Pharmacological therapy of neonatal abstinence syndrome

Key points

Neonatal abstinence syndrome (NAS) secondary to maternal use of opioids during pregnancy continues to remain a major problem in neonates.
Nonpharmacological measures are the first-line treatment in the management of NAS.
Morphine remains the most popular medication in the treatment of NAS, although methadone and buprenorphine are also effective.
Adjunct medications (e.g., phenobarbital, clonidine) are not without adverse effects and may be necessary when NAS is not controllable with primary medications.

Neonatal abstinence syndrome (NAS) is a constellation of clinical signs that are a consequence of the abrupt discontinuation of chronic fetal exposure to substances used, misused, or abused by the mother during pregnancy. As the opioid crisis expanded across the United States, the incidence of NAS grew in parallel. The incidence of NAS increased from 1.6 per 1000 in-hospital births in 2004 to 8.8 per 1000 in-hospital births in 2016, increasing by 83% from 2010 to 2017. The incidence differs among countries, regions, and states; within states, counties, and county areas; and between rural and urban areas. In 2016, approximately 31,765 infants with NAS were cared for in hospitals across the United States. The incidence of NAS in the southern United States was nearly twice as high as that in the Northeast or Midwest and almost three times as high as that in the West. Another study showed that 42% of infants with NAS were born in the southern United States in 2016. In 2016, the rate of NAS in West Virginia was the highest for any state (53 per 1000 live births). NAS has become more common in rural counties than in urban counties. Among rural infants, the incidence of NAS increased from 1.2 to 7.5 per 1000 hospital births from 2004 to 2014 and from 1.4 to 4.8 per 1000 hospital births among urban infants. The incidence of NAS was higher in areas with higher long-term unemployment and greater shortages of mental health clinicians. Regional variations in the incidence of NAS have led to a disproportionate burden in highly affected areas within the country.

The incidence of opioid use disorder (OUD) in pregnancy increased from 3.5 to 8.2 per 1000 delivery hospitalizations in the United States between 2010 and 2017. In a study of 10,741 mothers with OUD, 58% of infants developed NAS. In a study of 8059 mothers that was conducted from 2012 to 2018, 41% of infants exposed to opioids in utero required neonatal intensive care unit (NICU) admission, compared to 14% of infants not exposed to opioids. The prevalence of polysubstance use increased from 60.5% in 2007 to 64.1% in 2017. It has increased more rapidly in rural areas than in urban areas in recent years. Polysubstance use is associated with more severe and increased incidence of withdrawal in infants born to mothers with OUD. Medication use for OUD during pregnancy is associated with decreased fetal death, preterm birth, growth restriction, and reduced maternal overdose. ^, It has been reported that, for each week of medication for OUD during pregnancy, the odds of preterm births decreased by 1%, the odds of overdose decreased by 2%, and the odds of NAS increased by 41%. The COVID-19 pandemic has worsened the opioid problem among pregnant women due to social distancing, “stay-home” limitations, and lack of access to resources, among other pandemic-related issues.

NAS is more common among Caucasians and in the population using Medicaid. In a study of 32,128 pediatric NAS admissions in 4200 hospitals across the United States in 2016, 80% were Caucasians and 84% were on Medicaid. . The majority of infants were born in low-income ZIP Code areas. Opioid-exposed infants had lower birth weights, shorter birth lengths, smaller head circumferences, and lower gestational ages than unexposed infants. Male gender, maternal smoking, and high methadone doses are other risk factors for NAS. NAS is less common and less severe in preterm infants compared to term infants. The signs of withdrawal are usually seen within 2 to 3 days of birth. The risk of NAS also depends on the dose, duration, and timing of the prenatal opioid exposure. The average length of hospital stay (LOS) for pharmacological treatment is 16 to 18 days. There is a higher chance of readmission among infants with NAS after discharge from the hospital, and 9.1% of NAS infants compared to 6.2% of non-NAS infants needed readmission within a year of discharge in a study of 10,087 readmissions. Similar observations were reported in another study of 3842 infants with NAS. The pathophysiology and clinical presentation of these infants were described in the previous edition of this text.

Terminology

The National Institutes of Health uses the term neonatal opioid withdrawal syndrome (NOWS) because NAS is often a result of opioid use during pregnancy by the mother. However, the term NOWS is restricted to opioid withdrawal and excludes other illegal substances such as amphetamines, cocaine, and marijuana, as well as medications such as selective serotonin reuptake inhibitors, benzodiazepines, or tricyclic antidepressants, which can also cause withdrawal in infants. In addition, the use of combinations of opioids and nonopioids, prescribed and unprescribed drugs, or legal and illicit substances has become common. In a study of 659 cases of NAS, one-third of the infants did not have evidence of exposure to opioids. In a recent observation from Japan, 54% of infants born to mothers on oral psychotropic or anticonvulsant drugs during pregnancy developed withdrawal symptoms (32.4% of those born to mothers taking a single drug and 62.9% of those born to mothers taking two or more drugs). There have been instances where the term NOWS has been used for opioid-exposed infants, and the term NAS has been used for polysubstance-exposed infants. Inconsistent terminology may further complicate this complex problem. We believe the term NAS is more encompassing, and NOWS is more limiting. Hence, NAS is used in this chapter.

Problems in the management of NAS

The major problems hindering progress in NAS management are related to the limited ability to diagnose, assess severity, include nonpharmacological measures, and apply evidence-based guidelines for pharmacological treatment.

Clinical definition

Every disease requires a simple, reliable, and acceptable diagnosis. A definitive diagnosis is necessary for proper clinical management, future research, public health surveillance, and implementation of control measures. Moreover, a standardized case definition can contribute to a better understanding of the exact incidence of disease, disease spectrum, disease burden, and effects of individual substance exposure. Currently, the diagnosis of NAS is clinical, with most reports being based on clinical diagnosis by physicians. Most of the scientific literature is based on the International Classification of Diseases (ICD) codes. The diagnosis differs among providers and hospitals, and this may cause underreporting or overreporting. Opioid exposure does not imply opioid withdrawal. States across the United States use a variety of different definitions. Some states require toxicology confirmation, clinical withdrawal signs, Finnegan scores, and/or >2 days of hospitalization. . The Council of State and Territorial Epidemiologists published a position statement in 2019 recommending standardized surveillance definitions for use across the United States. . However, the definition was soon found to have issues with its applicability. In a retrospective analysis of 863 cases of confirmed NAS identified by ICD codes, 66% received pharmacotherapy, 23% did not require pharmacotherapy, and 9% did not meet the criteria for NAS. In January 2022, the U.S. Department of Health and Human Services announced criteria for the clinical definition of NAS that include (1) in utero exposure to opioids with or without other psychotropic substances (recommended to be collected via confidential maternal self-report; toxicology testing also acceptable with maternal informed consent), and (2) two of the five signs: excessive crying, fragmented sleep, tremors (disturbed or undisturbed), hypertonia, and gastrointestinal disturbances. This definition may improve diagnosis, but it requires clarification regarding timing, mothers’ refusal of toxicological screening, and definitions for some of the clinical signs.

Clinical assessment

A fundamental problem in the management of NAS is the lack of an ideal instrument to assess the severity of withdrawal in infants. The Modified Finnegan Neonatal Abstinence Scoring Tool (M-FNAST) is the most commonly used scoring system for NAS assessment. However, the M-FNAST is complex and lengthy, and the items included in the M-FNAST are based on subjective criteria, with arbitrary item weighting. ^, In addition, it lacks precise definitions for some items and includes some signs unrelated to NAS severity. Several other scoring systems have been proposed, but many have not achieved widespread adoption for several reasons, including uncertainty about their reliability, validity, and utility. ^, Scoring systems that shortened or simplified the M-FNAST were mostly statistical models and were never used in clinical settings. ^, In addition, different studies used different criteria for initiating pharmacotherapy, further complicating the management of NAS. ^, Grossman et al. included the infant’s ability to successfully breastfeed, sleep, and be consoled in their Eat, Sleep, and Console (ESC) system. However, such an assessment does not quantify withdrawal, lacks objectivity, and may not be appropriate for all infants with NAS. In addition, the ESC system did not change the length of hospitalization or treatment (LOT) when nonpharmacological measures were not included. Clinicians have been looking for a better system for the assessment of NAS in infants. Hence, we have proposed a new scoring system, NAS SCORES, a 10-item, user-friendly scale instrument. NAS SCORES is a physiology-based assessment of withdrawal, with equal emphasis on the infant’s central nervous system, autonomic nervous system, and neurobehavior. A prospective randomized study to determine the benefits of NAS SCORES in managing infants with NAS is still needed.

Management of NAS

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