Continuing Education Activity

Neonatal Abstinence Syndrome (NAS) is a spectrum of clinical manifestations seen in neonates due to withdrawal from intrauterine drug exposure. It is more commonly associated with maternal opioid use. The incidence of NAS has increased fivefold in the past decade, increasing hospital expenses. There is significant long term neurodevelopmental morbidity and mortality among NAS babies. This activity reviews the evaluation and management of NAS and highlights the healthcare team's role in improving care for patients with this condition.

Objectives:

• Identify the etiology and epidemiology of neonatal abstinence syndrome.
• Describe the typical presentation, evaluation options, and assessment tools for neonatal abstinence syndrome.
• Outline the management models, treatment options and long term outcomes for neonatal abstinence syndrome.
• Explain the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by neonatal abstinence syndrome.

Introduction

During pregnancy, substance abuse is on the rise, especially opioids, both prescribed and illicit, resulting in a hidden epidemic of neonatal abstinence syndrome (NAS). NAS is diagnosed every 25 minutes in the United States. It is a multisystemic disorder resulting from chronic in-utero exposure and its abrupt cessation at birth. The predominant symptoms include central nervous system (CNS), gastrointestinal (GI), and autonomic manifestations. The pathophysiology of this condition remains unknown. Multiple neonatal and maternal factors affect the expression of symptoms, including gestational age, sex, genetics, and maternal polysubstance abuse or smoking. The diagnosis is made based on an accurate maternal history and neonatal clinical features, with or without biological testing. Multiple assessment tools exist, but the traditional Finnegan scoring system is the most commonly used to evaluate neonates and make management decisions. Non-pharmacological care, like rooming-in and control of environmental factors, is the first clinical management strategy and should continue even after discharge from the hospital. Breastfeeding should be strongly encouraged unless there is maternal polysubstance abuse or maternal medical contraindication. When withdrawal signs are severe, pharmacotherapy is initiated. Although no clear consensus exists on which medication is best, morphine remains the most commonly used first-line agent.

More recent evidence supports methadone or buprenorphine to treat NAS as their use is associated with shorter hospital stays and decreased pharmacologically treated days. Phenobarbital and clonidine are useful as second-line agents with variable effects. A standardized approach to both non-pharmacological and pharmacological treatment is essential. A new management approach called "eat, sleep, and console" is based on the basic functioning of the infant, standardized non-pharmacological care, and an increase in the family's involvement in the care of the baby. This approach is showing promising results.[1]

Management of NAS must also address maternal issues such as coexisting mental illness, intimate partner violence, and limited healthcare access to maintain the mother-infant relationship necessary for the infant's normal development. NAS is associated with long-term consequences, including but not limited to neurodevelopmental delays, behavioral problems, and, when untreated, death. Adequate data still lacks long-term outcomes attributed to NAS because of the existence of multiple uncontrollable confounding factors. A public health approach is necessary to reduce the incidence of NAS and the resultant economic burden.[2][3]

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota. 

Etiology

The clinical features of neonatal abstinence syndrome (NAS) result from chronic in-utero exposure to certain drugs or substances of abuse and its abrupt cessation at birth. Research cites several drugs as possible etiologies, but traditionally opioids have been the number one etiological agent. Among opioids, heroin or morphine has been the most commonly abused drug since the 1800s. However, with improved drug manufacturing over the decades, neonatal withdrawal from prescription opioids like hydrocodone, oxycodone, and opioid-containing combination products has also been found. Likewise, NAS can also result from synthetic and semi-synthetic opioids like methadone and buprenorphine, which have been the standard for opioid addiction (medication-assisted therapy or MAT) during pregnancy.[4][2] 

During pregnancy, psychiatric medication usage like antidepressants, selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antipsychotics, both typical and atypical, have been implicated in causing neonatal withdrawal signs and symptoms. However, caution is necessary while interpreting these symptoms as these studies have used Finnegan’s scoring to describe NAS, which he initially developed for babies having withdrawal from opioids. Several other substances like benzodiazepines, nicotine, alcohol, methamphetamine, and inhalants also may produce signs and symptoms consistent with NAS.[5]

In addition to the possibility of being the sole etiology for NAS, substances like gabapentin, benzodiazepines, cocaine, and nicotine also alter the severity of NAS expression. Polysubstance abuse during pregnancy further potentiates the severity. Marijuana usage in pregnancy, which is the most commonly abused substance during pregnancy, and its effect on modifying the severity of NAS, is unclear.[2][6]

Epidemiology

The incidence and prevalence of neonatal abstinence syndrome require an understanding of maternal substance use epidemiology during pregnancy. Globally, as of 2016, the highest prevalence for any substance use disorder (SUD) was in Australasia, while opioid dependence disorder was highest in North America.[7] Throughout the world, the prevalence of opioid use disorder increased by 47% over the past approximately 25 years (1990 to 2016). Representing the highest increase among any substance abuse disorder. Even though the increase in prevalence was more among men, approximately one-third of all SUD were women. Estimates are that 10 million women are affected by opioid dependence as of 2016.[7] 

In the US, the prevalence of opioid use during pregnancy has increased by 333% over 15 years (1999 to 2014) and continues to rise.[8] Among women in the US who had public insurance Medicaid, approximately 1 in 4 women (21.6%) were prescribed opioids during pregnancy. The increase in the prevalence of substance abuse in pregnancy, especially opioids, has correlated with an increase in NAS incidence. Just over a decade (2004-2014), the incidence of NAS among babies insured by Medicaid dramatically increased by five-fold (1.3 in 1000 to 5.8 in 1000 births) as per hospital data from the National Inpatient Sample, which has data from 97% of the population in the US.[9] This data is equivalent to diagnosing one newborn with NAS every 25 minutes. More recent evidence from a study of 24 tertiary care hospitals has reported a massive incidence of 23 per 1000 births.[10] A survey of 28 states found regional differences in NAS's incidence; the highest rates were West Virginia, Vermont, and Kentucky.[11][12] Even in the states where NAS reporting is mandatory, variations in case definitions and required data result in difficulty in surveillance and quantifying NAS's precise incidence.[13] Hence, there must be standardization of NAS definition across states to address the opioid crisis further.[14] 

The increasing incidence of NAS has, in turn, lead to increasing admission rates to NICU, from 7 per 1000 to 27 per 1000 cases.[15] As a result, the hospital cost for management of NAS has also increased almost seven times, costing $462 million in 2014, just among the population covered by public insurance.[9] Tennessee had a five-fold increase in hospital admission for NAS over a decade, but legislative efforts did not get passed for decreasing the incidence of NAS.[16] Given the long-term consequences of NAS, both medical and social, lawmakers must address the opioid epidemic and the resultant NAS epidemic.

The incidence of NAS rose from 21,732 in 2012 to 32,128 in 2016, while hospital charges have tripled to $2.5 billion.[17][18] The incidence of NAS also rose from 4.6 to 6.7 per 1000 in-hospital births between 2012 and 2016.[19][18]

Pathophysiology

Neonatal abstinence syndrome is influenced by many factors, including maternal-fetal-placental pharmacokinetics, neurotransmitter dysregulation, genetic and epigenetic factors. The pathophysiology underlying NAS has not been fully understood. However, rat models show differences between neonatal and adult withdrawal processes. Although several mechanisms have been proposed as potential pathways, there appears to be a complex interaction between the various neurotransmitters (like dopamine, serotonin, and glutamate), lack of adequate expression of some opioid receptors (kappa and delta receptors), and differential maturation of neuronal circuit.

Genetic mechanisms for differences in NAS expression have additionally been suggested. Single nucleotide polymorphisms (SNP) in the genes for opioid receptors (mu - OPRM1, delta - OPRD1, and kappa - OPRK1) and dopamine metabolism pathway (catechol-O-methyltransferase (COMT) gene) are associated with shorter hospital stay and duration of treatment. Studies evaluating SNPs in the genes for opioid metabolism like the ABCB1 gene and cytochrome P450 (CYP) genes like CYP2B6, CYP2D6, and CYP34A have been inconclusive. Besides the genetic mechanisms, epigenetics, like DNA methylation resulting in decreased expression of OPRM1 genes, have also correlated with increased NAS expression severity.[20]

Several neurotransmitters play some role in NAS, but most signs and symptoms of NAS are secondary to increased noradrenergic output from locus ceruleus, which is the leading site for noradrenaline production in the brain. Chronic opioid stimulation in-utero and sudden cessation post-birth lead to increased norepinephrine levels through upregulation and super-activation of intracellular cyclic adenosine monophosphate (cAMP). Through the same pathway, other neurotransmitters are also altered and believed to cause NAS's clinical manifestations. For example, decreased serotonin causes sleep deprivation, decreased dopamine causes hyperirritability, and increased acetylcholine causes cholinergic symptoms such as sneezing and diarrhea in NAS babies. Increased corticotropin release from activation of the hypothalamic-pituitary-adrenocortical axis has also been noted to cause stress and hyperphagia during the opioid withdrawal process in the neonates.

The mechanism for signs and symptoms of withdrawal from other drugs seems to be almost similar to opioid withdrawal, although some distinction exists. Withdrawal symptoms from in-utero exposure to SSRI/SNRI may be secondary to excessive serotonin and norepinephrine. Neonatal TCA withdrawal may be due to excess cholinergic transmitters. Withdrawal symptoms from in-utero exposure to Benzodiazepines are probably due to increased gamma-aminobutyric acid (GABA).[21][2]

Toxicokinetics

Low molecular weight and lipophilicity allow opioid drugs to transfer across the placenta to the fetus easily. Due to the same reason, these drugs can accumulate in the developing fetal brain by crossing the blood-brain barrier. There appears to be a direct relationship between the gestation age and the amount of opioids transferred across the placenta. Variations in the ability to cross the placenta also exist among the opioids; semisynthetic opioids are transported across the placenta in a lower amount than synthetic opioids. Slow metabolism and longer half-life of opioids in the fetus may be one reason for severe withdrawal symptoms.[2]

History and Physical

Neonatal abstinence syndrome is a constellation of signs and symptoms with multisystem involvement. The clinical features categorize into CNS, autonomic, respiratory, and GI system disturbances. Initial clinical presentation varies widely; however, the most specific presentation for withdrawal is a triad of increased muscle tone, tremors when undisturbed, and exaggerated Moro reflex. Other initial presenting symptoms include excessive high-pitched crying, irritability, sneezing, and diarrhea, all of which are due to increased noradrenergic state.[22][2]

CNS symptoms typically include hyperirritability, high-pitched cry, jitteriness, and tremors. Hyperirritability, in turn, leads to sleep disturbances and difficulty maintaining a calm state.[23] Myoclonic jerks and seizures are also possible. The occurrence of seizures secondary to withdrawal have been debatable; in the past, the frequency of seizures in NAS has been between 2% to 11%; interictal EEGs have found it to be myoclonic jerks rather than true seizures, and many recent studies corroborate the rare occurrence of seizures secondary to withdrawal.[24][25] Autonomic instability leads to changes in vital signs such as tachycardia, tachypnea, and hyper or hypothermia. Skin perfusion becomes altered, leading to mottling and sweating. Frequent yawning, nasal stuffiness, excessive sneezing, and nasal flaring may also be present. Some of these may persist for months, especially in cases of withdrawal from buprenorphine.[22]

GI symptoms observed in NAS include poor feeding, regurgitation, vomiting, and diarrhea. Heroin withdrawal is notable for severe GI symptoms leading to dehydration and electrolyte disturbances. Diarrhea, in turn, leads to skin breakdown around the perianal region and the resultant rash. Withdrawal is a state of excessive caloric demand; this, combined with the GI losses and excessive autonomic stimulation, can lead to weight loss and failure to thrive. Hence it may be necessary to increase caloric intake with feeding.[2]

Neonatal abstinence syndrome clinical features are also believed to be due to neurobehavioral dysregulation. An imbalance exists between the four behavioral components, i.e., state control/attention, autonomic control, sensory processing, and motor and tone control. When the infant spends more time in one subsystem, such as increased muscle tone, the energy consumed in another subsystem, like attention, is very minimal, and this imbalance is also considered to be a hallmark feature. The neonate's self-regulatory capacity is lost, leading to hyperirritability and difficulty being consoled by the caregiver; this also alters the infant's developmental trajectory.[3]

Neonatal abstinence syndrome babies have significant variability in the presenting symptoms and severity of the presentation. Inter and intra-subject differences also exist.[5] Multiple factors can affect the timing and severity of presentation, like the type of drug exposure, type of opioids exposed in-utero, the timing of the last dose, cumulative dosage, and simultaneous exposure to other abuse drugs. For example, withdrawal from short-acting heroin presents on the first day of life (24 to 48 hours), while withdrawal from long-acting buprenorphine (36 to 60 hours) and methadone (48 to 72 hours) presents in the first three days of life.[22][26] However, the onset can delay for as late as four weeks. While antenatal buprenorphine exposure affects the timing of onset, it also correlates with less severe features and shorter hospital stay duration.[27] Cumulative dosage of methadone is not directly related to the severity of NAS symptoms, even though doses under 30 mg have correlated with a lesser degree of symptoms. Sedative hypnotic withdrawal has a wide range of onset, from 7 days for barbiturates, 12 days for diazepam, to 21 days for chlordiazepoxide. Polydrug exposure, especially the combination with benzodiazepines, simultaneous cigarette exposure, and male gender, has been associated with increased severity. Premature infants are less likely to express severe symptoms and have a milder course, and research has not yet determined why. Breastfeeding has correlations with less severe symptoms, shorter length of hospital stay, and pharmacological treatment, with only trace quantities of opioids identified in breast milk.[28] Genetic factors are also likely to influence the severity of symptoms.[2][12]

Evaluation

Neonatal abstinence syndrome is a clinical diagnosis based on pertinent signs and symptoms in the setting of a high index of suspicion. A verbal history from the mother about drug use or abuse, taken in a non-judgmental, non-threatening, and caring manner, helps identify the majority of the NAS cases. However, this history may not be readily available, and hence, testing the infant may be necessary. Several methods are available to identify and/or confirm the in-utero drug exposure; the infant's urine, meconium, cord blood, or hair can be useful options. Testing the infant's urine or meconium for drugs is most commonly practiced because of its ease of collection and timely results. Urine testing can identify drug exposure only a few days before delivery. Depending on the type, the timing of the last dose, and the cumulative amount of drug exposure in-utero, the maternal drugs may be identified in the infant's urine between 2 to 4 days. If there is a delay in collecting neonatal urine, there is a high chance of false-negative results. Hence it is important to collect the urine as soon as possible, preferably the first void urine. Meconium testing can identify drug exposure dating back to 20 weeks of gestation and hence, more sensitive than the urine test. Internal metabolism and clearance of drugs in both the mother and the fetus can also affect the result. Most opioids can be identified by either of these tests, except for synthetic and semi-synthetic opioids, which require a specialized test to identify. Although these immunoassay screening tests are easy to perform in most hospitals, confirmatory mass spectroscopy tests are expensive and require advanced expertise. Hair and umbilical cord testing for drugs have also been evaluated but found to be less sensitive, with practical difficulties, and hence, its clinical utility is limited. All of the above tests have false positive and false negative results and require cautious interpretation. False-positive results are common with amphetamine exposure, when there was soap or alcohol used before collecting the specimens or when meconium has urine contamination. Maternal usage of analgesics during the peripartum period can positively result in the infant's test and hence also require cautious interpretation. False negatives can occur after marijuana exposure or improper storage of meconium. The best yield for confirmation is a combination of maternal urine and infant meconium testing.[2][21]

The assessment for babies with known or suspected fetal exposure must start at birth. Several tools have been developed over decades to assess the severity and the need to start, adjust and wean interventions, specifically pharmacological agents. The Finnegan Neonatal Abstinence Scoring System (FNASS) and its modified versions have long been considered the "gold standard" for NAS assessment.[29] It continues to be widely used among the pediatric community even though in 1998, the American Academy of Pediatrics recommended the 11 items Lipitz scoring tool due to its ease of use. FNASS, consisting of 21 clinical signs and symptoms divided into three categories, was originally developed for opioid-exposed infants and full-term babies. Scoring occurs approximately every 3-4 hours, and depending on the score, clinicians can decide on further management. A cumulative score of 8 or more is suggestive of starting treatment. However, the cutoff basis is on FNASS scores in non-opioid exposed, healthy neonates, and there is no consensus based on well-designed studies to use it as a cutoff for starting treatment.[30][31] The FNASS and its modified versions have found wide adoption, but it has several limitations. It needs the training of the rater, has high inter-rater variability due to the subjective nature of the items, includes items of low clinical significance like sneezing or yawning, the need to disturb the baby for accurate assessment, and the lack of generalizability to preterm infants and it's usage in withdrawal from drugs other than opioids.[32] Several studies have noted a longer length of hospital stay and pharmacological treatment when using an FNASS based protocol.[12]

To overcome the limitations of FNASS, multiple scoring tools have undergone development.[33] A modified FNASS called MOTHER NAS removed the overlapping items and added irritability and failure to thrive, tallying to 19 items. This scoring has been the measure in some studies but still lacks validation.[34][27] Other scoring tools like Neonatal Withdrawal Inventory (NWI), Neonatal Narcotic Withdrawal Index, and Finnegan Neonatal Abstinence Syndrome Tool – Short Form, have been studied and noted to have high inter-rater reliability and almost 100% correlation with FNASS.[12]; however, they have not been put to use in many hospitals due to reasons that remain unclear.[29]

Alternative assessment approaches have also been attempted. A new approach called the "Eat, Sleep, Console" model was recently developed based on the basic functioning of infants, the family's involvement in the infant's care, and maximizing the non-pharmacological treatments before starting medications.[25] It was started as a quality improvement project to evaluate the ESC approach against the FNASS approach and found that only 12% of the infants received morphine using the ESC approach, which is five times less likely to FNASS approach. There were studies conducted further to validate the functional ESC model and found a significant reduction in length of stay and need for pharmacological treatment.[35][27] It remains a relatively new approach, and more well-designed RCT studies are required to corroborate the findings, including the long-term outcomes. Besides the ESC approach, scoring tools with objective parameters are also available. For example, short scoring scales based on skin excoriations, muscle tone and tremors, salivary cortisol level, pupillary size, and serum levels of brain-derived neurotrophic factor (BDNF); and skin conductance exist. Such tools have some clinical significance, but their application in day-to-day management is subject to limitations by practical difficulties and limited data that validate its significance.[12]

Treatment / Management

Management options for neonatal abstinence syndrome can broadly divide into non-pharmacological, alternative, and pharmacological treatments.

Non-pharmacological Treatment

Treatment should always begin with non-pharmacological care while maintaining the mother-infant dyad and should continue even after discharge from the hospital. The goal of non-pharmacological treatment is to assist the self-organization of the neonate and support the neuro-maturation. AAP has also recommended it as first-line in the management of NAS.[22] These may include changes to the physical environment like darkening the room and quietening the surroundings to decrease visual and auditory stimuli. Techniques such as gentle vertical rocking, side-lying C-position, containment with hands held, swaddling, and swaying can be soothing and may help reduce irritability and hypertonicity.[26] Avoiding unnecessary tactile stimuli by clustering care and providing skin-to-skin is effective. Skincare using topical barrier cream for diaper dermatitis is necessary to reduce irritability. Pacifier use can decrease oral hypersensitivity. These infants also have difficulty maintaining the 3 hours of scheduled feeding and may become irritable secondary to hunger. Hence, it is imperative to provide frequent, small volume, on-demand feeding to make the infant more comfortable.[36] Calorie dense, thickened feeds are required to meet the energy requirements of 150 Kcal/kg/day in these infants to prevent growth failure.[22] The use of partially hydrolyzed formula has not been shown to be beneficial in infants with NAS.[37] It is essential to understand that these infants have neurobehavioral dysfunction with disorganized behavior rather than adaptation problems. Because of this, individualizing the non-pharmacological care specific to the infant may be beneficial. Health care professionals should involve the mother and help her identify these interventions that alleviate the dysfunctional behaviors specific to her baby. Having the care for mother and infant in the same location, i.e., parental rooming-in, promotes more time spent on skin-to-skin and breastfeeding, resulting in huge benefits such as a reduced length of stay and decreased the number of days on pharmacological treatment.[38][25]

Since opioids are present in minute quantities in breastmilk, breastfeeding should be strongly encouraged unless the mother has other absolute contraindications such as HIV, Hepatitis B or C, polysubstance abuse, or IV drug abuse. The support for breastfeeding has also received endorsement by various organizations, including the American Academy of Pediatrics. But several barriers to breastfeeding among women in Medication-Assisted Treatment (MAT) program exist, and efforts must take place to overcome those to reap the benefits of breastfeeding that is beneficial to the infant's neurodevelopmental outcomes.[3]

There may be a debilitation of maternal well-being in the perinatal period. Hence, multi-level professional care must be offered to the mother and maintain the mother-infant dyad. Despite many studies showing the benefits of preserving the dyad, significant barriers exist. For example, mothers report feeling guilty or having mistrust and judgmental behavior from the staff caring for their baby. Provider biases preventing the involvement of the mother in the individualized care of the infant also exist. Hence to reap the benefits of this strong relationship, physicians must support and teach the parent in a non-judgemental way to optimize the non-pharmacological care for their infant, which can be easily provided at the bedside by the parent and continued even after discharge from the hospital.[39][25]

Alternative Treatment

Many alternative therapies have undergone evaluation for their use in NAS. Massage therapy, foot and auricular acupressure therapy, and Reiki have correlated with soothing effects and positive changes in the baby's vitals. A recent study on laser acupuncture has shown a reduction in LOS, although the LOS is comparatively longer than the national average. Besides these, ongoing studies are evaluating the effects of aromatherapy and music therapy, as well.[40][39]

Pharmacological Treatment

Even though nonpharmacological treatment remains the first line, AAP endorses the use of pharmacotherapy when indicated, keeping in mind that it is also associated with a more extended overall stay in the hospital, which is detrimental to the mother-infant dyad.[22] There are reports that 27 to 91% of infants with NAS required pharmacological intervention.[2] The goal of pharmacological treatment is to improve the withdrawal signs in the short-term by reducing the scores of FNASS or any other scoring tool.

Multiple studies, including randomized control trials, have been conducted to find the optimal medication. Still, the results have varied widely in length of stay in hospital and treatment duration. Despite these variations, opioids remain the preferred mainstay pharmacological agent in the treatment of NAS, although there is no clear consensus on the choice of opioids.[27][29] Paregoric (a drug with anhydrous morphine) and dilute tincture of opium were very popular in the past. But due to its high alcohol content, toxic contents with multiple side effects, and very long length of hospital stay (even up to 79 days), these medications have been discontinued and no longer used.[22] Morphine, a short-acting opioid, remains the most commonly used and preferred opioid based on the PHIS database.[10] It is frequent dosing every 3 to 4 hours, allows for easy adjustment in management, but it also means disturbing the infant more frequently. The dose basis is on the severity of the symptoms and the scores, but generally, it starts at 0.04 mg/kg/dose with a maximum dose of 0.2 mg/kg/dose. However, morphine treatment is associated with longer length of hospital stay ranging from 5.9 to 42 days, probably due to slower weaning. Hence, current studies are exploring the use of other opioids.[40]

Methadone, a long-acting synthetic opioid, has been evaluated as an alternative. It has the advantage of being dosed twice daily due to its long half-life, but that also limits the dose's frequent titration. The length of stay had ranged from 16 to 44 days when using methadone. Recent evidence shows only a modest reduction of LOS with methadone compared to morphine.[41][42] Besides, the drug undergoes extensive metabolism by cytochrome 450 enzymes and interacts with multiple medications, and hence caution is needed, especially when used with Phenobarbital or antiviral medications.

Buprenorphine, a partial agonist opioid, has recently drawn attention because it correlates with shorter length of stay than morphine and methadone and its ease of use through sublingual administration. Even though the LOS range was between 12.4 days and 32 days, recent RCT showed that the median LOS was significantly shorter by 12 days compared to morphine.[34] It also correlated with a significant reduction in the number of pharmacologically treated days proposed due to its partial agonism, functional antagonism, and relatively long half-life. However, caution is necessary when interpreting the results as those infants predominantly suffered exposure to methadone in-utero. While one RCT showed promising results, more well-designed studies are necessary for its widespread use. The current drug formulation of buprenorphine with 30% ethanol might be a deterrent for its widespread use.[39][43][34]

Second-line pharmacotherapy for infants whose symptoms remain uncontrolled with maxed opioid treatment includes Phenobarbital and clonidine. Again, there is no clear consensus that among the two, one is more effective, but Phenobarbital is used more frequently in the US than clonidine.[44] Both drugs can be used as an adjuvant to first-line opioids in severe NAS. Phenobarbital, an anti-seizure medication, may be more effective in cases of polydrug exposure and opioid plus benzodiazepine exposure. However, its side effects, such as oversedation, uncertain long-term neurodevelopmental outcomes, and its high alcohol content, must merit consideration. Clonidine, an alpha-2 agonist, has been shown to be effective in reducing the duration of pharmacotherapy. Even though there is a risk of hypotension and bradycardia, a few studies showed the low occurrence rate of cardiovascular side effects, and preliminary data supports its use in neonatal withdrawal. But it is crucial to know that the safety profile for both drugs has not been adequately established.[27]

Naloxone, an opioid antagonist, is not recommended in the management of NAS because it can precipitate withdrawal symptoms. Its efficacy, dosing, and safety profile in neonates have not received adequate study as well.[45]

Pharmacotherapy can get weaned and discontinued once the NAS signs and symptoms are well-controlled based on the scoring tool used. Many institutions have used a 10 to 20% reduction in the daily dosing of the opioid as the weaning protocol. However, there is no consistency among institutions, and the necessity of longer weaning protocols is also questionable.[46][27] This factor may be among the reasons for the longer length of stay. Hence, many studies have called for the standardization of the weaning protocol and pharmacotherapy regimen.[47][22] One quality improvement study has used 'as needed' treatment protocols and shown reduction in the amount and days on pharmacotherapy.[1]

Location of the Treatment

Babies with neonatal abstinence syndrome have long received treatment in the NICU, and this has been a traditional practice than evidence-based. According to a recent Pediatric Health Information System (PHIS) database, about 87% of neonates with NAS were managed in the NICU.[10] While the NICU admission may be necessary because of the severity of symptoms or comorbidities, the environment is not ideal because of multiple distractions and could be overstimulating to these infants. Rooming-in, which promotes mother-infant relation, skin to skin, and breastfeeding, is currently the preferred model of care as it has correlated with reduced severity of NAS expression.[38][40] This activity can be best achieved in the postnatal ward, and one study showed a consequent reduction in the duration of pharmacotherapy and LOS.[27] Another quality improvement study proved the same results in a general inpatient pediatric ward.[1] Thus it may be time to reconsider the age-old practice of admitting all infants in the NICU to manage NAS. Some studies have also evaluated the possibilities of outpatient only and combined inpatient-outpatient management and found a relative reduction in LOS and costs with outpatient management. However, outpatient management was associated with increased days on pharmacotherapy, and concerns exist among physicians in handing over opioid prescriptions to caregivers of those infants who are at risk of relapse.[12]

Differential Diagnosis

It is vital to consider other diagnoses before attributing the clinical features to neonatal abstinence syndrome, even if there is a clear history of prenatal drug exposure. In some cases where maternal history is unyielding or unclear, physicians can mistake some signs and symptoms of NAS as a different condition. For example, autonomic instability leading to mottling, sweating, tachypnea, and changes in temperature in NAS can be mistaken for sepsis.[22] Irritability may be due to brain injury or GE reflux. Fever can be secondary to hyperthyroidism or sepsis. Jitteriness may be secondary to hypoglycemia or hypocalcemia. Poor feeding may occur due to oro-motor dysfunction, congenital anomalies, or immaturity. Seizures secondary to withdrawal, even though rare, must be differentiated from CNS infections, Hypoxic-ischemic encephalopathy, and electrolyte disturbances. Myoclonic jerks, often mistaken for seizures in NAS, need to be identified accurately to avoid unnecessary confusion and testing. Besides all these, signs of early adaptation in a healthy neonate secondary to pain, hunger, improper handling, and suboptimal physical environment must also merit consideration.[3] When assessing an infant for NAS, care must be exerted on maternal and neonates characteristics to rule out other causes or rules in NAS's diagnosis. Maternal history like medications use in pregnancy, substance misuse, adequacy of prenatal care, unexplained fetal demise, and psychiatric diagnosis require inclusion. Neonatal birth history, including gestational age, birth weight, presence of a perinatal insult, or other congenital anomalies, must be thoroughly reviewed. When all signs and symptoms are consistent with NAS, and there is a maternal history of drug use/misuse, confirmatory testing in the neonate is the suggested approach to corroborate the diagnosis.

Essential diagnoses to consider in evaluating a patient with NAS include:

• Sepsis
• Birth trauma
• Gastrointestinal reflux
• Hyperthyroidism
• Hypoglycemia
• Hypocalcemia
• Hypoxic-ischemic encephalopathy

Prognosis

Poor long-term outcomes have correlated with infants with prenatal opioid exposure. Research exists about adverse changes in neurodevelopment, cognition, school performance, behavior, vision, and mortality. However, researchers have inferred many of these results from observational studies. The presence of multiple prenatal confounders such as polysubstance exposure, prematurity, intrauterine growth retardation (IUGR), and postnatal confounders like NAS pharmacotherapy, continued maternal drug abuse, maternal socioeconomic and environmental factors, makes it challenging to attribute prenatal opioid exposure as the cause for the poor outcomes.

Studies have consistently shown a significant difference in neurodevelopmental outcomes in opioid-exposed infants versus their counterparts.[48] These findings are consistent from 12 months of age through adolescence, although most data did not show any difference below one year of age. Several evaluation tools like McCarthy Motor Scale, Vineland Social Maturity Scales have consistently identified these differences, but there are conflicting results with Bayley Scales of Infant Development.[49] Visual-motor problems like strabismus and nystagmus, and visual acuity impairment secondary to refractive errors, are common among infants with NAS. Significant cognitive deficits like lower aggregate IQ scores, poor verbal performance, impaired short-term memory, and executive functioning have been found in children more than three years of age who had prenatal opioid exposure compared to controls. School performance deficiencies in NAS children have manifested with low mean academic test scores in every grade and domain, the most significant difference noted in seventh grade. Experiments have sought to understand the mechanism behind poor neurodevelopmental and cognitive outcomes in this population. Preliminary data showed a regional decrease in brain volume, alteration in the maturation of connective neuronal tracks, and relative microcephaly among opioid exposed infants that may underlie the adverse outcomes in NAS infants.

Prenatal opioid exposure has been linked to psycho-behavioral problems, as well. These children are two times more likely to be identified with attention-deficit/hyperactivity disorder, conduct disorders, and adjustment disorders. They are also more likely to be aggressive and have anxiety disorder compared to their controls. Infants with NAS are reportedly at increased risk of rehospitalization during childhood due to maltreatment, trauma, and behavioral problems. The mortality rates have been consistently higher among opioid-exposed infants for many decades and across many developed countries, with rates as high as four times in New York City. These indicate the need for continued support for this highly complex and vulnerable population.

Despite all these findings, a large randomized control trial called MOTHER (Maternal Opioid Treatment: Human Experimental Research) study evaluated the neurodevelopmental and growth outcomes among NAS infants and found conflicting long-term outcomes.[50] The research studied babies prenatally exposed to buprenorphine or methadone and followed them until three years of age at regular intervals to monitor their neurodevelopment using a battery of tests at each visit. The authors found no significant difference in neurodevelopmental and growth outcomes among opioid-exposed infants. They concluded that buprenorphine or methadone exposure did have any harmful effect on physical, mental, and behavioral development in those children. One may argue that the close follow-ups with health professionals may have positively impacted the mother-infant dyad by offering consistent support to the mother, thus resulting in an enriched home environment that allowed the normal development of the infants.[2][12]

Complications

Opioid-exposed babies, more commonly after heroin exposure, are more likely to be born premature, have intrauterine growth restriction and low birth weight. As alluded to earlier, due to the hypermetabolic state combined with difficulties in feeding and increased intestinal losses, these babies are at high risk for growth failure. NAS has been associated with life-threatening complications - seizures, especially in methadone-exposed infants, even though recent evidence shows it's a rare occurrence secondary to withdrawal. Ultimately, NAS babies are at higher risk for death as well.[26][2]

Postoperative and Rehabilitation Care

Following discharge from the hospital, a close follow-up must be arranged with the medical provider to assess for relapse or late onset of NAS symptoms, monitor weight to prevent growth failure, and reinforce caregiver education. Arranging follow-up with subspecialty clinics such as developmental pediatrics, child psychiatry, pediatric ophthalmology, pediatric neurology, occupational therapist, physical therapist, and dietician may be necessary for early identification and management of the long-term problems that commonly present in NAS infants.[51][52][2] It is prudent to refer these infants in early intervention.[53] A plan of safe care for the baby is a must. Not all mothers are equipped to care for their infants in the postnatal period, and US laws require them to be placed in foster care. But whenever possible, the medical provider should develop a good rapport and trusting relationship with the mother by providing non-judgmental and caring support to her. Child welfare services must be engaged only when there is child neglect, abuse, or harm. Adequate support to the mother may include connecting her to a women’s clinic, mental health clinic, substance use disorder clinic, breastfeeding support, social worker referral for adequate home, financial and legal support, and evaluation for violence exposure. Such multi-layered interdisciplinary care is required to maintain the highly vulnerable mother-infant dyad.[3]

Deterrence and Patient Education

The mother or caregiver and the patient's family should receive education on natural history, medical management, complications, and NAS prognosis. Any women of the childbearing age group must be informed about the potentially harmful effects of drug abuse, including NAS. It is a preventable condition if the woman stops drug usage before becoming pregnant or stops the drug usage once pregnant. It may be necessary to enroll the woman in a safe, supervised medical program - MAT if it is not safe to stop the drugs during the pregnancy. Symptoms of NAS can happen within 24 to 48 hours of life or as late as one week after birth. So it is necessary to look out for such symptoms even after discharge from the hospital. Management during hospital stay includes supportive care for the baby, and the mother should be actively involved in their baby's care. Some babies may require medications to relieve discomfort and other problems of withdrawal. Breastfeeding is strongly encouraged as the benefits are immense, and it does not affect the symptoms of NAS. Breastfeeding is a contraindication only if the mother has any medical contraindication. After discharge from the hospital, it is crucial to have close follow-up with medical providers to avoid NAS complications. More information for the patient's family is available at the American Academy of Pediatrics website.

Enhancing Healthcare Team Outcomes

Several authors have called for national public health measures to curtail the opioid epidemic and the hidden public health crisis of neonatal abstinence syndrome. A multi-faceted, interprofessional team approach involving healthcare professionals, researchers, and government officials is required to improve mothers' care with substance use disorder (SUD) and their infants with NAS.[54]

Management of NAS must start from the prenatal period and span across the perinatal period.[2] Medical providers must be responsible while prescribing opioids, especially during pregnancy, screen and treat SUD during pregnancy, including enrolling mothers in MAT and arranging for them to deliver at facilities equipped to care for their infants with NAS. The medical team should include obstetrician-gynecologists, neonatologists, advanced practice providers, and Pediatricians. They must work, coordinate and communicate with nurses, pharmacists, social workers, child welfare services, lactation specialists, home care, OT/PT, and speech therapists, among other paraprofessionals, to improve patient outcomes, patient safety, and enhance patient-centered care and team performance. Specialized neonatal nursing staff can collaborate with all specialties to help the patient understand their condition and care for the newborn child. Pharmacists should closely examine the patient's medication record and vet any new dosing that might manage the condition. Regular education must be provided to team members from all disciplines across the continuum of care to avoid detrimental effects on the mother-infant dyad because of the epidemic.[25][31] [Level 5] THis interprofessional approach to care gives the greatest benefit to both mother and newborn. [Level 5]

NAS assessment requires standardization, and tools must be developed based on strong clinical data instead of psychometrics. Non-pharmacological care must be provided to all infants with NAS, be standardized, and include couplet care across units to promote rooming-in, breastfeeding, and skin-to-skin.[2][47])[38][25] [Level 5] Research must be focused on well-designed RCT of drugs that also includes standardization of non-pharmacological care and also on weaning protocols to guide and make recommendations on pharmacological management of NAS.[2][26] More Research is also necessary for mothers who are not in MAT or who are polydrug users.[22]

State and federal governments need to recognize the growing problem of NAS, which remains a hidden consequence of the opioid epidemic. States must have laws that clearly define what is reportable. The diagnosis and definition of NAS must be standardized to better surveillance and understand the epidemic.[14] [Level 5] States must also have a non-criminalizing approach that will enable women with SUD to come forward for their prenatal care to avoid the detrimental effects on mother-infant dyad and the potential intergenerational drug dependence and epidemic.[39][54] [Level 5]