Managing newborns at risk for neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS): Updates and emerging best practices

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Introduction

The Canadian Institute for Health Information (Quebec excluded) reported, from 2010 to 2020, an increase in newborns diagnosed with neonatal abstinence syndrome (NAS) from 3.5 to 6.3 per 1000 live births^[1]. Many of these cases are attributed to opioid exposure and result in neonatal opioid withdrawal syndrome (NOWS)^[2]. Reports indicate that while observation for withdrawal symptoms is increasing, NAS/NOWS cases are still under-reported in Canada^[3]. The costs of hospitalization speak to the significant burden this problem places on the health of infants and families, along with hospital units, health care providers, and other community resources^[4].

The most recognized effects of fetal exposure to opioids are the short-term complications, with NAS/NOWS predominating. NAS/NOWS symptoms can affect a newborn’s central nervous, gastrointestinal, respiratory, and musculoskeletal systems^[5]. Long-term outcomes are difficult to predict due to multiple, interrelated risk factors that are known to impact developmental outcomes^[6][7] and the paucity of quality research on long-term follow-up for these infants and their families.

Opioids are the most common class of drug inducing a withdrawal state in the newborn for which management strategies need to be addressed. In this statement, unless otherwise specified, “withdrawal” refers to withdrawal from opioids. The ‘Eat Sleep Console’ (ESC) assessment and non-pharmacological strategies presented here can be used to support withdrawal from other substances. This statement updates a previous Canadian Paediatric Society practice point from 2018^[8].

Optimal engagement in prenatal care and screening

For women/persons with a substance-exposed pregnancy (SEP), the pregnancy period may present unique opportunities to engage in health (and self-) care which can positively influence health outcomes for themselves and their fetus^[9]-[12]. Culturally sensitive, trauma-informed prenatal care is essential for supporting those with a SEP^[12]. This approach can help foster disclosure of substance use, if previously undisclosed, leading to earlier supportive care and management. For those with a SEP, there can be frequent intersections with negative social determinants of health. Stigma, racism, sexism, poverty, gender inequities, exposure to gender-based or intimate partner violence, housing or food insecurity, and trauma are experiences that can either discredit or discourage health care-seeking (or both). In Canada, such factors may further compound historic and ongoing effects of colonization and Indigenous-specific racism in health care, which are serious barriers to accessing care^[12]-[14]. As early as possible, and in addition to routine prenatal screening and social history, a health care provider (HCP) should obtain a comprehensive determinants history.

A further barrier to seeking timely prenatal care for those with a SEP is the history and persistent fear of triggering a ‘birth alert’, where a representative from a child welfare agency notifies the hospital of a pending birth for intervention at or shortly after delivery^[14]-[16]. Birth alerts have been abolished in many regions of Canada, and there is no duty to report for a fetus. HCPs are required to stay informed of child welfare practices in their area.

As part of the focused history, enquire non-judgmentally but specifically about consumption of any prescribed or over-the-counter medication(s), unregulated substances (including complementary and alternative medicines), alcohol, marijuana, and nicotine use. Counsel and support informed decision-making moving forward using a harm reduction approach. Communicate that risk for infections such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) increases with certain modes of consumption, specifically inhalation and injection.

Comprehensive health care services can have ’treatment as prevention’ effects on newborns by helping to disrupt intergenerational effects of substance use^[11]. Disruption may, in turn, reduce the risk of an affected newborn going on to misuse substances in later life^[11]. Collaborating and consulting for individualized care with perinatology, paediatrics, and neonatology as required is recommended.

For individuals with a SEP and a known opioid use disorder (OUD), initiating or continued support of opioid agonist therapy (OAT) is recommended^[17]-[21]. OAT during pregnancy reduces the risk of overdose and use of unregulated substances overall, decreases infectious morbidity, and improves prenatal care and obstetric/neonatal outcomes^[20]-[23]. Buprenorphine may be associated with less NAS compared with methadone. One study found that the diagnosis of NAS was 69.2% in those receiving methadone and 52% in those receiving buprenorphine 30 days before delivery^[20]. 

Newborn clinical presentation and assessment

Newborn presentation of NAS/NOWS varies considerably depending on substance(s) and exposures in utero, frequency of consumption, dose, timing, adult metabolism, and gestational age (GA) at time of birth. Symptoms include a constellation of neurologic, gastrointestinal, respiratory, and musculoskeletal disturbances shown in Table 1^{[22][24]-[27]}. Times of presentation vary based on the half-life of individual drugs, with typical onset of NAS/NOWS symptoms shown in Table 2^{[22][24]-[27]}.

Preterm infants are at lower risk for NAS/NOWS and their symptoms may not be as apparent^[28][29]. The shorter duration of exposure, decreased placental transmission, inability of the immature kidneys and liver to fully metabolize, and minimal fat stores lead to lower opioid deposition and activity, with a limited capacity to express NAS/NOWS symptoms by the immature brain^[29].

Within the literature, reported rates of newborns who go on to require pharmacological treatment is broad: from 50% to 80%^[30][31]. One outlier, a Canadian centre, reported pharmacological therapy as low as 3.5% of newborns (n=57) when rooming-in became the model of care compared with 83.3% (n=24) for those admitted to a neonatal intensive care unit (NICU)^[32]. Length of stay in hospital declined from 24 to 5 days on average, highlighting the importance of rooming-in^[32].

Neonatal conditions such as hypoglycemia, hypocalcemia, central nervous system injury, hyperthyroidism, and sepsis or other infections, may present with similar symptoms to NAS/NOWS and need to be considered as part of any differential diagnosis. See this CPS statement on Reducing perinatal infection risk in newborns of mothers who received inadequate prenatal care^[33] for additional resources.

Table 1. Signs and symptoms of Neonatal abstinence syndrome (NAS)/Neonatal opioid withdrawal syndrome (NOWS)

Characteristics*

W – wakefulness

I – irritability, tone and Moro reflex increased, inability to console, inability to coordinate oral feeding

T – tremors (jittery), temperature instability or fever, tachypnea

H – hyperactivity, high-pitched or excessive crying, hiccups, hypersensitivity to sounds, hyperreflexia (including yawning)

D – diaphoresis, disorganized suck, diarrhea (explosive), disturbed sleep, disruptive feeding behaviours (including excessive non-nutritive sucking and decreased oral intake)

R – respiratory distress, runny nose, regurgitation, rub marks (excoriation), rejecting feeds

A – apnea, autonomic dysfunction (heart and respiratory rate)

W – weight loss resulting in increased caloric demands

A – alkalosis (respiratory)

L – lethargy and lacrimation (eye-tearing)

S – snuffles, sneezing, seizures

Reproduced from references^{[22][24]-[27]}
*Note: May include any or all of the above. Most signs become apparent 48 to 72 hours post-delivery and they can persist for weeks (from 10 to 30 days). Irritability, sleep disturbances, feeding difficulties may persist for 4 to 6 months.

Table 2. Onset of Neonatal abstinence syndrome (NAS)/Neonatal opioid withdrawal syndrome (NOWS) signs and symptoms based on pharmacological agent
Agent	Time since delivery*
Methadone	24 to 72 hours
Buprenorphine	24 to 72 hours
Heroin	24 hours
Fentanyl	24 hours
Benzodiazepines	Hours to weeks depending on agent

Reproduced from references^{[22][24]-[27]}
*Note: The time frame can vary significantly and be influenced by the presence of polysubstance use. Benzodiazepines are included due to the contaminates found in the unregulated drug supply.

Assess newborns born of a SEP for any symptom(s) of withdrawal to determine whether additional monitoring, nursing care, medical, or pharmacological treatment is required^[34]. Newborns should be assessed during a natural wake cycle and not be disturbed during sleep or feeding. 

A widely used assessment tool is the Finnegan score, which identifies behaviours associated with withdrawal^[35]. An initial Finnegan score is obtained within the first 1 to 2 hours post-delivery, then re-checked every 3 to 4 hours thereafter, in conjunction with HCP assessments and in coordination with newborn sleep/wake cycles.

The ‘Eat Sleep Console’ (ESC) model of care is an emerging, evidence-based alternative to Finnegan scoring^[36][37]. ESC is a family-centred, functional assessment of the newborn’s ability to eat, sleep, and be consoled, with focus on keeping dyads together as the primary intervention^[35]. ESC has been shown to decrease hospital length of stay (from 15 to 8 days) and need for pharmacological treatment, without increasing adverse events or readmissions significantly^[38][39]. Based on these benefits, centres are increasingly transitioning from Finnegan scoring to ESC.

Using either tool, a series of accurate, consistent symptom assessments are needed to ensure that both the newborn and their family receive appropriate care^[40]. Assessments should be conducted for a minimum of 72 hours and continue up to 120 hours with exposure to a longer-acting opioid^[27], and throughout the initiation, duration, and discontinuation of pharmacological treatment, if prescribed^[40]. A variety of resources, instructional videos, online self-directed modules, and “train-the-trainer” approaches are now available to educate the HCP team on accurate, consistent assessment of NAS/NOWS^[41][42]. A recommended example is Perinatal Substance Use.

Management

Several factors influence outcomes: accuracy of assessment, dyad togetherness, whether newborn-led care is practiced, how symptoms are managed, the physical care environment, and HCP knowledge and experience. Multidisciplinary involvement (e.g., by nursing, neonatal medicine, paediatrics, social work, pharmacy, nutrition, and community supportive services) is optimal for managing symptom and appropriate discharge^[43]. Treatment goals include preventing complications associated with NAS/NOWS and restoring normal newborn activities such as sleep, feeding sufficient for growth and weight gain, and environmental adaptation.

Dyad separation is detrimental to early attachment and bonding. The literature supports keeping mothers/birthing parents who are opioid-dependent with their newborn(s) from birth, with practices such as rooming-in ^[44]-[48]. Additional benefits are lower NICU admissions, higher breast/chest or human milk feeding initiation rates, less need for pharmacotherapy, and shorter hospital stays^[44]-[48]. A rooming-in model should be prioritized whenever newborns are term or late preterm, medically stable, the mother/birthing parent is able to be the primary caregiver, and resources are in place to support both the family and HCPs^[48].

Non-pharmacological interventions

Initial management is primarily supportive because medical interventions can prolong hospitalization, disrupt dyad togetherness, or subject a newborn to medications that may not be necessary. Non-pharmacological interventions have been shown to reduce the effects of withdrawal and should be implemented at delivery^[3][48]. Examples include skin-to-skin care, newborn-led care, safe swaddling, gentle waking, quiet environment, minimal stimulation, lower lighting, and developmental positioning^[24][48][49].

Direct breast/chest and expressed human milk feeding should be encouraged because it can delay onset and decrease severity of withdrawal symptoms and reduce the need for pharmacological treatment^[50][51]. Birthing parents who are HIV-negative, established on OAT, and not consuming unregulated substances should be supported to breast/chestfeed if they so choose^[17]. Breast/chestfeeding provides optimal nutrition, promotes attachment, and facilitates parenting confidence and competence. Birthing parents who have had a SEP may require extra support because they are less likely to initiate breast/chest or expressed human milk feeding and more likely to stop early ^[48][52][53]. Newborns with poor weight gain from disruptive (or disrupted) feeding may benefit from supplementation to increase caloric intake or total fluid intake^[54].

Pharmacological interventions

Newborns whose withdrawal symptoms persist despite optimizing non-pharmacological care, or those who are unable to eat, maintain sleep, or be consoled are likely to require pharmacological intervention^[42]. When pharmacological treatment is initiated, it is common practice to admit the newborn, and ideally the dyad, to a unit for cardiorespiratory monitoring and observation, or for higher level care when the newborn is medically unstable. One Canadian centre has successfully established oral morphine initiation on a postpartum unit in an unmonitored setting without adverse outcomes^[55][56]. If separation occurs, a newborn should be transferred back to rooming-in as soon as medically appropriate^[46][48]. While several pharmacological agents have been used to treat NOWS, there is insufficient evidence from clinical trials to establish optimal therapy (Table 3)^{[27][42][57]-[64]}.

A 2021 Cochrane review evaluating pharmacological treatments found that use of an opioid was associated with reduced treatment failure compared with phenobarbital, diazepam, or chlorpromazine^[65]. Morphine and methadone remain the most common first-line medications^[66] and appear to be similarly safe and effective. Morphine and methadone had similar rates of treatment failure, initiation of breast/chest or expressed human milk feeding, adverse events, and out-of-home placement^[65]. A few studies have reported shorter hospital length of stay with methadone compared with morphine^[67]-[70].

Non-opioid sedatives can be added as adjunct agents to opioids when NOWS symptoms are not adequately controlled using a single agent. Phenobarbital and clonidine are the most prescribed, but there is insufficient evidence to guide which is preferable. In one retrospective cohort study, length of hospital stay and duration of morphine treatment were shorter for infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Newborns were more likely to be discharged from the hospital on phenobarbital than clonidine^[71]. A 2021 Cochrane review found no difference in treatment failure in newborns receiving phenobarbital versus clonidine as adjunctive agents to opioids (two studies). Also, there was no difference in adverse events between the two sedatives, but this finding was based on very low certainty evidence^[72]. The long-term neurodevelopmental effects of phenobarbital exposure remain largely unknown.

Phenobarbital may be the preferred adjunctive agent for NAS from polysubstance exposure including sedatives and hypnotics (i.e., benzodiazepines). The 2021 Cochrane review compared phenobarbital to diazepam for newborns exposed to opioids and other substances and found a lower treatment failure rate with phenobarbital^[72]. While limited, case reports and case series of neonatal benzodiazepine withdrawal describe successful treatment of symptoms using phenobarbital^[73].

Where opioid exposure has occurred prenatally or at time of delivery, or for the treatment of NOWS, naloxone should not be administered to a newborn with NAS/NOWS because it can exacerbate the underlying withdrawal syndrome, including development of seizures^[24][74].

Table 3. Pharmacological treatment of NAS/NOWS
Medication	Mechanism of action	Dose	Comments
Morphine	Mu receptor agonist	0.03 to 0.05 mg/kg/dose every 3 to 4 h, orally Increase by 0.03 to 0.05 mg/kg/dose as needed [58] Weans are variable and patient-specific: Decrease by 10% to 20% every 24 to 48 h as tolerated	Half-life [57]: Preterm infants: 9 h Term infants: 6.5 h Most used as first-line treatment. Practice varies. Dose listed is a general initial range. Sample protocol [42]
Methadone	Mu receptor agonist; N-methyl-D-aspartate receptor antagonist	0.05 to 0.1 mg/kg/dose every 6 to 12 h, orally Increase by 0.05 mg/kg every 24 to 48 h Wean: Decrease by 10% to 20% every 24 to 48 h as tolerated	Half-life [59]-[61]: 14 to 44 h Used in many countries as a first-line treatment when mother/birthing parent is on methadone. Symptom triggered dosing (PRN) using ESC can be considered.
Phenobarbital	Gamma aminobutyric acid (GABA) receptor agonist	Loading dose (optional): 10 to 20 mg/kg, orally Maintenance dose: 5 mg/kg/day, orally daily in one or two divided doses Wean: Decrease by 10% to 20% every 24 to 48 h when symptoms are controlled	Half-life [62][63]: Preterm: 140 h Term: 100 h Decreases with age: 67 h at 4 weeks of life. May be used in conjunction with opioids, especially in poly-substance use and in cases involving benzodiazepines.
Clonidine	Alpha-2 adrenergic receptor agonist	0.5 to 1 mcg/kg/dose every 4 to 6 h, orally Limited data indicate maintenance dose may be titrated up to 2 mcg/kg/dose every 4 h Wean: Decrease by 25% of the total daily dose every other day (every 4 h to 6 h × 48 h, to every 8 h × 48 h, to every 12 h × 48 h at bedtime, then discontinue)	Half-life [64]: 17 h Option in conjunction with opioids, especially when autonomic symptoms of NAS are present. Abrupt discontinuation may cause rapid rise in blood pressure and heart rate. Gradual weaning is recommended.

Note: It is recommended that organizations develop and follow standardized protocols to manage NAS, including pharmacological treatment and dosing^[27][42].
ESC Eat Sleep Console; h Hours, HS Bedtime, Neonatal abstinence syndrome (NAS), Neonatal opioid withdrawal syndrome (NOWS), PRN As required

Discharge considerations

The key to successful transition to community is to ensure continuity of care, with advanced planning for when discharge criteria are met. Length of stay in hospital varies depending on prenatal substance exposure(s), the severity of withdrawal symptoms, whether pharmacological treatment was required, and social factors^[75][76]. When pharmacotherapy is not required within 72 hours for short- to 120 hours for long-acting opioids, the newborn is eligible for discharge^[28][77]. Individualized discharge planning should include appropriate referral to a primary HCP familiar with the management of NAS/NOWS, local family- or caregiver-supportive resources, and infant neurodevelopmental assessment. Communicating with the newborn’s family and primary HCP about discharge planning and follow-up is essential^[47][78]. Community referrals should be culturally appropriate and may include ongoing substance use treatment programs, public health child services (e.g., early years programs), a community support worker, infant development programs, and parent support groups^[8].

Recently, some practitioners have opted to discharge newborns receiving pharmacological treatment to community, where they continue to wean. One small Canadian study^[79] compared weaning off morphine in hospital versus community for two groups with similar opioid exposure in pregnancy and baseline characteristics. Weaning in community (32 days in community versus 19 days in hospital) was associated with fewer return visits to hospital to manage NAS/NOWS (2% versus 14%). Also, discharge to community with a weaning strategy was found to save an estimated $11,000 per newborn. A Canadian systematic review^[80] examined weaning in community, the benefits of which included a shorter length of stay (ranging between 7.9 to 18.9 days compared with 15.7 to 39.6 days in hospital). With appropriate supports, an in-community approach has led to successful transitioning without increasing adverse events at home or readmissions to hospital. Increased rates of breast/chestfeeding or expressed human milk feeding were also observed when newborns were weaned from pharmacotherapy in-community^[81]. In-hospital HCPs must make sure that a newborn can tolerate pharmacological tapering before discharge, and provide a medication access and weaning plan for the community HCP and family to follow at home.

Recommendations

1. Prospective birthing parents with a substance-exposed pregnancy (SEP) should be engaged early for prenatal care using culturally safer, trauma-informed approaches. Take a history of determinants and ask non-judgmental questions about the nature and extent of substance use. Explain to birthing parents that their role as observers of neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) signs and symptoms following birth is a crucial one, and integral to their newborn’s care. Collaborating and consulting for individualized care with perinatology, paediatrics, and neonatology are recommended.

2. Strategies that support dyad care, rooming-in, and human milk feeding are essential. Prioritizing and optimizing non-pharmacological interventions, and providing pharmacological treatment when indicated, are key components of a comprehensive plan. Establishing trauma-informed, culturally safer guidance for dyad care in-hospital and management of NAS/NOWS symptoms are recommended.

3. All newborns at risk for developing NAS/NOWS should be assessed accurately and consistently at time of delivery and for at least 72 to 120 hours post-birth, depending on substance exposure(s) and symptoms. Using the ‘Eat Sleep Console’ (ESC) tool is recommended.

4. Coordinating discharge, consultation, and follow-up care should start at or even before admission. Focus on the family, involving interprofessional health care providers, optimizing non-pharmacological care, and a planned medication and weaning schedule when required, are essential steps for a successful transition to community and maintaining continuity of care.

5. Longitudinal follow-up and research are recommended for newborns born to a SEP to further inform evidence-based best practices.

Acknowledgements

The authors wish to acknowledge and thank Dr. Thierry Lacaze-Masmonteil and Pat O’Flaherty for their 2018 practice point titled ‘Managing infants born to mother who have used opioids during pregnancy’, the wellspring for this statement, which was reviewed by the Community Paediatrics and First Nations, Inuit and Métis Health Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE (2023-2024)

Members: Michael Narvey MD (Chair), Heidi Budden MD (Board Representative), Souvik Mitra MD MSC, Eugene Ng MD, Gabriel Altit MD, Nicole Radziminski MD, Anne-Sophie Gervais MD (Resident Member)
Liaisons: William Ehman (College of Family Physicians of Canada), Chantal Nelson (Public Health Agency of Canada), Eric Eichenwald (American Academy of Pediatrics, Committee on Fetus & Newborn), Douglas Wilson (The Society of Obstetricians and Gynaecologists of Canada), Isabelle Milette (Canadian Association of Neonatal Nurses), Emer Finan MBBCH (CPS Neonatal-Perinatal Medicine Section)
Authors: Michael Narvey MD, Danica Hamilton RN MN MBA, Vanessa Paquette BSc(Pharm) ACPR PharmD

Funding
There is no funding to declare.

Potential Conflict of Interest
The authors have indicated they have no conflicts of interest.

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.