Signs 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 'Postnatal effects'.)

Nicotine – Nicotine-exposed infants can have withdrawal manifestations, including alterations in tone and alertness, and a greater need for handling and poorer self-regulation than infants not exposed to nicotine [87-89]. However, it is not clear if this is a transient drug effect versus a true withdrawal phenomenon [90,91]. Infants exposed to opioids and nicotine may have more severe NAS signs [92]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Postnatal'.)

Psychotropic medications (eg, antidepressants or antipsychotics) – Infants exposed to psychotropic medications can have variable signs of withdrawal, including restlessness and sleeping and feeding difficulties [93]. These medications can also increase risk of opioid-induced withdrawal [47]. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes".)

Kratom – Kratom is a product from the plant Mitragyna speciosa. It produces similar effects to opioids and has been used by some people as a recreational drug or to treat certain conditions, including pain [94]. Kratom-exposed infants can have withdrawal manifestations similar to those in opioid-exposed infants.

Long-term outcomes of exposure — The long-term outcomes of neonates exposed to prenatal substance use/misuse are discussed in detail separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Long-term outcomes'.)

EVALUATION OF NAS

Maternal screening

Screening for substance use – All pregnant people 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. Unfortunately, pregnant people with substance use disorder often fear stigmatization and possible child removal [95]. Thus, it is important that screening occurs without pejorative attitudes or criminal sanctions. Screening and biologic testing 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 (ie, syphilis, chlamydia, gonorrhea, human immunodeficiency virus [HIV]), mental health concerns (ie, 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'.)

Clinical evaluation

Neonates with known exposure — For all neonates with known prenatal exposure to opioids or other substances (based on positive maternal screen), we assess for manifestations associated with NAS starting at birth and every four hours throughout the entire birth hospitalization. We use an abstinence scoring system (form 1), which provides a semi-objective and standardized assessment of the withdrawal severity. Although the development of any manifestations associated with NAS (ie, irritability, poor sleep, jitteriness, hypertonicity, loose watery stools) in such neonates is likely related to withdrawal and supports the diagnosis of NAS, we also evaluate for and rule out other causes of such signs (ie, blood glucose to check for jitteriness due to hypoglycemia; sepsis evaluation for fevers, seizures). We also submit the first urine for toxicology testing. (See 'Differential diagnosis' below and 'Neonatal screening' below.)

Neonates with NAS should continue to undergo routine assessment of withdrawal severity, which informs the management approach. This is discussed in detail elsewhere. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Ongoing assessment'.)

All neonates with substance exposure, regardless of whether they show clear withdrawal signs, benefit from nonpharmacologic approaches that are used to treat NAS. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Managing individual manifestations'.)

Neonates with consistent features but no known exposure — NAS may be suspected in neonates whose presentation is highly consistent with withdrawal (ie, irritability, poor sleep, jitteriness, hypertonicity, loose watery stools) but were born to a person without confirmed substance use. NAS may also be suspected in neonates born to parents in whom substance use is suspected but not confirmed. In these cases, we assess the neonate for withdrawal severity (form 1) as soon as the possibility of NAS is raised. In addition, we screen the parent again for substance use/misuse and evaluate the neonate for other causes of such manifestations.

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

Complete blood count – An elevated or markedly decreased white blood cell count may indicate systemic infection. Normal red blood cell count distinguishes NAS from polycythemia.

Serum glucose and calcium – Normal serum glucose and calcium distinguish NAS from hypoglycemia and hypocalcemia.

Additional testing for certain patients includes:

For neonates in whom sepsis is a concern (ie, hyper- or hypothermia with irritability) – Blood cultures and empiric antibiotics (see "Management and outcome of sepsis in term and late preterm neonates")

For neonates with clinical signs of hypothyroidism (ie, hypotonia, large tongue, large anterior fontanelle) – Thyroid function studies (see "Clinical features and detection of congenital hypothyroidism")

A positive parental screen for substance use supports the diagnosis of NAS. Otherwise, we make a presumptive diagnosis of NAS if no alternate etiology is found. In both cases, we continue ongoing assessment for signs of withdrawal (form 1) and send neonatal specimens for toxicology testing. Infrequently, neonatal testing may confirm the diagnosis of prenatal substance exposure in infants with signs of NAS and negative maternal screening. (See 'Neonatal screening' below.)

Neonatal screening

Toxicology screening — Testing in neonates with prenatal substance exposure varies among institutions. At our institution, we send a first-void urine from all exposed neonates for toxicology screening. Although a positive screen for opioid (or other substances) in a neonatal specimen is not required to make the diagnosis of NAS, it can be helpful to confirm the diagnosis when uncertain or to document it. However, given testing limitations, a negative neonatal test does not rule out the possibility of NAS.

Neonatal testing can be done on an infant's first void, first meconium, or umbilical cord blood. Each test has clinical advantages and limitations [2,8,32]:

Urine – This is relatively easy to obtain and results from urine testing are rapid. However, urine screening of the newborn has a low sensitivity (high false-negative rate) because only recent exposure results in positive testing for most substances (table 2) [96]. Thus, negative toxicology screening 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 screening 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 [13,97]. 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.

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 [98,99]. However, its utility in medical management is limited because it does not quantify maternal use nor reflect periods of drug abstinence closer to delivery [100,101].

Although positive tests on neonatal toxicology screening indicate exposure in the infant, they cannot be used to diagnose substance use disorder in the parent. Urine tests reflect recent parental use but cannot quantify it. Meconium and umbilical cord assays reflect exposures in the second and third trimesters and so would not reflect periods of abstinence closer to term.

Of note, testing for both meconium and umbilical cord blood and tissue may not be available on-site at birth hospitals, and results from outside reference laboratories are often not received in time to affect management in the postpartum period.

Screening for associated conditions

Congenital infections – Substance-exposed neonates are screened for maternal infections including hepatitis, syphilis, and HIV, since infants born to mothers with substance use disorder are at higher risk for congenital infections [55]. (See "Overview of TORCH infections" and "Prenatal evaluation of women with HIV in resource-rich settings" and "Hepatitis viruses and the newborn: Clinical manifestations and treatment".)

Congenital malformations – Although there does appear to be an association between congenital malformations and prenatal substance exposure, most data are inconclusive [102-110]. An exception is the association between prenatal opioid exposure and cleft lip and/or palate, which has been reported in multiple observational studies [102,105,106,111]. Substance-exposed neonates are screened for congenital malformations by careful physical examination. Further evaluation (ie, with echocardiogram and/or sonogram) is needed if there is a concerning physical examination finding. (See "Identifying newborns with critical congenital heart disease", section on 'Risk factors'.)

DIAGNOSIS OF NAS

Diagnostic criteria — For clinical purposes, we use an approach suggested by a panel of maternal and child health experts to make a working diagnosis of NAS, as follows:

Diagnosis of NAS requires the presence of both of the following [5]:

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 screening).

Two of the following five characteristic signs of substance withdrawal:

-Excessive crying (ie, irritability).

-Fragmented sleep (ie, less than two to three hours at a time after feeding).

-Tremors (ie, jitteriness with or without being disturbed).

-Increased muscle tone (ie, muscle stiffness).

-Gastrointestinal dysfunction (ie, hyperphagia, poor feeding, feeding intolerance, loose or watery stools).

However, the approach to monitoring and nonpharmacologic management of neonates with in utero substance exposure is the same regardless of whether they meet the criteria above, as even infants without signs of NAS remain at risk for later development of NAS. The more clinically relevant criteria are those used to define the treatment threshold. This is discussed separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Threshold for treatment'.)

Reporting the exposure/diagnosis — 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 state 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 [112]. 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 [113,114]. The linked website provides a list for each state's reporting requirements and available plans of care.

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

Seizures – Neonates with seizures should have a complete diagnostic evaluation, as neonatal seizures can be seen in a number of conditions (ie, sepsis, meningitis, intraventricular hemorrhage, severe hypoglycemia). This is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Fever and irritability – Fever and irritability in a newborn with NAS should prompt evaluation for sepsis. Infectious illnesses are more common among substance-using/misusing populations, especially people who inject drugs. Therefore, substance-exposed infants are at increased risk for neonatal infections. Sepsis and fever in a neonate are discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Evaluation'.)

Irritability and poor weight gain – Irritability and poor weight gain can be seen in a number of neonatal conditions (ie, viral infection, congenital heart disease, inborn errors of metabolism). These are discussed in detail separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and "Ill-appearing infant (younger than 90 days of age): Causes" and "Evaluation and management of neonatal Graves disease".)

Poor feeding – Poor feeding can also be a sign of anatomic or functional abnormalities; the approach to evaluating such patients 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 5th to 6th 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 10th to 12th 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 and terminology – 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.)

Clinical manifestations of NAS – Although the characteristic signs of NAS from many substances are similar, the clinical manifestations of NAS vary depending on the infant. Characteristic signs of NAS reflect dysfunctional regulation in the central and autonomic nervous systems, as follows (see 'Clinical manifestations of NAS' above):

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

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

Autonomic dysfunction – This manifests as sweating, sneezing, mottling, fever, nasal stuffiness, and frequent yawning.

Sensory processing – Easy overstimulation, sensitivity, or hyperarousal result in irritability and crying (usually a high-pitched cry) with any stimuli. Infants may have tachypnea, gastrointestinal problems (gassiness, vomiting, loose stools), difficulties with feeding (suck-swallow incoordination), and oral hypersensitivities resulting in poor weight gain.

Newborns with prenatal cocaine exposure may present with episodes of apnea or tachypnea in addition to the manifestations listed above. (See 'Cocaine' above.)

Polysubstance exposure – Infants exposed to substances in addition to opioids can have an atypical NAS or more severe NAS than infants without polysubstance exposure. (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, we assess for signs associated with NAS starting at birth and every four hours throughout the entire birth hospitalization using an abstinence scoring system (form 1). We also evaluate for and rule out other causes of such manifestations (ie, blood glucose to check for jitteriness due to hypoglycemia; sepsis evaluation for fevers, seizures). (See 'Neonates with known exposure' above.)

For neonates with features of NAS but no known exposure, we assess the neonate for withdrawal severity (form 1) as soon as the possibility of NAS is raised. We also screen the parent again for substance use/misuse and evaluate the neonate for other causes. (See 'Neonates with consistent features but no known exposure' above.)

Neonatal testing – We send all exposed neonates' first void for urine toxicology screening. A positive neonatal screen for opioid exposure is not required to make the diagnosis of NAS, and a negative neonatal test does not rule out the possibility of NAS in an exposed infant. Neonatal testing can be done on an infant's first void, first meconium, or umbilical cord blood. Testing protocols for exposed neonates vary among institutions. (See 'Neonatal screening' above.)

Diagnosis – The clinical syndrome of NAS is nebulous and there are no specific, well-established diagnostic criteria for NAS. We use the following approach to make a working diagnosis of NAS, which requires the presence of both of the following (see 'Diagnostic criteria' 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 screening).

Two of the following five characteristic signs of substance withdrawal:

-Excessive crying (ie, irritability).

-Fragmented sleep (ie, less than two to three hours at a time after feeding).

-Tremors (ie, jitteriness with or without being disturbed).

-Increased muscle tone (ie, muscle stiffness).

-Gastrointestinal dysfunction (ie, hyperphagia, poor feeding, feeding intolerance, loose or watery stools).

The approach to monitoring and nonpharmacologic management of neonates with in utero substance exposure is the same regardless of whether they meet the criteria above, as even infants without signs of NAS remain at risk for later development of NAS. The more clinically relevant criteria are those used to define the treatment threshold. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes", section on 'Threshold for treatment'.)

Differential diagnosis – Clinical signs of NAS should not be attributed solely to withdrawal without appropriate assessment and diagnostic tests because other neonatal problems may have similar features to NAS (ie, seizures, fever/irritability, poor weight gain). (See 'Differential diagnosis' above.)

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Topic 5010 Version 56.0

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