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Neonatal Abstinence Syndrome

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Neonatal Abstinence Syndrome

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Dariki Campbell

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SEMIN PERINATOL 49 (2025) 152019

Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Introduction

In the last 20 years, there has been a considerable shift in the land discuss prenatal treatment of pregnant people with OUD and the coun
scape of neonatal abstinence syndrome (NAS), a collection of with terproductive, punitive approaches that some states have taken.
drawal signs that may be seen in infants after in utero opioid exposure.1 The next three chapters cover the management of infants with NAS.
In 2004 the incidence of NAS was 1.3 per 1000 births, most infants with Dr. Kia Johnson and colleagues compare the two major treatment ap
NAS were managed using the Finnegan Approach and much of the proaches: the Eat, Sleep, Console Approach and the traditional Finnegan
research on NAS was focused on determining the best medication or Approach to care. Dr. Kimberly Spence surveys the non-pharmacologic
combination of medications.2 There was also a lack of consistency in the aspects of care as well as the different pharmacologic choices. Dr.
definition of NAS. Twenty years later, the incidence of NAS has Frances Cheng examines the discharge process, early interventions and
increased at least 6-fold with the highest incidence in West Virginia (63 hospital sequelae related to NAS, with a particular focus on weight loss.
per 1000 births).3 A radical change in management approach was ush In the eighth chapter Dr. Elisha Wachman analyzes the potential
ered in with the Eat, Sleep, Console Approach and focus has now shifted genetic components that inform the symptomatology of NAS. In the
more to non-pharmacologic interventions and supporting the birthing ninth chapter Dr. Lisa Cleveland reviews the experiences of the parents
parent-infant dyad. In 2022, Jilani et al. published a paper attempting to and staff which again highlights the impact of stigma on the parent-
standardize the diagnosis of NAS as prenatal exposure to opioids and the infant dyad. In the final chapter Dr. Hendree Jones looks at the long-
presence of at least 2 major signs of withdrawal – excessive crying, term sequelae of NAS.
fragmented sleep, tremors, increased muscle tone and gastrointestinal I am grateful to Dr. Ian Gross for the opportunity to serve as the guest
dysfunction.4 A new, more specific term, neonatal opioid withdrawal editor for this important issue. I am proud and honored to be associated
syndrome (NOWS) has gained favor as well. Both terms will be used in with the authors of this issue of Seminars in Perinatology and I hope the
this issue. contents provide useful information and arguments for clinicians, sci
The articles in this issue of Seminars in Perinatology highlight the entists, and policymakers.
insights of experts with substantial input into the field and thought-
provoking viewpoints. This issue aims to provide clinicians with a
deeper understanding of both the clinical management of infants with References
NAS and the challenges faced by families. The issue begins with a
chapter by Dr. Prabhakar Kocherlakota providing an overview of the 1. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134:e547–e561.
2. Winkelman TNA, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW. Incidence
history of NAS starting with the earliest uses of opioids. The next three
and costs of neonatal abstinence syndrome among infants with medicaid: 2004-2014.
chapters touch on some of the potential negative impacts of how we, as a Pediatrics. 2018;141(4), e20173520.
health care system and society at large, treat pregnant people with 3. Ko JY, Patrick SW, Tong VT, Patel R, Lind JN, Barfield WD. Incidence of neonatal
opioid use disorder. In the second chapter Dr. Sharon Ostfeld-Johns abstinence syndrome - 28 States, 1999–2013. MMWR Morb Mortal Wkly Rep. 2016;65
(31):799–802.
provides a detailed discussion of screening and testing in NAS with 4. Jilani SM, Jones HE, Grossman MR, et al. Standardizing the clinical definition of
particular focus on the disparities in testing and the potential harms of opioid withdrawal in the neonate. J Pediatr. 2022;243:33–39. e1.
some of the current approaches as well as guidance on a thoughtful
approach to testing and screening. In the third chapter Dr. Nichole Nidey Dr. Matthew Grossman
and colleagues describe the impacts of four types of stigma: self, inter Department of Pediatrics, Yale School of Medicine, Yale-New Haven
personal, structural, and policy and their effect on parents of infants Children’s Hospital, United States
with NAS. In the fourth chapter Dr. Mishka Terplan and colleagues E-mail address: [Link]@[Link].

[Link]

Available online 16 December 2024

Downloaded for Anonymous User (n/a) at [Link] [CK] from [Link] by Elsevier on February 27, 2025.
For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved.
SEMIN PERINATOL 49 (2025) 152007

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The history of neonatal abstinence syndrome

Prabhakar Kocherlakota *
Associate Professor of Pediatrics, Division of Neonatology, Department of Pediatrics, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical
College, Valhalla, NY 10595, USA

The history of neonatal abstinence syndrome (NAS) is embedded proliferation of morphine use in the treatment of several medical ail
with several significant changes and challenges from the time of its ments, as well as recreation, led to a high incidence of opioid addiction.
initial discovery. Knowledge of the fascinating history of NAS is essential Another opioid, heroin, was synthesized in 1874, and its commercial
for understanding the basic concepts of diagnosis and management of production commenced in 1898. Heroin was initially regarded as a
NAS. Let us start our exciting journey from the ancient history of opium. wonder drug and was used to treat various ailments, including morphine
addiction. Ultimately, opium was banned in China in 1729, Britain in
Ancient history of opium 1879, and the US in 1905.6 Several more potent natural, synthetic, and
semisynthetic opioids, including codeine (1834), oxycodone (1916),
The history of opium dates to the Sumerian civilization in Meso hydrocodone (1923), Methadone (1937), meperidine (1939), and fen
potamia (modern-day Iraq) from 13,000 BCE to 5000 BCE. The Sume tanyl (1960), were developed and used extensively—alone or in com
rians, who are known for building the “Cradle of Civilization,” called bination with other analgesics—in the 20th and 21st centuries.7 The
opium gil (joy) and the opium poppy, they called hul gil (the joy plant).1 concurrent use of prescription opioids, illicit opioids, stimulants, mari
The Ancient Assyrians, Babylonians, Greeks, Romans, and Egyptians are juana, psychotropic medications, and other substances brought about
also known to have used opium—each for several centuries. An ancient the current opioid epidemic.
people in what is now Switzerland ate poppy seeds in 2500 BCE, and the
ancient Greeks drank poppy juice in 300 BCE.2 The use of opium History of opioid addiction
eventually spread to other regions, with Arab traders introducing opium
to areas as far as India and China during the Dark Ages.3 Between the Opium addiction was recognized as early as 1030 CE. Descriptions of
tenth and thirteenth centuries, opium made its way from Asia to all parts opioid abuse and addiction in sixteenth-century Türkiye, Egypt, Ger
of Europe. Opium smoking probably emerged in the United States with many, and England can be found in various manuscripts. In addition, the
the arrival of Chinese workers spurred by the California gold rush in the use of opium as a painkiller increased significantly during wars. The
middle of the 19th century.1 Franco-Prussian War in Europe and the American Civil War led to
hundreds of thousands of soldiers becoming dependent on morphine or
History of opioids other opioids. Consequently, this dependence was initially called “sol
dier’s disease.”8 Notably, there had been no mention of opioid addiction
Opium was initially used for religious and medicinal purposes and in North America prior to 1860. Thereafter, opioid addiction spread to
later for recreational use. Opium was also used as an analgesic, hypnotic, every corner of the country due to increased availability,
and cough suppressant. The great physicians Hippocrates and Galen are over-the-counter accessibility, increasing prescribing practices among
acknowledged for using opium medicinally.4 Opioids became staples in medical professionals, and the use of increasingly potent opioid prepa
several medications, including elixirs and tonics, and were used as a rations. In the US alone, there were 300,000 persons with opioid use
treatment for alcohol addiction. The opioid morphine was isolated in disorder (OUD) at the beginning of the twentieth century and 750,000
1803, and commercial production commenced in 1827.5 Morphine was by the middle of the century, which increased to 2 million at the start of
introduced as a cough suppressant, pain killer, and medication for the 21st century.9 According to the National Institute of Drug Abuse
treating alcohol and opium addictions. The development of hypodermic Statistics, 3.6 % of the adult US population in 2022 had an OUD.10
needles saw morphine being administered via intravenous injection in Liberal prescription practices led to increased misuse of prescription
addition to its use via oral preparations and inhalation. Eventually, the opioids, and subsequent stricter prescription practices led to increased

* Corresponding author at: Elaine Kaplan NICU, Montefiore St. Luke’s Cornwall Hospital, 70 Dubois Street, Newburgh, NY 12550, USA.
E-mail address: pkocherlaj@[Link].

[Link]
Received 18 October 2024; Received in revised form 10 November 2024; Accepted 16 November 2024
Available online 20 November 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

use of heroin and other illicit substances. State of New York were aware of infants with “congenital narcotic
addiction.”15 Furthermore, 55 physicians requested guidance from the
History of addiction among women Department of Narcotic Control in the State of New York regarding the
management of infants born to heroin addicts in 1921.15 Several re
Ancient literature described Helen of Troy giving some sort of searchers reported an increased incidence of NAS in the US (53 infants)
“opium” preparations to “calm down” her uneasy guests, according to in 1928 and in Germany (50 infants), in 1934.15,21 The first report of an
Homer.1 Early modern history mentioned women began using opium as infant born to a mother with heroin addiction appeared in 1956, though,
early as 1701.11 Medical establishments prescribed opiates for “men heroin addiction was present from early 1900.24 Many more infants
strual problems,” including menstrual cramps, dysmenorrhea, melan were treated, but, not all were reported, and most of the reports were the
choly (depression), headaches, and toothaches.12 The availability of experiences of the individual practitioners. Possible causes may include
numerous opium preparations and the false assumptions regarding the a) opium and heroin had been banned in Europe and the US, b) legal
safety of these opium preparations for women, especially at low doses, repercussions for narcotic prescription abuse across the US, or c) the
led to widespread addiction among women in Europe and America unavailability of heroin due to import restrictions imposed during World
during the eighteenth and nineteenth centuries. In addition, the avail War I and World War II.25 In a review, Cobrinik summarized 204 cases of
ability of opiates over the counter led to increased use of opiates, NAS presented till 1959 and added another 22 from his observation.26
especially among middle- and high-class women, celebrities, and sex There were other publications, including reports of 56 infants in 1963,
workers. Until 1892, there was the assumption that opium use was 23 in 1967, 38 in 1969, and 384 in 1971.27-30 Vancouver General Hos
associated with decreased sexual desire, cessation of menstruation, and pital in British Columbia, Canada, reported a six-fold increase in NAS
inability to conceive.13 However, Happel presented detailed medical babies in 20 years.31 New York Medical College, then located in New
histories of 11 pregnant persons with OUD and proved that morphine York City, US, reported a rise in NAS from 1 in 164 babies in 1960 to 1 in
use in women does not affect menstruation, reproduction, or child 27 in 1972.30 Neonatal mortality used to be four times more common for
bearing.13 There were several reports from across Europe and the US infants born to pregnant persons with heroin addiction compared to the
that 60 % to 80 % of people with a substance use disorder were female. general population.18 However, the use of methadone as a maintenance
Furthermore, most of these women were of reproductive age (14–40). treatment of opioid addiction during pregnancy decreased intrauterine
Reports on Michigan (1878), Illinois (1880), and Iowa (1885)—states in deaths and prematurity and prolonged the pregnancy but increased the
the US—put the female proportion of the populations of individuals with incidence of NAS. National studies conducted in the US observed an
a substance use disorder at 61 %, 72 %, and 63 %, respectively.14 In increased incidence of NAS from 0.4 per 1000 live births in 1995 to 1.2
1921, there were 800 pregnant persons with OUD registered in the city in 2000, 3.9 in 2009, 6.0 in 2012, and 8.8 per 1000 live births in
of New York.15 In a 1958 study conducted at a hospital in New York City, 2016.32-34
one in every 149 mothers delivered was a person with OUD, and 22 % of
these patients signed out of the hospital against medical advice.16 In History of terminology of NAS
1961, there were 46,798 narcotic addicts, of which 8973 (19 %) were
females. Among them, 89 % were under 40 years of age, with the ma It was initially thought that maternal use of opium or morphine does
jority between 21 and 30 years old.17 Acute detoxification was never an not cross the placenta and does affect infants born to pregnant persons
option during pregnancy then and now. Methadone treatment programs, with opioid addiction. However, when babies born to mothers with
initiated in 1960, decreased intrauterine deaths, premature births, and opioid addiction were symptomatic—first observed in 1875—the term
prolonged pregnancy among women with opioid addiction.18 There was congenital morphism was used to describe the condition.35 With the
a blurring of the distinction between the medicinal and recreational use advent of heroin, codeine, and other opioids, a growing number of
of opium among the population; this led to the current opioid epidemic. pregnant women became addicted to opioids. As babies who were born
Women are more likely to use prescription opioids and often progress to mothers addicted to opioids were symptomatic—and the mothers
from substance use to substance dependence. were using different opioids—the term was changed to congenital
neonatal narcotic addiction syndrome.36 When it was observed that the
History of opioid overdose in children signs and symptoms in these infants were somewhat similar to those of
opioid withdrawal in adults, the term was changed to neonatal narcotic
Opium overdose in children was reported in Great Britain during the withdrawal syndrome in 1940–1950.37 As various substances other than
18th and 19th centuries. Opium was used as a cough suppressant and to narcotics came to be associated with withdrawal, the terminology
calm crying infants. Various baby-calming liquids containing opium, changed to neonatal abstinence syndrome in 1975.38 From 2015 to 2016,
such as Godfrey’s Cordial and Mrs. Winslow’s Soothing Syrup, were federal agencies began using the term neonatal opioid withdrawal syn
extensively popular in Europe and America during the Victorian drome (NOWS) to describe the withdrawal experienced by neonates born
period.19 Working-class mothers used to give such liquids to keep their to mothers with an opioid use addiction.39 Because NOWS excludes
babies calm. “Paregoric by the bottle/Emptied down the throttle” was an withdrawal from other substances such as amphetamines and cocaine,
old but true ballad. Accidental lethal poisoning was not uncommon with as well as medications such as selective serotonin reuptake inhibitors,
such practice. Infant doping, common in the early 19th century, benzodiazepines, and tricyclic antidepressants, many experts use the
decreased after the Infant Life Protection Act of 1872 and compulsory latter terminologies interchangeably.40
birth-death registration in Great Britain and other countries.20
History of assessment of NAS: (Fig. 1)
History of NAS in infants
In 1975, Lorretta Finnegan (Fig. 2) presented a detailed report on the
The first reported case of an infant born to a mother with OUD signs and symptoms associated with neonatal opioid withdrawal sec
occurred in 1875 in Germany.21 Though opioid addiction was prevalent ondary to opioids in term neonates.38 The Finnegan Neonatal Absti
in society, there were no significant reports till 1892, when Happel from nence Scoring Tool (FNAST), informally known as the “Finnegan score,”
Tennessee in the US reported the birth of 12 infants to mothers with was the first instrument proposed for diagnosing and assessing the
OUD, and none of the infants survived.22 Pettey, in 1912, reported 20 severity of opioid withdrawal in neonates. The Finnegan score had
infants born to 4 mothers, including one mother who lost 15 of 16 in become a significant turning point in the management of NAS. The
fants, and the last one had an uneventful recovery.23 In a study con National Institute of Drug Abuse modified various items in the Finnegan
ducted in 1921, it was found that 10 % of practicing physicians in the score into 21 items in 4 subcategories.41 Lipsitz and Ostrea produced

Fig. 1. History of Neonatal Abstinence Syndrome (NAS) assessment. Names of researchers (year of publication) and the assessment details: ESC: Eat, Sleep, Console;
FNAST: Finnegan Neonatal abstinence screening tool; IRR: Inter-Rater Reliability; ICC: Intraclass correlation coefficient; MOTHER: Maternal Opioid Treatment:
Human Experimental Research; NAS: Neonatal Abstinence Syndrome; NDWSS: Neonatal Drug withdrawal Screening Score; NIDA: National Institute of Drug Abuse;
NNWI: Neonatal Narcotic Withdrawal Index; NWI: Neonatal Withdrawal Inventory; NWS: Narcotic Withdrawal Score; RCT: Randomized Control Trial.

different scoring systems almost simultaneously.42,43 However, the Maguire, and Gomez.47-49 Grossman et al. introduced a different
modified Finnegan score is the most used assessment system for NAS in approach to assessing and managing NAS in 2018.50 Grossman et al.
the US.44 Green and Zehorodony devised different scoring systems included only three functional items: able to feed 1 oz of feed, sleep for 1
without much success.45,46 The Finnegan scores were modified, hour, and console the baby within 10 min, that is, eat, sleep, and console
simplified, and shortened by multiple researchers, including Jones, (ESC). In a recent multicenter randomized controlled trial (RCT), the

severity with uniform grading and guidance for the treatment.52 NAS
SCORES is the first prospectively evaluated scoring system. NAS
SCORES is comparable to the Finnegan score, less complicated, and
more nursing friendly. (Fig. 2). The AAP has no recommendation
regarding which tool is ideal or beneficial for treating NAS.

History of treatment of NAS

The first report of Congenital morphinism appeared in 1875. For 30

years, there was no report of survival of infants. The first report of
survival of a newborn with morphine treatment was made in 1903.53
Survival gradually improved with treatment with morphine. In a study
of 204 cases of infants, 90 % of infants treated with morphine medica
tion survived, compared to only 16 % who were not treated.26 In another
study published in 1956, Goodfriend observed a mortality rate of 34 %
in the treated group compared to 93 % in the untreated group.24 In
another study of 93 patients conducted from 1947 to 1962, Hill and
Desmond observed that 86 % of the babies in the study sample were
symptomatic, 71 % required treatment, and the mortality rate was 9
%.27 Rosenthal observed that 61 % of 102 live births born to mothers
with opioid addiction were symptomatic infants, with 74 % of these
symptomatic infants requiring treatment and a mortality rate of 2.1 %.36
The mortality rate decreased from 100 % in 1892 to 34 % in 1959 to 9 %
in 1963 and 2.1 % in 1964.13,26,36 Survival further improved due to
maternal treatment and care of infants with management of infants with
NAS in NICU. Zelson (1971), in their ten-year observation period from
1960 to 1969, observed that 67 % of 384 infants were symptomatic, and
46 % required treatment.30 Cobrinik 1959 observed that 41 % of infants
had mild withdrawal, and no treatment was needed.26 Non
pharmacological measures, including breastfeeding, became part of the
treatment as early as 1940. Nonpharmacological measures- holding,
rocking, and using pacifiers-have become part of the management of
infants with NAS from then onwards. Cobrinik, in 1959, observed that
Fig. 2. Loretta P Finnegan MD (Permission obtained). 25 % of mothers breastfed their infants and observed improvement in
breastfeeding.26 As there was significant morbidity and mortality among
eat, sleep, and console method decreased the need for pharmacological symptomatic infants, pharmacological treatment has become a mainstay
treatment, length of stay, and length of treatment (LOT) compared to in the management of infants with NAS. Grossman initiated treating
usual care.51 With the modified FNAST being so long and comprehen infants with NAS outside of the NICU in 2018.50
sive, Loretta Finnegan proposed improving the instrument by excising
the ambiguous and redundant items.38 Hence, this author recently History of pharmacological treatment of NAS (Fig. 3)
published another scoring system, NAS SCORES, which incorporates
three central nervous system signs, three autonomic system signs, and Since the initial report of survival of infants with morphine, opioids
three neurobehavioral signs, with escalating scores depending upon the have become the mainstay of the treatment. Nonopioids had become

Fig. 3. Timeline of treatment of Neonatal abstinence syndrome (NAS). Medication and the year of initiation in the treatment of NAS. All medications in the
lower Panel are no longer utilized to treat NAS. DTO: Deodorized tincture of opium.

Fig. 4. Paregoric with dose on the back of the bottle.

Fig. 5. Multiple formulations of tincture of opium (Laudanum) were available at that time.

part of the treatment as there was a concern about the safety of opioids opioid withdrawal in infants treated with paregoric. Paregoric was
in infants. Seizures associated with withdrawal was another reason for especially effective in improving sucking behavior in infants with
pharmacotherapy. Till the 1990s, Paregoric, Phenobarbital, Chlor NAS.57 Paregoric was found to be superior in eleven of the fourteen
promazine, and Diazepam were the most used medications for the comparative studies.54 and was the treatment of choice at the turn of the
treatment of NAS.26,54 20th century. AAP recommended paregoric treatment until 1998.58 The
initial treatment started with 5 to 10 drops and was then increased to a
maximum of 20 drops, with the dose frequency ranging from every 10
Paregoric (Fig. 4)
min to every 4 h, and the treatment lasted for 4 to 6 weeks. The Pare
goric brand name has been discontinued in the US; however, generic
Paregoric was formulated by Jakob Le Mort, a professor of chemistry
equivalents are available.
at Leiden University in Germany, in the early 18th century as an elixir
for treating asthma; hence, it was also called elixir asthmatic.55 Paregoric
(camphorated tincture of opium) was listed in London Pharmacopeia as Tincture of opium (Laudanum) (Fig. 5)
early as 1721. Paregoric is a compound containing multiple substances,
including opium, honey, licorice, benzoic acid, camphor, and glycerin, Laudanum is a deodorized tincture of opium prepared from extracts
and has 44–46 % alcohol.56 The composition of paregoric was also of Papaver somniferum in ethanol formulated by Paracelsus, a 16th-cen
changed several times. Paregoric was extensively used to treat numerous tury Swiss scientist.59 Laudanum was listed in British Pharmacopeia as
ailments, including cough, diarrhea, asthma, and pain, and was a early as 1618. and could be purchased over the counter until 1914;
household remedy in the 18th, 19th, and 20th centuries. Paregoric has 4 however, it was later designated a Schedule II drug. Tincture of opium
% opium and was used in the management of NAS from 1903.53. It was was used in the treatment of NAS since 1909. Laudanum is a processed
not considered a narcotic until 1970, when it was classified as a opium preparation without alkaloid noscapine (narcotine); hence, it is
Schedule III drug. Early in the 20th century, the US federal government also known as Denarcotized Tincture of Opium or Deodorized Tincture
began regulating the sale of paregoric because its main ingredient was of Opium (DTO). Laudanum contains 10 % opium and is twenty-five
opium. However, it was available over the counter at most pharmacies times more potent than paregoric. Laudanum contains morphine, co
well into the 1970s. Multiple studies have reported improvements in deine, other opioid alkaloids, sugar, and ethanol –15 % alcohol.60 DTO

can be diluted to 1:25 for use in infants and given at a dose of 0.05 ml thebaine with partial μ-receptor agonist, was discovered in 1966 and has
every three hours to a maximum dose of 0.7 ml and continued over three been used in the treatment of NAS since 2008.70 Multiple RCT and an
to five weeks. Tincture of opium is available on prescription and is used alyses were done comparing one opioid with another, There is no uni
as an analgesic and as an antidiarrheal medication. Multiple varieties of form opinion about the superiority of a single opioid.71-74
Laudanum used to be available in the market. The use of tincture of Thus, the history of NAS goes back less than two centuries, though
opium in the treatment of NAS has not been reported in the last 10 years, opium has been known to humanity for thousands of years. The history
Both Paregoric and Tincture of Opium are no longer used in the of NAS has had a significant and exciting course, with major changes and
treatment of NAS in infants because of the following: a) toxicity of improvements every 25 years since its first discovery in 1875. NAS is an
components, b) the alkaloid content is not standardized, c) high alcohol unnecessary transgenerational affront and is avoidable, easily treatable,
content, and d) the availability of morphine preparation without alcohol and completely preventable.
as an alternative. The AAP advised against the inclusion of Paregoric and
Tincture of Opium in the treatment of NAS.61 CRediT authorship contribution statement

Chlorpromazine Prabhakar Kocherlakota: Writing – review & editing, Writing –

original draft, Visualization, Validation, Data curation,
Chlorpromazine is a phenothiazine developed in 1950 and was used Conceptualization.
in the NAS treatment from 1959 onward.26 At a time, Cloropromazine t
was the drug of choice for the treatment of NAS and the only treatment
approved in some hospitals— used alone or along with Paregoric.26 Declaration of competing interest
Adverse effects, including lowering seizure threshold, were a critical
concern. A recent RCT study reported a moderate decrease in treatment The authors declare that they have no known competing financial
failure with morphine compared to Chlorpromazine and was without interests or personal relationships that could have appeared to influence
any adverse events in either group.62 the work reported in this paper.

Diazepam Data availability

Diazepam, a long-acting benzodiazepine, was developed in 1958 and No data was used for the research described in the article.
was introduced as a treatment for infants with NAS in 1971.63 The sig
nificant drawbacks of diazepam included increased sedation and jaun References
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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Comparisons of management approaches in neonatal opioid withdrawal

syndrome: The eat, sleep, console approach vs. the Finnegan approach
Kia Johnson * , Adam Berkwitt , Lyubina Yankova , Rachel Osborn
Yale School of Medicine, New Haven, CT, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Increased incidence of Neonatal Opioid Withdrawal Syndrome has prompted innovation in assessment and
Neonatal opioid withdrawal syndrome management approaches. The Finnegan Approach and the Eat, Sleep, Console are the two most commonly
Neonatal abstinence syndrome described approaches, though they differ substantially. The goals of this review article are to describe and
Finnegan scoring tool
compare these approaches and published outcomes, including areas of uncertainty that may inform future
Eat Sleep Console
directions.

Introduction FA.6 The ESC moves away from a number-based scoring tool to focus
primarily on functional assessments of the infant and prioritizes the
Neonatal Opioid Withdrawal Syndrome (NOWS) consists of a implementation of non-pharmacologic treatments as first-line therapy,
constellation of signs following intrauterine opioid exposure that affects including feeding on demand and parental rooming-in. Pharmacologic
the central nervous, metabolic, vasomotor, respiratory and gastroin therapy is used on an as needed basis when non-pharmacologic in
testinal systems.1 Recent data documents staggering increases in the terventions do not adequately treat infants in withdrawal. The adoption
rates of NOWS, closely mirroring the dramatic rise in opioid use disorder of the ESC method amongst multiple hospitals has shown decreased LOS,
observed across the nation.2 The growing number of infants with NOWS decreased exposure to opioids, and lower costs to the healthcare sys
has added significant strain to the healthcare system, mainly arising tem.6–8 This article will review and compare these two main approaches
from overreliance on neonatal intensive care (NICU) utilization and to the management of NOWS, including their respective outcomes.
prolonged inpatient lengths of stay (LOS).3 This strain has prompted
innovation in assessment and management approaches for this growing The Finnegan approach (FA) defines the management for
patient population.4 decades
The Finnegan Approach (FA) and the Eat, Sleep, Console Approach
(ESC) are the two most commonly described management paradigms for The original scoring system, which came to be known as the FNASS,
the inpatient treatment of NOWS, though they differ substantially. The was first published in 1975 by Dr. Loretta Finnegan and colleagues with
FA centers on the use of the Finnegan Neonatal Abstinence Scoring the goals of standardizing treatment of infants diagnosed with “passive
System (FNASS), a scoring tool developed in the 1970s to identify and narcotic addiction” secondary to maternal opioid usage, partially
assess the severity of NOWS.5 Infants are traditionally treated in a NICU through the developmental of a scale to guide the use of pharmacologic
setting without parental involvement, and decisions regarding the use of therapies.5 This initial version contained 21 signs (Table 1); each sign
scheduled pharmacologic therapy are guided by numerical values had an assigned point value based on its correlation to narcotic with
assigned by nurses using the FNASS. Once started on pharmacologic drawal (5 being the most pathologically significant). The FNASS was
therapy for sustained scores above treatment threshold, infants are developed at a single center NICU and required that multiple trained
subsequently weaned off opioid replacement therapy, sometimes over nurses score the infant within 15-minutes of each other to improve
the course of weeks, when scores consistently remain below treatment inter-rater reliability and limit differences in scoring due to the pro
threshold. gression of withdrawal.5
The Eat, Sleep, Console (ESC) method was first implemented in 2015 The initial research for NOWS treatment centered nearly exclusively
and was developed in direct response to limitations observed within the on the traditional FA that dominated the landscape of care for decades to

* Corresponding author.
E-mail addresses: [Link]@[Link] (K. Johnson), [Link]@[Link] (A. Berkwitt).

[Link]
Received 2 October 2024; Received in revised form 26 November 2024; Accepted 17 December 2024
Available online 18 December 2024
0146-0005/Published by Elsevier Inc.

Downloaded for Anonymous User (n/a) at [Link] [CK] from [Link] by Elsevier on February 17, 2025.
For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved.
K. Johnson et al. Seminars in Perinatology 49 (2025) 152021

Table 1 under the FA, minimal attention was given toward its application. Par
Original Finnegan Neonatal Abstinence Scoring System. ents were frequently discouraged (or even disallowed) from providing
Item Score care for their children. There was almost no attempt to utilize infant-
driven feeding; nearly all infants were maintained on a strict q3 h
High Pitched Crying
Excessive 2 schedule for all care. Non-pharmacologic interventions, including
Continuous 3 common practices to console irritable babies such as swaddling, holding
Length of Sleep Post Feed, hours and use of pacifiers, was deemed secondary to pharmacologic therapies.
<1 3
<2 2
<3 1
A novel approach: introduction of the Eat, Sleep, Console (ESC)
Moro Reflex model of care
Hyperactive 2
Markedly hyperactive 3 It was not until 2010 that Dr. Matthew Grossman and colleagues
Disturbed Tremors
began to rethink the approach to the management of NOWS (Figure 1).6
Mild 1
Marked 2 Given the significant increase in infants with NOWS due to the national
Undisturbed Tremors opioid epidemic of the early 21st century, limited NICU capacity forced
Mild 3 more of these infants to be admitted to the general unit. This move
Marked 4
afforded the opportunity for more parents to room-in with their infants,
Increased Muscle Tone 2
Generalized Convulsions 5
as was traditionally done for all patients admitted to the general ward.
Frantic Sucking of Fists 1 This change alone differed significantly from the NICU setting, where
Poor Feeding 2 patients at the time were generally grouped into large, loud rooms
Regurgitation 2 shared by 10–12 infants on monitors.
Projectile Vomiting 3
Under this rooming-in model of care, providers immediately saw the
Stools
Loose 2 power of the maternal-infant dyad in treating NOWS.14 Having the
Watery 3 parents at the bedside enabled them to provide immediate
Dehydration 2 non-pharmacologic therapies, including swaddling and providing
Frequent Yawning 1
feeding in a true on demand fashion (often much more frequently than
Sneezing 1
Nasal Stuffiness 1
every 3 h). While the 2012 American Academy of Pediatrics policy
Sweating 1 statement on neonatal drug withdrawal described the importance of
Mottling 1 non-pharmacologic intervention as first-line therapy, its power had not
Fever been fully harnessed under the traditional FA where pharmacologic
Less than 101◦ F 1
therapies were prioritized. In fact, the policy statement itself gave
Greater than 101◦ F 2
Respiratory Rate significantly more weight toward the description of second-line phar
> 60 breaths/min 1 macologic care, with approximately 4 times as much text devoted to
> 60 breaths/min with retractions 2 describing pharmacologic interventions.15
Excoriation of Nose 1 Grossman and his colleagues witnessed the undeniable impact of
Excoriation of Knees 1
Excoriation of Toes 1
non-pharmacologic care and subsequently committed to implementing a
non-pharmacologic bundle of care as first-line therapy. Their new
approach focused on creating a soothing, low stimulation environment
follow. Infants were cared for in NICUs, with nursing staff un-swaddling with low lights and noise levels, moving patients and their families from
them to assign FNASS values every 4–6 h. A score ≥ 8 indicated concern the NICU to the general ward much earlier to allow for this plan of care.
for opioid withdrawal. Two consecutive scores > 8, or an average score They ensured that parents were at the bedside to care for their infants
≥ 8 during a 24-hour window, prompted the initiation of pharmacologic and worked with them to provide the tools they needed to help treat
therapy for symptom management. Opioid dosing increased until the their infants in withdrawal, focusing on utilizing the 6 S’s for calming
infant had consistent scores < 8. Once this goal score was achieved, irritable babies: Swaddling, sucking (pacifier), swaying, sideways
pharmacologic therapy was typically weaned by 10% of the original holding, shushing and skin-to-skin contact. Providers stressed the
dose every 24–48 h if scores remained below threshold.5 At some cen importance of feeding that was truly on demand, helping to satiate and
ters, infants would eventually be transferred to the general inpatient unit calm babies in withdrawal who often experienced hyperphagia and
once deemed stable to complete similar prolonged weans of opioid increased caloric needs. Finally, providers worked with all staff mem
replacement therapy. Caregivers were identified and brought in toward bers to overcome biases towards patients with substance use disorders.
the end of a lengthy hospitalization to learn the care of the newborn and Staff would provide families with the empowering message that the
plan for outpatient follow-up. parent-infant dyad was crucial to optimizing first-line therapy.
Under this approach, average reported LOS in the early 2000s was Grossman’s team also developed the novel ESC assessment method,
more than 21 days, with variations showing extended LOS greater than which pivoted from assigning numerical values to the signs of with
70 days for some infants.6 Much of the primary focus of research under drawal to focus on how the infant functioned in the setting of with
the FA was aimed at determining the optimal pharmacologic regimen to drawal. The ESC method involved a simple 3-criteria assessment that
reduce FNASS values and LOS: Was morphine better than methadone? evaluated the infant’s ability to successfully complete basic functions
Was opium better than morphine? Results of these studies were mixed expected of all newborns: could the infant eat (breastfeed or take at least
and showed wide variations in the primary outcome of LOS.9,10 Adju 1oz per feed), sleep undisturbed for at least 1 hour and be consoled
vant medications were added to existing opioid replacement schedules within 10 min. Infants no longer had to be un-swaddled and bothered
with similarly mixed results.11 Institutions also focused efforts on every 4–6 h to obtain a numerical value for the FNASS. Instead, infants’
adapting the original FNASS to determine if the scoring tools could be functional status in the setting of withdrawal was continuously assessed
simplified and/or improved to affect interrater reliability and adherence while also optimizing non-pharmacologic interventions (Fig. 1).16.
to protocols.12,13 To this day, no comparative evidence clearly supports If these criteria were not met with non-pharmacological measures,
the use of an FNASS score of 8 as the optimal severity threshold neces second-line pharmacotherapy was initiated. In contrast to the FA, the
sitating pharmacologic management. pathway for ESC utilized as-needed doses of medication instead of
While non-pharmacologic care was described as first-line therapy scheduled dosing and prolonged weaning regimens (Fig. 2). Under the

Fig. 1. ESC Implementation Goals.

FA, giving a medication one time meant a minimum of at least ten extra is safe and beneficial for the long-term well-being of the opioid
days in the hospital if the patient were to wean by 10% of the original exposed infant. Jansson and Velez lay out a physiologic argument
dose every day. Under this new model of care, pharmacologic therapy for why the ESC approach may result in developmental harm in
was used on an as needed basis when non-pharmacologic, first-line their 2019 commentary, and there are animal models arguing
therapy was ineffective as per the functional ESC assessment. Just that rapid withdrawal of opioids in rats leads to extreme stress
because an infant required one dose of a second-line pharmacologic responses and behavioral and learning difficulties modulated
therapy did not mean that a minimum of 80 more doses was indicated. through the brain-derived neurotrophic factor.19 However, ani
mal models are unable to account for the endogenous effects of
Exploring the impact on care: outcomes of ESC vs FA non-pharmacologic therapy. We know that these strategies
reduce pain symptoms in neonates with other diagnoses, and thus
Since its development, other institutions have adopted and adapted also reduce the developmental risks postulated by critics of
the ESC approach and we are now able to compare the FA to ESC across ESC.20
several domains as delineated below. C) Parental Bonding and Developmental outcomes: Family per
spectives of care under the ESC model were evaluated in a
A) Length of Stay and Cost: The initial publication of the ESC qualitative study performed by Dr. McRae, et al., in which parents
approach in 2017 reported a significant reduction in LOS from 22 (predominantly mothers) were asked their feelings on the ESC
to 6 days when all components of the ESC approach were fully method. Parents found the ESC approach to be “normalizing” of
implemented.6 Prior to the adoption of ESC, all infants were newborn care, felt encouraged to lead their infant’s care, appre
scored and treated according to the FA approach. This was a ciated the fewer interventions and shorter hospital stay, and
single site study over a prolonged period of time, but subsequent noted the opportunity to express guilt and fear over their infant’s
work, most notably of Young, et al. in the ACT-NOW trial, utilized condition.21 In contrast, a qualitative study evaluating familial
a clustered randomized design to demonstrated a much shorter experience using the FA revealed predominantly feelings of
LOS for infants in the ESC arm compared with the FA arm of 6.7 judgement and hidden guilt.22
days (CI95 4.7 - 8.8).17 It is generally accepted across the field of Extrapolating data from other disease-states emphasizes the
experts that the ESC approach results in shorter LOS, and thus importance of family-based approaches to all neonatal illness, as
reduced hospital costs. family-based interventions with a focus on parental-infant
A cross-sectional analysis performed by Dr. Tolia and col attachment have been shown to improve behavioral and mental
leagues demonstrated an almost 4-fold increase in prevalence of health outcomes.23 The ESC approach generally focuses more on
NOWS in NICUs across the country just within a decade’s time the familial aspects of non-pharmacologic care, but with effort
that could account for a 35% increase in hospital costs.18 The FA the FA could also prioritize this approach more effectively.
contributed to prolonged LOS and subsequently higher hospital D) Safety: Multiple studies have demonstrated equivalent short-
bills, given the conservative approach to weaning pharmaco term safety profiles for the ESC & FA. The initial ESC study did
therapy in most protocols. One can extrapolate significant cost not find a progression to seizures in the test subjects and no in
reductions for hospitals with the shorter LOS in the ESC model. fants were readmitted to the hospital within 30 days related to
B) Opioid Exposure to the Newborn: The initial data from ESC withdrawal symptoms.6 The ACT-NOW collaborative also
implementation demonstrated an 84% reduction in use of phar demonstrated similar safety data.17 Long-term data, such as
macotherapy compared to the traditional FA.6 To compare the neurocognitive outcomes are lacking for both models of care.
opioids that would have been given using the FA, researchers Infants with prenatal substance exposure are at high risk for
initially continued to obtain FNASS for all infants exposed to learning and behavioral struggles, but it is unclear which
opioids in-utero. Dr. Grossman and colleagues found that 62% of approach best mitigates these risks.
opioid-exposed infants would have received pharmacotherapy in
the FA, versus the 12% that did receive pharmacotherapy using Uncertainties and future directions
the ESC method. The ACT-NOW trial demonstrated a lower but
still dramatic reduction in opioid therapy in the ESC group Both treatment approaches have raised questions and concerns in the
compared with FA group (52% vs. 19.5%).17 Similar results have literature. The specificity for NOWS of some signs included in the
been replicated across other centers, providing strong evidence original FNASS has been questioned. For example, Dr. Lori Devlin and
that the ESC approach results in less opioid exposure.7,8 colleagues demonstrated yawning was only present in 5% of infants and
It remains controversial whether this reduced opioid exposure logistic regression did not demonstrate a statistically significant

Fig. 2. NOWS Clinical Pathway featuring ESC.

correlation to need for pharmacologic intervention.13 The practical support which approach is best for the longer-term outcomes of the in
consideration that to score a FNASS, the infant needs to be disturbed, fant. Proponents of the FA would argue that rapid reduction in opioid
thereby potentially exaggerating symptoms of withdrawal has also been dosing causes physiologic stress that can impair brain development.
raised by a number of voices in the field. Most would agree that the tool Proponents of the ESC approach would argue that reduced hospital LOS
was a needed intervention in 1975, given rising incidence of the disease and increased familial engagement (including improved breastfeeding
and lack of standardized approach, but some question its continued rates) offers an effective counter to the theoretical risks of this physio
utility. logic stress.
The ESC method has shown success in frequently measured out Following patients enrolled at birth for many years is challenging,
comes, including LOS and cost. Families report improved hospital ex particularly given the socio-economic challenges disproportionately
periences with this model. There is simply no comparison data to faced by this population. Head-to-head comparisons of this important

outcome may never be published, and centers will need to rely upon 8. Amin A, Frazie M, Thompson S, Patel A. Assessing the Eat, Sleep, Console model for
neonatal abstinence syndrome management at a regional referral center. J Perinatol:
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editing, Writing – original draft, Resources, Conceptualization. Lyubina neonatal abstinence syndrome in US children’s hospitals, 2004-2011. J Perinatol.
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2012. J Perinatol. 2015;35(8):650–655. 20. PhDPhD Hane Amie A, Myers Michael M, Hofer Myron A, et al. Family nurture
3. Milliren CE, Gupta M, Graham DA, Melvin P, Jorina M, Ozonoff A. Hospital intervention improves the quality of maternal caregiving in the neonatal intensive
variation in neonatal abstinence syndrome incidence, treatment modalities, resource care unit: evidence from a randomized controlled trial. J Dev Behav Pediatr. 2015;36
use, and costs across pediatric hospitals in the United States, 2013 to 2016. Hosp (3):188–196. [Link] April|.
Pediatr. 2018;8(1):15–20. 21. McRae K, Sebastian T, Grossman M, Loyal J. Parent perspectives on the eat, sleep,
4. Gomez-Pomar E, Finnegan LP. The epidemic of neonatal abstinence syndrome, console approach for the care of opioid-exposed infants. Hosp Pediatr. 2021;11(4):
historical references of its’ origins, assessment, and management. Front Pediatr. 358–365. [Link]
2018;6:33. [Link] 22. Cleveland, Lis M., and Rebecca Bonugli. "Experiences of mothers of infants with
5. Finnegan LP, Connaughton JF, Kron RE, Emich JP. Neonatal abstinence syndrome: neonatal abstinence syndrome in the neonatal intensive care unit." J Obstetr, Gynecol
assessment and management [review of neonatal abstinence syndrome: assessment Neonatal Nurs 43(3); 201: p 318–329.
and management]. Addict Dis: An Int J. 1975;2(1):141–158. 23. Pineda R, Bender J, Hall B, Shabosky L, Annecca A, Smith J. Parent participation in
6. Grossman MR, Berkwitt AK, Osborn RR, et al. An initiative to improve the quality of the neonatal intensive care unit: predictors and relationships to neurobehavioral and
care of infants with neonatal abstinence syndrome. Pediatrics. 2017;139(6), developmental outcomes. Early Hum Dev. 2018;117:32.
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2019;24(2):115–120. [Link]

Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Non-pharmacologic and pharmacologic care of the neonate with opioid

withdrawal syndrome☆,☆☆
Kimberly Spence a,b,* , Sarah Milota a,b
a
SSM Cardinal Glennon Children’s Hospital, Saint Louis, MO, USA
b
Saint Louis University, Saint Louis, MO, USA

A R T I C L E I N F O A B S T R A C T

Keywords: There has been a significant paradigm shift in the management of infants with NOWS to emphasizing the role of
Neonatal opioid withdrawal syndrome (NOWS) non-pharmacologic care centered on the mother-infant dyad. By promoting bonding through rooming-in, breast-
Prenatal opioid exposure (POE) feeding and skin-to skin contact in a low stimulation environment, short and long-term outcomes have
Dyad
dramatically improved, resulting in reduced length of stay and need for pharmacologic treatment of the
Non-pharmacologic care
newborn. This shift in care also empowers the mother and promotes bonding and attachment, providing a solid
foundation for a safe discharge. When non-pharmacological treatments are not sufficient to control the infant’s
withdrawal symptoms then medications can be used as an adjunct, to the minimum extent necessary and should
never be used in isolation of non-pharmacological interventions. Quality improvement efforts should focus on
optimizing and standardizing both non-pharmacologic and pharmacologic care to best serve this population.

Introduction Non-pharmacologic care

Historically treatment for neonatal opioid withdrawal syndrome Non-pharmacologic care of the neonate with NOWS is a multi-
(NOWS) centered around pharmacologic management. However, over pronged approach best implemented as a “bundle”. The goal of non-
the past 15 years, the overall approach to the care of these infants has pharmacologic care is to promote infant self-organization and regula
shifted to emphasize the role non-pharmacologic care can play in tion and should be tailored to the infant’s individualized needs.1 Most
improving both short and long-term outcomes for these babies and their care bundles that have been studied include rooming-in, skin-to-skin
families. Additionally, the approach to non-pharmacologic care has contact, breastfeeding, parental involvement, frequent feedings,
pivoted to be more inclusive of the family, highlighting the role the containment, low-stimulation environments, and therapy service
family can play in caring for and managing the symptoms of NOWS. involvement. Of these, dyad-centric care such as rooming-in has been
Pharmacologic management is an adjunct therapy employed judiciously shown independently to decrease neonatal length of stay and need for
after optimization of non-pharmacologic care. These changes in pharmacologic treatment.2-8 However, the other interventions when
approach reflect a paradigm shift in the care of the prenatal opioid- bundled as part of a larger quality improvement effort are also associ
exposed (POE) neonate. A multidisciplinary approach to treatment is ated with improved outcomes such as reduced length of stay (LOS) and
essential to optimize outcomes for NOWS. In addition to the medical need for pharmacologic intervention.9-14
providers, parents, nursing staff, pharmacists, therapists, and dieticians
all play a role in caring for these infants and understand the central Rooming-in
tenets to care are a safe withdrawal and a safe discharge.
Prior to the paradigm shift, most infants with POE were cared for in
the nursery or admitted directly to the newborn intensive care unit or

☆
Conflict of Interest and sources of funding: none☆☆ This manuscript is original and has not been previously published. No AI tools were used to create this
manuscript.
* Corresponding author: Division of Neonatal-Perinatal Medicine, SSM Health Cardinal Glennon Children’s Hospital, 1465 South Grand Blvd, Saint Louis, MO
63104, USA
E-mail address: [Link]@[Link] (K. Spence).

[Link]
Received 19 September 2024; Received in revised form 4 December 2024; Accepted 13 December 2024
Available online 15 December 2024
0146-0005/© 2024 Published by Elsevier Inc.

Downloaded for Anonymous User (n/a) at [Link] [CK] from [Link] by Elsevier on February 15, 2025.
For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved.
K. Spence and S. Milota Seminars in Perinatology 49 (2025) 152020

pediatric floors.2-4,15 Care in the neonatal intensive care unit (NICU) has discomfort, crying and emesis.
many downsides. The first issue with care in the NICU or special Another important benefit of breastfeeding is the impact on
care/nursery is the separation of mom and baby. Separating mom and maternal-infant attachment and reduction in maternal feelings of
baby can negatively impact bonding and place the dyad at higher risk for shame. Mothers with OUD are at uniquely high risk for insecure
an insecure attachment.16,17 Insecure attachment is associated with attachment due to the changes in the rewards system pathway in the
higher rates of infant abandonment18 and child maltreatment.19 Infants brain and the associated stress of dealing with a substance use disorder
as well benefit from secure attachment with lower rates of develop and common concurrent history of trauma. As discussed above
mental delays.20,21 The NICU environment also fosters the role of the maternal-infant attachment is critical to improving outcomes for these
bedside nurse as the primary caregiver; this care model has been shown dyads. The oxytocin surge that occurs with breastfeeding helps combat
to lead to parental feelings of powerlessness, inadequacy, and shame.22 feelings of stress and promote relaxation and attachment. The mother
Feelings of shame and guilt are common for parents with substance use can also witness the direct benefit breastfeeding has on improving the
disorder (SUD) and are only exacerbated by the NICU setting, contrib withdrawal symptoms of her child. This observation can help assuage
uting to higher levels of stress.23 Mothers with SUD also report feeling the feeling of guilt and powerlessness that many mothers have in the
negatively judged by the nurses in the NICU, which can lead to them not post-partum period watching the effects of NOWS.
feeling welcome and not visiting as often. Thirdly separation of mothers Another theory is that breastmilk from mothers on medication for
and infants decreases the ability to have someone present at the bedside opioid use disorder (MOUD) contains enough methadone and bupre
continuously to provide the intensive non-pharmacologic care needed norphine to provide some clinically significant amount to reduce or
for these babies. mitigate the symptoms of withdrawal. This is a controversial theory as
One of the earliest studies that evaluated the impact of rooming-in the evidence supporting this are case reports of rebound withdrawal
compared with standard care of newborns with POE was done at after stopping breastfeeding or mother’s own milk feeds.31,32 Breastmilk
British Columbia Women’s Hospital in 2001.2 Rooming-in allowed the is known to have relatively low amounts of methadone with levels
neonate to be cared for in the mother’s room after delivery and not ranging from 27 to 260 ng/ml, with a mean level of 95 ng/ml for this
separating the mother-infant dyad. This landmark study found: 1) a study cohort.33 This translates to about 0.04 mg/day of methadone
significant decrease in the need for pharmacologic treatment with an transferred to an infant over a 24-hour period if an infant consumed 150
unadjusted relative risk of 0.45 (CI 0.23–0.87); 2) reduction in LOS, 5.9 ml/kg/d of breastmilk; the average starting dose of methadone for in
days vs 18.6 days (p-value of 0.007); and 3) newborns who room in with fants with NOWS is 0.09 mg/kg every 8 hrs.34 Similarly, low levels of
their mothers were significantly more likely to be discharged in the buprenorphine are transferred into breastmilk with reported concen
custody of their mothers than babies not allowed to room-in, relative trations of 1.0 to 14 Ng/mL,35 and it has very low oral bioavailability.
risk of 2.23 (CI 1.43–3.98).2 Since that original study, other studies have There are more likely reasons for acute worsening of withdrawal
confirmed the benefits of rooming-in by reducing both the use of symptoms such as the cessation of the act of breastfeeding, including all
pharmacotherapy (RR, 0.37; 95 % CI, 0.19–0.71; I2 = 85 %) and LOS its benefits such as holding, skin-to-skin contact, frequent small volume
(WMD, − 10.41 days; 95 % CI, − 16.84 to − 3.98 days; I2 = 91 %).6 feeds and increased tolerance of breastmilk itself as well as the separa
Rooming-in has multiple subsequent benefits. It allows for increased tion of the maternal-infant dyad and loss of that
parental involvement, bonding, a lower stimulation environment, an attachment/relationship.
opportunity for parents to learn and provide the care of their infant, and The Academy of Breastfeeding Medicine encourages breastfeeding
increased feasibility for breastfeeding.24 Rooming-in facilitates parental for mothers “who have stopped non-prescribed substances by the time of
presence at the bedside which in turn has been found to decrease LOS delivery”.36 Institutions should have a consistent policy that mitigates
and need for pharmacotherapy.25 Additionally, surveyed mothers report bias but also provides enough flexibility to allow breastfeeding care
that they want to do what is best for their infants and being physically plans to be individualized. Many factors should be considered and
present with their babies allowed them to bond and remain involved in monitored for such as other medications or substance use, relapses, and
the care.26 The opportunity to demonstrate their ability/capacity to care ongoing SUD treatment. Most importantly, if a mother is hoping to
for their own baby then empowers and helps increase confidence in their breastfeed her infant, initiation of direct breastfeeding or pumping
skills at the time of discharge. Rooming-in remains important for infants should be started as soon as possible after birth to help establish her
who will not be discharged home with their biological parents due to supply. Even though relatively low amounts of drug are transferred to
custodial issues. These infants can still benefit from rooming-in and the baby via breastmilk, the mother should still be educated to observe
bonding with their parent until the time when parental custody is for any increase in somnolence if her MAT dosage is increased at some
removed. If the change in custody occurs before discharge, these infants point.
would benefit from volunteer cuddlers or early foster parent presence to
promote positive infant attachment in the absence of their biological Other feeding interventions
parents.27
Infants with POE often have feeding difficulties due to issues with
Feeding interventions irritability, poor state regulation, excessive sucking, and an overall less
efficient eating pattern.37 Despite these issues, there is not much
Breastfeeding/Provision of mom’s own milk empirical evidence to support a certain feeding practice in this popu
lation besides breastfeeding and breastmilk as already discussed. Expert
As with rooming-in, multiple observational studies have shown that opinion recommends frequent, small volume, on demand feeding. The
breastfeeding or being fed mother’s own breastmilk is associated with logic being smaller volume feeds will be better tolerated and babies with
less severe withdrawal symptoms, shorter LOS and decreased need for NOWS would benefit from more frequent feeds to compensate for their
pharmacologic treatment.28-30 Therefore, breastfeeding should be higher metabolic demands. Frequent breast/feeds also help satisfy the
encouraged in eligible dyads. Breastfeeding is thought to improve out excessive sucking and hyperphagia symptoms of NOWS. Rigid regimens
comes for infants with POE due to a combination of factors including the that insist on feeding babies with NOWS every 3 h could lead to missed
act of breastfeeding itself which involves holding the baby skin-to-skin opportunities to follow a baby’s cues, providing too large of volume that
and opportunity for frequent small volume feedings, as well as won’t be tolerated or potentially not enough volume leading to inade
improved neonatal tolerance for breastmilk over formula. Babies with quate weight gain or weight loss. On demand feeding is utilized in
NOWS have hyperphagia and excessive sucking; breastfeeding can multiple QI bundles which utilize ESC that led to decreased LOS,
satisfy these urges without over-feeding which can lead to abdominal symptom severity and rates of pharmacologic intervention.13,14,38

However, none of these studies evaluated on demand feeding in isola when dressing their baby.
tion so effectiveness could not be evaluated. Maguire and colleagues39 Scent: Maternal odor has been found to be soothing to neonates with
conducted focus groups with speech-language therapists and nurses who reduction/cessation in crying and increased rooting.51 The odor could
described techniques to improve the success of feeding infants with be from the mother, the mother’s clothing, or mother’s own milk. When
NOWs. All the participants in the focus group emphasized the impor mom is not present, having a piece of fabric with maternal odor can be
tance of reading the cues of the infants.39 Other techniques mentioned used instead. Lavender and chamomile aromatherapy has also been
included feeding the baby in a flexed “C position”, finding the sweet spot trialed in infants with POE in a non-blinded randomized study with 38
on the infant’s palate either with the nipple or a gloved finger and then patients. Lavender is known to stimulate GABA receptors, and chamo
introducing the nipple to that spot, vertical rocking and feeding the mile stimulates benzodiazepine receptors. This small pilot study52 found
infant facing away.39 Another tip is to feed the baby before they become a 41 % reduction in duration of medication treatment and a 36 %
frantic, meaning wait to change the diaper and do not delay feedings. reduction in LOS and no adverse events.
Infants with POE also have higher rates of emesis, loose stools, and Non-nutritive sucking: Infants with NOWS also demonstrate exces
higher metabolic rates leading to higher rates of growth slowing by the sive sucking behavior. Providing a pacifier or placing the baby to breast
time of discharge.40 Besides frequent feeding, increasing caloric density provides comfort to babies and helps with neurobehavioral organiza
of expressed breastmilk or formula could also help mitigate weight loss tion; much of this data comes from studies in preterm infants.53-56 Like
in the NOWS population. In 2018, Bogen et al41 published results from a the other non-pharmacologic interventions, pacifier use has not been
double, blind randomized clinical trial of standard 20 kcal/oz versus studied as an independent intervention but is part of the “bundle” of care
high calorie formula (HCF), 24 kcal/oz, in POE infants. Though there provided to these patients.
were no differences in the main outcomes of weight nadir, maximum
percent weight loss, or days until return to birthweight, the HCF group Specialized beds
had a higher percent weight gained/per day compared the
standard-calorie group (P < 0.001), and there were no adverse events.41 There is some evidence to suggest that non-oscillating water beds
Kaplan et al42 found a small decrease in LOS with utilization of HCF were helpful in decreasing the severity of withdrawal and the amount of
(22kcal/oz) in their quality collaborative in Ohio (17.1 to 16.4 days), medication used while achieving weight gain earlier.57 Additionally, a
but low-lactose formula offered no benefits. A few institutions are uti rocking bed compared to a standard bed was associated with increased
lizing HCF or fortifying expressed breastmilk as part of their QI bundle in withdrawal symptoms and sleep disruption.58 Notably, the rocking bed
management NOWS from birth.13 If poor weight gain or excessive also produced audio meant to mimic in-utero sounds. There has not been
weight loss are issues, fortifying feeds is a practical first step. However, a study of infant motorized swings, which can provide a variety of
in the setting of poor feeding or ongoing weight loss, augmentation with rocking motion; careful attention should be given to each infant utilizing
gavage feeds may be needed. such devices to monitor for worsening of symptoms. For some infants,
the rocking/swinging motion may trigger their dysregulation especially
Environmental modifications if paired with sound. It is also important to ensure parents are educated
that keeping a baby in a swing while on cardiorespiratory monitors in
It is well-known that infants with NOWS have issues with dysregu the hospital is safe but emphasize safe sleep recommendations for the
lation of their neurological system.1,9,10,43 Current recommended prac infant once discharged to home.
tice to mitigate this involves following infant cues to decrease the
dysregulation that occurs when these infants are overstimulated.1,9,43 Massage therapy
This individualized approach ensures each infant’s unique triggers are
addressed. Environmental measures often used to assist with managing Massage is potentially beneficial in preterm infants.59 Some of the
the dysregulation include modification of lighting, sound, infant potential theoretical benefits of infant massage include increased vagal
handling and positioning, smells, temperature control, provision of and gastric activity and reduction in cortisol.60,61 This activation of the
pacifiers or non-nutritive sucking.1,43,44 parasympathetic nervous system could benefit infants with NOWS who
Lighting: Low-lighting has been shown to reduce symptoms of NOWS frequently demonstrate a dysregulation of their autonomic nervous
when implemented as part of bundles of care13,14 and recommended as system resulting in tachypnea, sweating, vomiting, and hypertonicity.
part of a low-stimulation environment by experts.1,45-47 Massage could attenuate some of the stress response seen in this popu
Sound: A quiet environment is also recommended as part of NOWS lation and promote better self-regulation non-pharmacologically. Rana
management to reduce overstimulation and minimize sleep et al. published a pilot study of 30 term infants with POE who underwent
disruption.1,13,14,45,47,48 However, like many of the non-pharmacologic total body massage for 30 min sessions an average of 7 ± 5 days during
measures, a quiet environment has not been studied independently. the hospitalization period with heart rate (HR), respiratory rate (RR),
Many institutions use music therapy and tout the benefits of maternal and blood pressure (BP) measured pre- and post-massage.62 All infants
singing or humming, but published evidence of impact on withdrawal had a marked decrease in their HR, RR, and BP but the improvement was
symptoms is scant. There is some NAS-specific music therapy literature greater in infants with NOWS (p < 0.01) than without NOWS.62 Hahn et
to date that examines the use of the Pacifier Activated Lullaby (PAL®) al63 performed a quantitative study exploring the impact of infant
and other music therapies on the impact on withdrawal symptoms which massage on both the mothers’ perceptions of their infants with Neonatal
are promising.49,50 PAL® is a Pacifier Activated Lullaby device which Abstinence Syndrome (NAS) and the mothers’ relationship to their ba
encourages and reinforces effective non-nutritive sucking by providing bies. During this study mothers were taught how to provide massage
positive feedback given to the infant in the form of music or the mother’s therapy to their baby and then described their experiences; consistently
voice as auditory input in direct response to sucking. the mothers in this study reported providing massage therapy to their
Temperature control: Infants with NOWS run higher body tempera baby led to feelings of improved bonding and empowerment.63 Both
tures due to dysautonomia. An elevated temperature can then contribute studies found infant massage to be well tolerated by this population.
to irritability, tachycardia, tachypnea, and diaphoresis. Consequently, it Massage, like many of the non-pharmacologic measures, is frequently
is critical to monitor the thermoregulation of infants with NOWS to help used as part of the bundled care approach for NOWS management.
mitigate any exacerbation of withdrawal symptoms. This can be Neonatal acupressure and acupuncture have also been studied in
managed by adjusting the temperature in the room, removing hats, limited sample sizes and mostly for feasibility and safety.64,65 Both
socks, or unnecessary clothing. Parents should be educated on the higher modalities in their various forms including auricular pressure and laser
risk of hyperthermia in this population and be cognizant of that risk and magnetic acupuncture seem safe, well-tolerated and effective at

reducing withdrawal symptoms.65 No adverse events were reported. Pharmacological treatment

Another important finding from these studies was the acceptance of
acupressure and acupuncture by parents and the medical care team as an When non-pharmacological treatments are not sufficient to control
adjunctive therapy.65 No randomized controlled trials have evaluated its the infant’s withdrawal symptoms based on an institution’s chosen
effectiveness, or which intervention, acupressure or acupuncture, is assessment and management tool, then medications can be used as an
better. adjunct therapy. They should be used to the minimum extent necessary
and should never be used in isolation of non-pharmacological
Weighted blankets interventions.

Historically some NICUs have used weighted blankets to help Choice of opioid
manage neonates with NAS. This practice came under fire as it breaches
the recommendation of safe sleep for neonates.66 There has been a single In the early years of NOWS treatment, infants were treated with
cross over randomized controlled trial to assess safety, feasibility, and diluted tincture of opium (DTO), camphorated tincture of opium
effectiveness in the care of infants with NAS.67 The study was not (Paregoric), and deodorized tincture of opium (Laudanum).69 DTO
blinded, enrolled 16 patients with each patient serving as its own control contains an equivalent amount of opium as Paregoric (0.4 mg/mL)
and used 1-pound blankets measuring 11 inches by 20 inches for which is twenty-five times more dilute than Laudanum (10 mg/mL).
30-minute intervals.67 There were no adverse events and neonates on Since two of these compounds can both be abbreviated DTO, obvious
average had lower heart rates and a reduction in withdrawal symptoms safety concerns related to dose or product confusion arose. Additionally,
as measured by the modified Finnegan Scoring tool.67 It is important to Paregoric also contains potentially toxic components including
note that the blankets did not increase the mean temperatures of these camphor, anise oil, alcohol, and benzoic acid.70 For these reasons, these
babies or cause respiratory distress. The study is encouraging but given products are no longer recommended for use in NOWS.70,71
the small sample size and need for continuous cardiorespiratory moni Presently, the AAP recommends using the same class of drug used for
toring cannot be widely implemented. However, in neonates already withdrawal therapy as that causing the withdrawal.71 Morphine and
admitted to the NICU, it could be considered with the caveat that fam methadone, both full opioid agonists, are most often used first-line as
ilies are educated that weighted blankets are only to be used while the they are widely available.72,73 Morphine has a much shorter half-life at
baby is on cardiorespiratory monitors during the acute withdrawal ~4–8 h with onset within 5–30 min.74,75 Methadone has a half-life of 26
phase. h with peak levels at 2–4 h after dosing but that reportedly is highly
variable.76 The shorter half-life of morphine allows for more rapid
Therapy services titration during the acute phase for symptom control. However, the
longer half-life of methadone may make it more suitable for more severe
Occupational and physical therapists are natural providers of non- withdrawal symptoms.77 The longer half-life of methadone perhaps
pharmacologic care for this population. The discipline of occupational smooths the peaks and troughs of morphine administration allowing for
therapy has a framework of care organized around Person-Environment- a more gradual weaning of an opioid off the mu opioid receptors with
Occupation (PEO).68 This model of care typifies the current care model more stable blood levels. Disadvantages of methadone include: 1) 8 %
for non-pharmacologic care of the infant with NOWS with adjustments ethanol content in oral solution; 2) risk of prolonged QT syndrome, and
of the environment (mother-baby unit, rooming-in vs NICU), person 3) possible drug interactions. There have been three randomized
(neonate) or occupation (eating, sleeping, gaining weight = baby’s controlled trials comparing these two drugs, of which two showed
occupation) to optimize functioning of the neonate. Pediatric therapists decreased length of stay and/or length of treatment with methadone and
are a crucial resource (when available) to assist with education of one showed no difference.78-80 Notably, all three studies were either not
families in feeding and massage techniques, swaddling and positioning designed for power or underpowered. Additionally, methadone use has
and helping the family to recognize cues that will help provide more been associated with higher overall opioid exposure.80 One retrospec
timely recognition of their baby’s needs. tive study looked at developmental outcomes after methadone versus
morphine exposure for NOWS and found that methadone was associated
Care giver availability with lower cognitive and gross motor scores on the Bayley Scales of
Infant and Toddler Development-Third Edition (Bayley-III).81 However,
A significant barrier to many of these non-pharmacological in one of the more recent randomized controlled trials that favors metha
terventions is a care provider available immediately and constantly. done over morphine78 found no difference in Bayley-III scores between
Sometimes parents and/or nurses are not able to be at the bedside. It is groups.82
essential to have many care providers to be able to step in and cuddle Despite multiple studies comparing morphine to methadone, no
these babies or provide routine care in a timely fashion. Cuddlers can be consensus has been reached as to whether one is superior to the other.
volunteers, medical students, residents, nurses, or other staff members. Many earlier studies also are of questionable relevance given: 1) their
Nursing assignments may need to be altered to provide the non- routine use of scheduled dosing instead of initiation with as needed or
pharmacologic care necessary to avoid administering medication or PRN dosing; 2) Lack of concomitant emphasis on optimizing non-
starting scheduled medication. Non-pharmacologic care should not be pharmacologic care such as standardized rooming-in and encourage
sacrificed for the sake of convenience. ment of breast-feeding; and 3) Symptom-triggered dosing with nearly all
Often infants are treated within a NOWS bundle that integrates these using a Finnegan approach. It is only since the publication of Grossman
treatments into a care package. Many of these interventions are simply et al. in 201814 describing their success of transition to Eat, Sleep,
routine newborn care such as holding, swaddling, rocking, and pacing. Console with utilization of as needed dosing of morphine that in
These interventions, however, must be tried iteratively and consistently stitutions started utilizing this approach. Since then, multiple studies
per the infant’s cues. Having parents at the bedside to assist with and quality improvement initiatives11-13 have confirmed the benefits of
determining which of these interventions is most effective at each such an approach, including a recent multicenter trial.38 Before this
moment is critical to a parent learning how to care for their baby and practice change, infants were routinely started on scheduled medica
subsequently feeling empowered to provide that care. Dyad care is tion.78-80 Long-term follow-up is critical to inform the safety of this
essential to success. approach. However, given the widening embrace of ESC in practice, it is
also important to study these pharmacologic interventions utilizing this
new management strategy and assess efficacy.

Buprenorphine, an emerging treatment for NOWS which showed a reduced length of stay, reduced total opium dose, and
decreased treatment failure in the clonidine group without short-term
Of note, there is emerging evidence to suggest that buprenorphine adverse events. More recently gabapentin has been described as an
may be a superior agent to both morphine and methadone.83,84 In both adjunctive medication in a small case series of patients,105 but cannot be
studies, treatment with buprenorphine was associated with decreased recommended at this time.
LOS and shorter duration of opioid treatment. A recent systematic re While NOWS symptoms can be treated with opioids, there are still
view and meta-analysis85 found buprenorphine to be superior to cloni concerns about the effects post-natal exposure of neonates to opioids can
dine, diluted tincture of opium and clonidine, diluted tincture of opium, have on development.106 Ondansetron had been postulated as a poten
morphine, methadone, and phenobarbital. Buprenorphine is a partial tial target for therapy, as rodents with opioid dependence demonstrated
opioid agonist and is administered sublingually. There have been con a highly heritable pattern of opiate withdrawal based on variance within
cerns with the 30 % ethanol content in the oral preparation as well as the coding region of the 5-HT3 receptor.107 The use of ondansetron to
need for sublingual administration which requires administration of reduce NOWS severity was studied in a multicenter, randomized
pacifier after dosing to reduce risk of swallowing. IV formulations are placebo-controlled double-blind trial in 90 infants; withdrawal severity
used to administer to neonates until sublingual preparations are as measured by Finnegan scores were lower in the ondansetron-treated
commercially available. There also has not been a multi-site trial con group (4.6 vs. 5.6, p = 0.02) but LOS was not significantly impacted.108
firming superiority/non-inferiority of buprenorphine to other opioids A larger trial would be necessary to better assess the impact on length of
when used as needed per symptom trigger. stay and the need for opioid rescue.
It should be noted that secondary agents rarely need to be used.14,38
Adjunctive pharmacologic treatments for NOWS When reviewing the quality improvement literature assessing imple
mentation of ESC, first-line agents were reportedly only used in only
When the primary agents are not enough to control the infant’s 19.5 % of the exposed population and secondary agents only 15.7 %.38 If
withdrawal symptoms, an additional medication may be useful. an institution has significantly higher pharmacologic use, intensive
Phenobarbital and clonidine are the most used.77 Phenobarbital was quality improvement efforts should be undertaken to investigate the
used in the past as a primary agent to control withdrawal symptoms underlying issues and address them so as not to expose neonates
given its ability to control the hyperactive symptoms of withdrawal.86 (potentially) needlessly to post-natal opioids and central nervous system
There is also some data to suggest that phenobarbital may decrease the agents.
severity of withdrawal symptoms, but the level of evidence is low.87,88
Importantly, it also has significant side effects including central nervous Dosing and weaning
system depression, impaired suck reflex, delayed dyad bonding, a long
half-life, and rapid tolerance to sedative effect making other agents Standardization of dosing and weaning of medication improves
preferable.69,89 Multiple reports of hospital surveys of withdrawal outcomes such as LOS and duration of pharmacotherapy.109 See Table 1
treatment have shown that phenobarbital is the most used secondary for dosing and weaning recommendations for individual agents. A sig
agent for withdrawal and is most often the first-line medication for nificant practice change since the embrace of the ESC care model has
withdrawal-associated seizures72,90,91 It was also found to be associated been a transition to symptom-triggered dosing, away from scheduled
with increased LOS and duration of treatment when used as a secondary dosing. In general methadone and morphine can be given PRN for
agent, but the reason for this is not well understood and could be related symptoms as triggered by the institution’s assessment method. Howev
to the initial exposure necessitating a secondary medication, the side er, some neonates still have severe enough symptomatology and func
effects from the phenobarbital, or other confounding reasons.72 tional impact to require escalation, even briefly, to scheduled dosing.
Clonidine is also commonly used as a second-line agent for with Once an infant has been on scheduled dosing for 5–7 days, iatrogenic
drawal symptoms uncontrolled by an opioid. Clonidine is an alpha-2 withdrawal symptoms from treatment are to be expected and rapid
adrenergic receptor agonist and works to alleviate withdrawal symp weaning or stopping of medication will likely not be tolerated. There is
toms by decreasing the sympathetic signals that lead to the excitatory an ongoing trial assessing the impact of rapid weaning compared with
state characteristic of withdrawal.92 Clonidine was studied in the liter slow opioid weaning among neonates with NOWS treated with
ature for NOWS as early as the 1980s and used as a primary and sec morphine or methadone.110
ondary agent. There is one randomized controlled trial by Bada et al93
comparing clonidine to morphine as monotherapy for NOWS. The re Conclusions
sults showed that clonidine may be appropriate for monotherapy with
shorter overall treatment times and improvement in NICU Network Critical to reducing post-natal exposure to opioids are ongoing ef
Neurobehavioral Scale (NNNS) scores during treatment in the clonidine forts by institutions to participate in quality improvement to ensure best
group. This study,93 however, was small with only 31 participants and practice is being implemented and sustained. This requires institutional
was unable to compare withdrawal severity. Studies investigating and individual commitments from members of the care team. It is
clonidine as a secondary agent have had mixed results. Some important to remember that these infants must withdraw but that it must
studies,87,94,95 including a randomized controlled trial,96 favor pheno be done safely and compassionately, optimizing and standardizing non-
barbital over clonidine with reduced morphine treatment days and pharmacologic care while minimizing exposure to pharmacologic
shorter LOS. However, patients often require discharge home on agents.
phenobarbital94,95 and weaning over time which can take months.96,97
Additionally, long-term developmental concerns have been demon CRediT authorship contribution statement
strated in animal studies98-101 and one human study.102 In contrast,
clonidine has historically had a favorable side effect profile in neo Kimberly Spence: Writing – review & editing, Writing – original
nates.44,92 Short-term side effects may include a decrease in heart rate or draft, Visualization, Supervision, Project administration, Conceptuali
blood pressure, but these are typically mild and clinically insignifi zation. Sarah Milota: Writing – review & editing, Writing – original
cant.103,104 Notably, one of the more recent studies favoring pheno draft, Project administration, Conceptualization.
barbital over clonidine as a secondary agent did show a higher
percentage of adverse events, including hypotension and rebound hy Declaration of competing interest
pertension, in the clonidine group.94 There is only one randomized
controlled trial, by Agthe et al.,103 comparing clonidine to placebo The authors declare that they have no known competing financial

Table 1
Summary of pharmacologic treatment for NOWSa.
Medication Primary or Mechanism of Time to Half-life Dose (Initiate at Commercially Weaningb Monitoring
Secondary Action Onset low dose and titrate available or
to control compound109
symptoms)

Morphine (oral) Primary Full opioid- 6–30m72 9h 0.03 to 0.1 mg/kg/ Compound 0.4 10–20 % of max Respiratory depression,
receptor agonist In adults: dose q3–4h mg/mL from oral dose q2–3d sedation, decreased gut
~30m Max: 0.2mg/kg morphine solution motility, nausea,
Peak: 1h111 vomiting, urinary
retention, itching
Methadone Primary Full opioid- Peak: 2–4h 16–25h 0.05 to 0.1 mg/kg/ Commercially 10–20 % of max Respiratory depression,
(oral) receptor agonist dose q6–24h available as 1 mg/ dose q24–48h sedation, decreased gut
mL oral solution No consensus on motility, nausea,
when to wean vomiting, urinary
frequency109 retention, itching, QTc
prolongation
Buprenorphine Primary Partial mu-opioid No 11h 15.9 mcg/kg/day Compound 0.075 10 % of max Respiratory depression,
(sublingual) receptor agonist, neonatal divided TID. Titrate mg/mL oral dose until at 10 hypotension,
kappa-opioid data up in 25 % solution from the % of max dose constipation, nausea,
receptor antagonist In adults: increments to injection then stop vomiting, oral
Peak: control symptoms infections111
30–60m109 Max: 60mcg/kg/
day
Place under tongue
then insert pacifier
to reduce
swallowing
If dose >0.5 mL
give in 2 aliquots
separated by 2 min
Phenobarbital Secondary Potentiate gamma- Peak: 74 to Initial: 16 mg/kg Compound 20 % of max Target drug level: 20–30
(oral) aminobutyric acid 1.5–6h111 155 h, once 10 mg/ mL from dose every other mcg/mL
(GABA) receptor up to 1w Subsequent: 1 to 4 tablets (alcohol day Respiratory depression,
opening mg/kg/dose q12h free) sedation, vein irritation,
disordered feeding,
Commercial hypotension
product: 15 %
alcohol
Clonidine (oral) Secondary Alpha-2 adrenergic Onset: 44 to Initial: 0.5 to 1 Compound 10 <35 w GA: 0.25 Decreased heart rate,
agonist 30–60m 72h mcg/kg mcg/mL or 20 mcg/kg Q6h111 hypotension, rebound
Peak: 3–5h Subsequent: 0.5 to mcg/mL from ≥35 w GA: hypertension once
1.25 mcg/kg/dose tablets 10–20 % discontinued
q4–6h q48h111
Gabapentin Secondary Not well Peak: 4.7h109 5mg/kg daily to Compound 100 Slow taper Nystagmus,
understood 2–3h109 TID mg/mL from bradycardia,
Max: 35mg/kg/day capsules oversedation

Abbreviations: m, minute. h, hour. mg, milligram. kg, kilogram. mL, milliliter. max, maximum. q, every. d, day. mcg, microgram. TID, three times a day. GA,
gestational age.
a
Unless otherwise cited, information in table is from Micromedex NeoFax112.
b
All weaning should be patient-specific based on withdrawal symptoms/scores.

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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

The role of genetics in neonatal abstinence syndrome

Sarah Vernovsky a,1, Ana Herning b,1, Elisha M. Wachman a,b,*
a
Department of Pediatrics, Boston Medical Center, Boston, MA, United States
b
Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Neonatal Abstinence Syndrome (NAS) after in-utero exposure to opioids remains a significant public health
NA concern. NAS is a highly variable condition in which presentation and severity cannot be explained by clinical
NA1 factors alone. Research in human subjects has identified both genetic and epigenetic associations with prenatal
opioid exposure and NAS severity, including single nucleotide polymorphisms, DNA methylation differences, and
gene expression modifications. Animal studies have also identified key gene pathways that are likely important
contributors to NAS phenotype. The clinical significance of identified genetic associations with NAS are unclear
and warrant further study to see how they could impact NAS management.

Background NAS,12,13 and both rooming-in models of care14 and parental presence15
are effective at decreasing overall NAS severity. More recently, differ
The rise of opioid use during pregnancy in the United States (U.S.) ences in biomarkers such as cortisol production16 and gut microbiota17
has resulted in rising cases of neonatal abstinence syndrome (NAS), have also been hypothesized to influence NAS presentation and severity.
otherwise known as neonatal opioid withdrawal syndrome (NOWS). However, NAS still remains highly unpredictable with genetic vari
From 2010–2017, the number of pregnant individuals who reported ability likely accounting for much of the differences in presentation and
opioid use increased by 131 % to approximately 8.2 for every 1000 severity. Research in adults with opioid use disorder has demonstrated a
hospital deliveries in the U.S.1 For the purposes of this review, NAS is genetic influence on propensity for addiction and withdrawal pheno
defined by evidence of in-utero opioid exposure by history or toxicology types.18,19 In particular, adult twin studies suggest that approximately
testing, with or without other psychotropic substance prenatal expo 50 % of an individual’s’ risk for developing an opioid addiction can be
sures, and the presence of clinical signs of opioid withdrawal.2 NAS is attributed to a combination of genetic factors.20 Candidate gene studies
associated with risk for pharmacologic treatment and associated pro and genome-wide association studies (GWAS) in adults and older chil
longed hospitalizations for affected infants.3 dren have identified single nucleotide polymorphisms (SNPs) that are
NAS is a highly variable condition with an unpredictable need for associated with risk for opioid addiction and response to opioid treat
pharmacologic treatment and a widely variable hospitalization dura ment, such as the common SNP rs1799971 in the mu opioid receptor
tion. Many clinical factors have been identified to date in association gene (OPRM1).21–23
with differences in severity, which is defined by receipt of pharmaco Dopamine is the main neurotransmitter involved in addiction.24
therapy and length of pharmacologic treatment and neonatal hospital Genetic variants in dopamine and endogenous stress pathways have also
ization for NAS. For example, differences in maternal opioid type (ex: been associated with differential response to opioids and risk for
methadone versus buprenorphine) and half-life of the opioid can influ addiction.25 Specifically, SNPs within the catechol-o-methyltransferase
ence timing and severity of neonatal withdrawal presentation.4,5 Poly (COMT) gene that encodes an enzyme responsible for dopamine meta
pharmacy and non-prescribed substance co-exposure have also been bolism in the central nervous system has been associated with opioid
associated with a more severe NAS phenotype.6–8 Conversely, lower dependence in adults.26 Moreover, epigenetic factors have been asso
gestational age and female sex have been associated with a lower ciated with risk for addiction and variability in response to opioids in
severity of NAS.9–11 Regarding non-pharmacologic factors, infants who adult populations.18 Studies have associated DNA methylation differ
receive breastmilk are less likely to receive pharmacologic treatment for ences in various genes, particularly OPRM1, with risk for opioid

* Corresponding author at: 801 Albany Street, Room 2003, Boston MA 02119.
E-mail address: [Link]@[Link] (E.M. Wachman).
1
Denotes co-first authors.

[Link]
Received 4 November 2024; Accepted 16 November 2024
Available online 17 November 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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addiction in adults.27–29 unexposed infants and those with less severe NAS in comparison to those
Therefore, genetic and epigenetic factors are likely major contribu with more severe NAS.38
tors to variability in NAS severity and hold promise for individualizing
treatment approaches in the future. The purpose of this chapter is to Opioid metabolism genes
provide a comprehensive review of existing studies of the genetic as
pects of NAS including the examination of genetic variants, epigenetic Genes that code for enzymes involved in the metabolism of opioids
modification, and gene expression changes associated with prenatal are also key candidate genes for influencing NAS severity. Specifically,
opioid exposure and NAS severity. Future recommendations for research the cytochrome P450 (CYP) family of genes have been investigated for
in this area are also discussed. association with NAS given their role in opioid metabolism. CYP2B6 and
CYP2D6 metabolize methadone and CYP34A metabolizes buprenor
Genotype associations (Table 1) phine, two first-line agents for the treatment of opioid use disorder in
pregnancy and also for the treatment of infants with NAS.39,40 Mactier
Opioid receptor genes et al. found that infants who received pharmacologic treatment for NAS
were more likely to carry the homozygous alleles in rs3745274 and
As likely targets for associations with NAS, opioid receptor genes rs2279343 within the CYP2B6 gene.36
have been studied primarily via candidate genetic association studies In addition, the ABCB1 gene codes for a membrane bound ABC-
examining SNP genotypes. The most extensively studied gene is OPRM1 binding cassette transporter. It is thought that this transporter regu
which encodes for the mu-opioid receptor 1, influencing opioid binding, lates opioid pharmacodynamics and encodes the P-glycoprotein trans
positive reinforcement, reward transmission, and opioid tolerance.23 In porter 170 that binds to morphine and methadone. Morphine remains
one of the first candidate gene association studies in infants with NAS, the most commonly utilized opioid to treat NAS.3 In previous studies in
the AG or GG genotype in rs1799971 within ORPM1 was associated with adults, an association between variants in the ABCB1 gene and higher
shorter length of hospitalization and reduced likelihood of receipt of methadone dose requirements was identified.41,42 However, in candi
pharmacotherapy for NAS compared to the AA genotype.30,31 date genes studies of infants with NAS, the common ABCB1 rs2032582,
The OPRK1 gene encodes for the kappa opioid receptor which is rs1128503, and rs1045642 genetic variants were examined and no as
located in mesolimbic pathways and regulates pain, cardiovascular sociation with NAS severity were identified.31,36
functioning, breathing, thermoregulation, feeding, and aspects of the
stress response.32 Infants with the minor C allele in rs702764 within Genome wide association studies
OPRK1 were more likely to demonstrate severe NAS requiring higher
amounts of medication treatment in a small genetic association study.31 Genome-wide association studies (GWAS) of larger cohorts are useful
The OPRD1 gene encodes the delta opioid receptor. A potential target in identifying loci and molecular pathways. GWAS studies have been
for treatment of pain, this receptor is also involved in regulation of previously utilized to identify genome-wide loci associated with opioid
gastrointestinal functioning and breathing.33 In one candidate gene dependence in adults. Loci identified include SNPs involved in potas
study, the presence of the rs204076 A allele in OPRD1 was associated sium and calcium voltage gated ion channels (KCNCC1, KCNC2, and
with more severe NAS with longer length of hospitalization and PITPNM3).43 Potential involvement of CNIH3,44 BEND4,45 SLC30A9,45
increased receipt of pharmacotherapy.31 OPRM1,46 and KDM447 have also been identified in adult GWAS studies
Lastly, OPLR1 encodes for the endogenous peptide prepronociceptin and offer insight into potential pathways that may be involved in NAS.
(PNOC), a precursor to the opioid-like receptor ligand. In a small Bibi et al. conducted the first GWAS study in infants with NAS in 476
candidate gene association study, Wachman et. al found that the PNOC opioid-exposed and 382 unexposed infants or primarily European
rs732636 A allele was associated with an increased likelihood of severe ancestry.48 In the GWAS analysis, none of the previously identified
NAS requiring adjunctive medication treatment.31 In a follow-up study significant genetic variants from candidate gene studies were implicated
in a larger cohort of 86 infants, those with the rs4732636 A allele were in association with prenatal opioid exposure or differences in NAS
less likely to receive pharmacotherapy for NAS, contradicting the prior severity. However, the receipt of NAS pharmacotherapy was linked to a
findings.34 The minor A allele in PNOC rs2614095 was also found to be new locus on chromosome 7 between the LINC02889 (long intergenic
associated with less severe NAS in that cohort.34 non-protein coding RNA 2889) and SNX13 [sorting Nexin(13)] genes.48
SNX13 is expressed in the brain and encodes a sorting nexin and regu
HPA axis and dopamine genes latory G protein involved in intracellular trafficking.49

Genes associated with the HPA axis and dopamine metabolism are Epigenetics of NAS (Table 2)
also likely candidates for influencing infant responses to opioid with
drawal. The most studied gene to date in this category is the catechol-O- Epigenetic modification in response to opioid exposure also plays a
methyltransferase (COMT) gene which plays a key role in dopamine role in NAS variability. Epigenetics describe heritable DNA expression
metabolism.35 Wachman et al. also found that the G allele in rs4680 was patterns that do not change DNA sequences themselves. This can occur
associated with reduced need for medication for NAS and shortened in the form of DNA methylation, chromatin remodeling to make genes
length of hospitalization.30 The A allele of the COMT SNP rs740603 in more or less accessible for expression, and effects on non-coding RNAs,
mothers with opioid use disorder was associated with reduced NAS including microRNAs (miRNA).50,51 The most studied mechanism of
pharmacological treatment in their infants.34 However, the same allele epigenetic modification related to NAS is DNA methylation. DNA
in infants was not found to have a significant association with NAS methylation prevents genes from being transcribed, effectively silencing
severity.31,34 Mactier et. al. examined common SNPs in rs4633, rs4680, them. This often occurs at sites rich in cytosine-guanine nucleotide
rs4818, and rs6269 within COMT but found no associations with NAS pairings (CpG islands) in the promoter region of genes. Epigenetic
hospitalization outcomes.36 modifications can occur with exposure to environmental stressors, such
Dopamine is involved in reward-based pathways and binds to the D2 as exposure to in-utero drug and other stressful stimuli. Differences in
subtype of dopamine receptors. Although previously only linked to infant neurobehavior in association with epigenetic modifications after
addiction in adults,37 the A2A2 allele for the dopamine D2 receptor gene exposure to stress and trauma have been previously reported.52
(DRD2) was most commonly identified in infants who had been exposed Numerous studies have also pointed to a causal role of epigenetic
to opioids in-utero compared with unexposed infants in one study.38 The modification in controlling drug-related reward and stress responses at
141ins allele within the DRD2 gene was also more common in opioid the molecular and behavioral levels in adults.53,54,55

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Initial studies in infants with NAS utilized saliva, buccal cells, and CpG sites within 17 CYP genes between the cohorts.69–70
cord blood samples to examine epigenetic variation. DNA methylation Recent studies have also elucidated miRNAs as key players driving
within the OPRM1 gene was the initial target of investigation. Wachman opioid-induced epigenetic changes. miRNAs affect gene expression
et al. demonstrated that hypermethylation within the OPRM1 promoter largely by binding to the 3′ untranslated region (3′-UTR) on untranslated
in infants with NAS was associated with greater receipt of pharmaco messenger RNA (mRNA) sequences. In the context of opioid addiction,
logic treatment.56,57 A study by Camerota et al. utilizing buccal cells miRNAs regulate the expression of mu-opioid receptors, potentially
collected before and after treatment of NAS with morphine identified the playing a role in opioid sensitivity.71 Radhakrishna et al. first reported
potential reversibility of epigenetic changes in OPRM1.58 Specifically, on unique miRNA methylation profiles in placentas with prenatal opioid
they demonstrated that pharmacologic treatment for NAS decreased exposure through a genome-wide analysis, identifying 28 hypomethy
methylation at specific CpG sites within OPRM1. This decrease in lated and 28 hypermethylated CpGs that may be associated with NAS.72
methylation was also associated with reduced NAS symptom severity
post-treatment.58 Gene expression studies (Table 3)
Other genes examined for DNA methylation variability include
ABCB1 and CYP2D6, discussed earlier in relation to genotype variation. A step beyond epigenetic modification is the examination of varia
McLaughlin et al. found that opioid-exposed infants had increased DNA tion in gene and protein expression. Recent studies have started to
methylation in the promoter region of these two genes, as well as examine such differences in expression levels between opioid exposed
OPRM1, compared to unexposed infants.59 In a pilot genome-wide DNA and unexposed infants. In one of the first studies, through analysis of
methylation study in 8 methadone and 8 control pregnancies from cord salivary gene expression in NPY2R (neuropeptideY2 receptor), LEPR
blood, the most frequently hypermethylated and hypomethylated genes (leptin receptor), POMC (proopiomelanocortin), and DRD2 (dopamine
that differed between the groups included those involved in cell growth, receptor type 2), Yen et al. examined the relationship between gene
neurodevelopment, vision and xenobiotic metabolism functions.60 expression and hyperphagia in infants with NAS in comparison with
opioid unexposed infants.73 Hyperphagia has been linked to increased
Placental epigenetic studies withdrawal symptoms causing augmented metabolic demand and could
therefore be used as a marker of overall NAS severity. They found that
The placenta, the temporary organ that serves as the connection male infants with NAS had increased LEPR gene expression compared to
between the mother and fetus during the pregnancy, is commonly female infants with NAS. Furthermore, DRD2 gene expression correlated
referred to as the master regulator of the in-utero environment. Much of with infant feeding volume intake, and expression of NYP2R, an appetite
this regulation is thought to be influenced by epigenetic modification, regulator, was inversely correlated with infant length of hospitalization
with a growing body of literature reflects the effects of opioid exposure for NAS.73
on placental epigenetics.61–64 Other studies have focused on the placenta for examination of gene
The OPRM1 gene remains of significant interest for epigenetic expression differences after prenatal opioid exposure. In a cohort of 32
modification within the placenta. While Wachman et al. noted hyper infants with NAS and 32 unexposed infants, Radhakrishna et al. iden
methylation in OPRM1 in infants with more severe NAS in comparison to tified 93 genes that had differential placental gene expression in the
those with less severe NAS in studies analyzing saliva samples,5657 they opioid-exposed cohort compared with the unexposed.74 The most
were not able to identify differences in placental OPRM1 DNA methyl significantly upregulated and downregulated genes are shown
ation between opioid exposed and unexposed pregnancies.65 Townsel inTable 3. Using Ingenuity Pathway analysis of the RNA-sequencing
et al. conducted a placental DNA methylation study involving pregnant data, common pathways involving the subset of differentially
individuals on methadone or buprenorphine and noted that hypo expressed genes in infants with NAS were examined. The netrin
methylation of ABCB1 was associated with more severe NAS.66 They signaling, endocannabinoid neuronal synapse, calcium signaling, CREB
also noted that hypermethylation at the CYP19A1 gene was associated neuronal signaling, synaptogenesis signaling, opioid signaling, and
with higher levels of norbuprenorphine, the primary metabolite of
buprenorphine, in the umbilical cord.66 Table 1
Other studies of placental DNA methylation have taken a genome- Genetic variants and associations with prenatal opioid exposure and/or neonatal
wide approach. In one of the initial genome-wide DNA methylation abstinence syndrome.
studies, notable differentially-methylated genes included PLD1, Study Study Population DNA Source(s) Gene SNP
involved in opioid receptor endocytosis and opioid desensitization, and
Oei JL38 48 opioid-exposed Dried blood DRD2 rs1799732
MGAM, a membrane digestive enzyme that may be a therapeutic point
infants; 49 spots
of interest given that feeding problems and lower birthweights are unexposed infants
common in opioid-exposed infants.67 The study also identified hypo Wachman 86 opioid-exposed Buccal cells; OPRM1 rs1799971
methylation of the potassium channel gene KCNMA1 in opioid-exposed EM,30 mother-infant dyads cord blood COMT rs4680
relative to unexposed pregnancies.67 Wachman 86 opioid-exposed Maternal OPRM1 rs1799971
EM, mother-infant dyads blood; cord OPRK1 rs702764
Radhakrishna et al. also identified differentially methylated genes in 201531 blood; saliva OPRD1 rs204076
the placentas of opioid-exposed infants with NAS through a genome- PNOC rs351776
wide analysis.68 They noted hypermethylation at the chaperone pro COMT rs2614095
tein BAG2 promoter in opioid-exposed infants with NAS, as compared to rs4732636
rs740603
opioid-exposed infants without NAS. Compared to unexposed infants,
Wachman 113 opioid-exposed Saliva; buccal PNOC rs351776
opioid-exposed infants demonstrated hypermethylation in the tran EM 34 mother-infant dyads cells COMT rs2614095
scription factor TCF3 gene and hypomethylation in the mechanosensi rs4732636
tive ion channel component FAM38A gene body. They also identified a rs4680
wide range of dysregulated pathways affected by DNA methylation, rs740603
Mactier H 36 21 opioid-exposed Maternal CYP2B6 rs3745274
including opioid signaling pathways, B cell receptor signaling, CREB mother-infant dyads blood; buccal rs2279343
signaling in neurons, synaptogenesis signaling, and axonal guidance cells
signaling pathways.68 Recent findings from Radhakrishna et al.69 also Bibi S, 48
* 476 opioid-exposed Buccal cells SNX13 rs73313786
demonstrate significantly different placental DNA methylation patterns infants; 382
unexposed infants
in cytochrome P450 (CYP) genes between opioid-exposed and unex
posed pregnancies. Their study identified 20 differentially methylated *Genome-wide association study

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Table 2 Table 2 (continued )

Epigenetic associations with prenatal opioid exposure and/or neonatal absti Study Study DNA Genes Sites or
nence syndrome. population Source regions
Study Study DNA Genes Sites or (s)
population Source regions CYP2R1 Cg24775120
(s) CYP4Z1 Cg25217269
Wachman EM, 86 opioid- Cord OPRM1 -10, -14, +84 CYP2D7P1 Cg00455178
201456 exposed blood; CYP51A1 Cg23276445
infants saliva CYP2R1 Cg12850546
McLaughlin P, 21 opioid- Buccal ABCB1 Promoter CYP2U1 Cg07641350
201759 exposed; 17 cells CYP2D6 Exon 1 CYP4 × 1 Cg03544918
unexposed OPRM1 Promoter, CYP2W1 Cg24775120
mother-infant Exon 1 CYP4V2 Cg26051329
dyads Cg20646556
Wachman EM, 68 opioid- Saliva OPRM1 -18, -14, +23, Cg10896827
66
201857 exposed -169, -152, Townsel C, 38 opioid- Placenta ABCB1 Promoter
mother-infant +84 exposed CYP19A1 Gene
dyads pregnancies
Camerota M, 37 opioid- Buccal OPRM1 -71
*Genome-wide DNA methylation study; **MicroRNA genome-wide DNA
202258 exposed cells
methylation
infants
Adegboyega O, 8 opioid- Cord ZFP3 Cg16551483 The minus symbol identifies CpG sites located in the upstream of the tran
202460 exposed; 8 blood ANXA6 Cg00356335 scription start site, and the plus symbol CpG sites located in the downstream of
unexposed KCNC1 Cg26703758 the transcription start site.
pregnancies C2orf62 Cg04066495
CLDN4 Cg21838924
SND1 Cg07304760 Table 3
ANKRD27 Cg27413643
Gene expression associations with prenatal opioid exposure and/or neonatal
TNIK Cg22901347
abstinence syndrome.
PPM1H Cg17330938
Placental Study Study population RNA Genes
studies Source
Wachman EM, 64 opioid- Placenta OPRM1 No significant
Yen E 73 50 opioid-exposed; 50 unexposed Saliva DRD2
202065 exposed; 29 differences
infants NRY2R
unexposed
Radhakrishna 32 opioid-exposed; 32 unexposed Placenta CYP1A1
pregnancies
U74 pregnancies FP671120.3
Radhakrishna 64 opioid- Placenta BAG2 Cg05952642
RAD1
U, 202168* exposed; 32 TCF3 Cg19598832
RN7SL856P
unexposed FAM38A Cg16651953
RNA5SP364
pregnancies
GRIN2A
Borrelli KN, 19 opioid- Placenta PLD1 Cg05771324
UNC5D
202267* exposed; 20 RP11–250B2.3 Cg07585558
DMBT1P1
unexposed RP11–32K4.1 Cg22393128
MIR3976HG
pregnancies AL159152.1 Cg24415698
LINC02199
MGAM Cg06547839
LINC02822
ASCL2 Cg06347739
PANTR1
Radhakrishna 64 opioid- Placenta miR-1268A Cg11210410
AC012178.1
U, 202372** exposed; 32 miR-5095 Cg14929554
CTNNA2
unexposed miR-558 Cg16769912
Ruyak SL 76 28 opioid-exposed, 20 alcohol and Placenta TNF-α
pregnancies miR-548G Cg13790797;
opioid-exposed; 20 unexposed
miR-548F1 Cg20276377
pregnancies
miR-301A Cg04312413
Sadovsky E75* 9 opioid-exposed; 88 unexposed Placenta SERPINB7
miR-548W Cg02656609
pregnancies PEG3
miR-1278 Cg10046367
ACER2
miR-5096 Cg26481500
miR-1273H Cg23632539 *Genome-wide RNAseq
miR-2117 Cg15350946
miR-548H3 Cg06769231
miR-548E2 Cg22395021 nicotine degradation pathways were all associated with differential gene
miR-1276 Cg00071872 expression in the NAS cohort.74
miR-34B Cg11479035 Another placental RNA sequencing study by Sadovsky et al. sought to
miR-129–2 Cg13767940
focus on expression of opioid receptors in placental tissue, and differ
miR-3621 Cg01514668
miR-548C Cg18576861 ential gene expression between opioid exposed and unexposed pla
miR-181C Cg20351875 centas.75 They identified 276 differentially expressed RNAs between
miR-1238 Cg25147193 opioid exposed and unexposed pregnancies. The most common differ
Cg06871184
entially expressed genes in the opioid-exposed placentas were SERPINB7
Radhakrishna 64 opioid- Placenta CYP19A1 Cg12932492
U, 69* exposed, 32 CYP1A2 Cg24182584;
(serpin family B member 7), PEG3 (paternally expressed 3), and ACER2
unexposed CYP1B1 Cg18256630 (Alkaline Ceramidase 2).75 Of note, PEG3 has been associated with fetal
pregnancies CYP24A1 Cg09799983 growth and nurturing behaviors.
CYP26B1 Cg02143877 In the first study of protein expression within the placenta after
CYP26C1 Cg18244289;
prenatal opioid exposure, Ruyak et al. found a negative association be
CYP2C18 Cg14447606
CYP2C9 Cg07225966 tween opioid exposure in pregnancy and TNF-α protein expression
CYP2U1 Cg09345077 within the placenta.76 Neural cell division, differentiation, migration,
CYP39A1 Cg24804666 organization, and synaptogenesis could be impacted due to alterations
in TNF-α resulting in altered fetal neurodevelopment.76

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Animal genetic studies Conclusions

Given the challenges with limited sample size and biological sam In conclusion, the examination of genetic, epigenetic, and gene
pling with human cohort studies and prenatal co-exposures compli expression variation in association with prenatal opioid exposure and
cating analyses, animal models of NAS have been helpful in advancing NAS represents novel areas of research that can potentially explain
research related to the genetics of NAS. Animal models provide insight mechanisms behind the variability in NAS phenotype. Research chal
into mechanisms for how opioids influence fetal development and NAS lenges remain with the complexity of co-exposures and differential NAS
phenotypes, with rodent studies of prenatal opioid exposure being the treatment algorithms. However, the recent development of animal
most common to date.77–79,80 models and utilization of genetic data models has expanded our ability
In a neonatal mouse model of NAS, morphine withdrawal appears to to study genetic influences on NAS and could lead to a better under
decrease myelin-related gene expression in brainstem tissue, specifically standing of key mechanisms and pathways.
within the nucleus accumbens – a known key area for opioid with
drawal.81-82 Another study highlighted sex-specific differences in gene CRediT authorship contribution statement
expression in prenatally fentanyl-exposed mice, where nucleus accum
bens tissue from male pups showed gene enrichment in mitochondrial Sarah Vernovsky: Data curation, Writing – review & editing. Ana
respiration, while nucleus accumbens tissue from female pups showed Herning: Data curation, Writing – review & editing. Elisha M. Wach
significantly alterations in expression of genes associated with synaptic man: Conceptualization, Data curation, Project administration, Super
signaling and vesicular cycling.83 Other animal studies have also shed vision, Writing – review & editing.
light on sex-specific differences in placental gene expression among
oxycodone-exposed mice, showing decreased ribosomal protein Rp1 and Declaration of competing interest
Rps gene expression for male pups and alternations in numerous pro
lactin gene isoforms for female pups.84 The authors declare that they have no known competing financial
Recent animal studies have also focused on the opioid-inflammation interests or personal relationships that could have appeared to influence
axis and genetic mechanisms underlying opioid-induced neuro the work reported in this paper.
inflammation.85 A rat model of NAS by Jantzie et al. demonstrated that
prenatal methadone exposure increased cytokine release in the neonatal Acknowledgements
peripheral circulation and while upregulating mRNA expression of
toll-like receptor 4 (TLR4) and myeloid differentiation primary response None
88 (MyD88), both of which are involved in immune cell signaling.86
These findings coincided with evidence of microstructural brain injury Disclosures
in diffusion tensor imaging of rat pup brains, as well as poorer perfor
mance in future adult rat learning and executive functioning tasks.86 The authors have no conflicts of interest to disclose. No funding was
Overall, these animal studies have helped us to identify key pathways utilized to support this work.
and mechanisms for how prenatal opioid exposure can alter brain
development and neonatal behavior. Data availability

Research challenges and future directions No data was used for the research described in the article.

There are several challenges in studying the genetic influences on References

NAS. First, the enrollment of a large cohort for genetic association
studies such as GWAS with prospective biological sample collection is 1. Hirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal abstinence syndrome
and maternal opioid-related diagnoses in the US, 2010-2017. JAMA. 2021;325(2):
inherently challenging and time consuming, particularly in a high-risk
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in neural tissue is not possible in a human neonatal patient population. opioid withdrawal in the neonate. J Pediatr. 2022;243:33–39. e1.
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This is an exciting field of research with enormous potential to newborns. JAMA Netw Open. 2022;5(8), e2228588.
6. Wachman EM, Warden AH, Thomas Z, et al. Impact of psychiatric medication co-
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cohort studies should examine the impact of varying opioid exposures 7. Kaltenbach K, Holbrook AM, Coyle MG, et al. Predicting treatment for neonatal
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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Pre-natal and post-natal screening and testing in neonatal

abstinence syndrome
Sharon Ostfeld-Johns
Yale University School of Medicine, Department of Pediatrics, Section of Hospital Medicine, United States

A R T I C L E I N F O A B S T R A C T

Keywords: The way we enact screening for substance use during pregnancy within our healthcare systems can work by
Substance use in pregnancy decreasing stigma, promoting engagement, and supporting people with reaching the end of their pregnancy in a
Perinatal substance exposure manner where the newborn can be well supported. The way we enact biochemical specimen toxicology testing
In utero substance exposure
for substance use during pregnancy and in newborns contributes to increased stigma, disengagement from care,
Newborn toxicology testing
and potential continuation of uncontrolled substance use up until delivery such that the newborn may not be able
to be well supported in the family environment. These effects are inequitably distributed, leading to worse
outcomes for families of color and families living in poverty. Serial screening with a validated questionnaire
starting at the first prenatal visit and continuing through the delivery hospitalization should occur and be fol
lowed up with service connections and substance use disorder diagnosis and treatment. Newborn toxicology
testing as a diagnostic tool for risk of withdrawal or the etiology of potential withdrawal symptoms represents a
failure in the effectiveness of compassionate communication by healthcare providers with the birthing person.
Given the current level of evidence of clinical utility and the inequitable consequences specific to these tests, they
are rarely needed.

The challenge inherent in this chapter is highlighted by the ground out in the associated chapters in this special issue).
covered in the title: the many potential touch points across the perinatal
spectrum represent a vast range of clinical venues, clinicians, and situ 1. Prenatal substance exposure occurs commonly1,2,3 and while
ations, with a chasm of difference socially, legally, and ethically, be substances used and patterns of use in pregnancy may differ by
tween the pre- and post-natal spaces. Prenatally, people who are population4 “substance use crosses every demographic,
pregnant may be screened and tested for substance use. Once a baby is geographic, and socioeconomic characteristic.”5
born, the birthing person may again be screened or tested, and 2. Prenatal substance exposure does not directly predict specific
biochemical specimens from the baby may be tested. After the newborn negative developmental, behavioral, and cognitive outcomes6,7
hospital stay, both the medical team caring for the parents and the our best evidence suggests such outcomes are mediated by the
medical team caring for the child may continue assessments for sub complex interplay of the prenatal environment8,9,10 specifically
stance use in the parents and effects on the child. To better capture this stress11,12,13,14 and the overarching social and health environ
spectrum, and the differing goals of screening and testing across it, the ment pre- and post-natally.6,15
chapter may have been better titled “Pre-natal and Post-natal Screening 3. Prenatal substance exposure is not child abuse, harm or
and Testing for Risk of Neonatal Abstinence Syndrome and Risk of Harm neglect.16,17
to a Child Related to Parental Substance Use” or even, aspirationally, 4. Neonatal withdrawal does not in-and-of-itself represent a nega
“Identifying and Supporting Families Affected by Substance Use in the tive outcome for a child18 – it can represent an expected and
Peripartum Period to Promote Family Togetherness and Thriving.” manageable effect of a medication used to support a healthy
Before delving into screening and testing for substance use during pregnancy and represent a healthy start in life for a child and a
pregnancy, and screening and testing newborns for risk for NAS, family.
describing the landscape in which this topic is situated will frame the
discussion (while several of these statements will be more fully fleshed

E-mail address: [Link]-johns@[Link].

[Link]
Received 16 November 2024; Accepted 19 November 2024
Available online 22 November 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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S. Ostfeld-Johns Seminars in Perinatology 49 (2025) 152009

5. The perinatal period is a time of particular treatment- evidence of, a diagnosis. The Society for Maternal-Fetal Medicine, the
responsiveness for birthing people with substance use American College of Obstetricians and Gynecologists, and the American
disorder.19,20 Society of Addiction Medicine (ASAM) jointly recommend that “all
6. Substance use disorder is responsive to treatment and many pregnant women be screened for substance use at the first prenatal visit
people achieve sustained remission.21 with the use of a validated questionnaire,”30 an approach affirmed by
7. Prenatal substance exposure should not in-and-of-itself result in a the American Academy of Pediatrics (AAP).31 Screening instruments use
judgement about the quality of parenting the birthing person is questions, either self-administered on paper or an electronic device, or
capable of.22 Judgements made about mothering in the context of asked by a clinician. The evidence base and all expert guidance has
a history of parental substance use exist in the context of systemic reached the consensus that universal screening with questions is the best
racism and the criminalization of parenting in poverty (see practice to evaluate for substance use during pregnancy.
Table 1).23 People with a history of substance use disorder can be There is no single well-established questionnaire and method of
and are successful parents.24 administration that is optimal for use during pregnancy based on the
8. It is in the best interest of newborns to remain within their natal current available evidence.32 Screening may be most effective in an
family, when that is the situation most desired by the parents, and electronic self-administered format, i.e. through electronic health record
when it is safe to do so.25 patient portals or tablets provided prior to appointments, which mini
9. There is trauma to families, and therefore children, wrought by mizes perceived bias or stigma from the screening clinician.33 Screening
interaction with child protective services (CPS) or family policing early in pregnancy, and repeatedly throughout the pregnancy, leads to
systems26,27,28 These harms are disproportionately wrought on decreased substance use detection in later pregnancy and at the time of
families of color due to systemic racism.29 delivery.34
10. Providing supports and services to families to promote their Universal screening of the general population of people who are
ability to parent a child can happen before, and separately from, pregnant with biochemical tests is not recommended.30
investigation for concerns of harm or neglect. Federal law, state
and local agency policies all have a role to play in enacting sup Diagnostic testing
port for families in ways that do not involve CPS.
11. There is a significant mitigating and protective effect of positive While the use of toxicology testing of biologic specimens can be used as
parenting on the potential risks for adverse health outcomes due part of the diagnostic evaluation for substance use, in pregnancy or the
to prenatal substance exposure, and interventions can promote general population, a positive result is not by itself diagnostic or indic
positive parenting behaviors.24 On the other hand, there are po ative of a substance use disorder. In ASAM’s Consensus Statement,
tential environmental, developmental, and psychiatric risks endorsed by the American College of Medical Toxicology entitled
associated with being parented by a person with active substance Appropriate Use of Drug Testing in Clinical Addiction Medicine, they state,
use disorder.6 somewhat conflictingly, first that “A review of recommendations for
clinical management of substance use in pregnancy encouraged
screening for all women of childbearing age. These procedures could be
Screening and testing for substance use in pregnant patients followed by drug testing only if the screening questions indicated substance
use. [my italics]” and later, “The expert panel recommends that
Screening and testing for substance use during pregnancy is highly comprehensive substance use assessment, which may include drug
variable across the United States, and it is further complicated by the testing with the patient’s consent, be considered part of obstetrical
many confusing and inaccurate uses of the words “screening” and practice.”35 There are no more specific evidence-based standards for
“testing” in the literature. Furthermore, available guidance from na toxicology testing in this population that have been put forward by other
tional organizations is not consistently followed. national organizations.
Urine toxicology testing, the most utilized method, has several lim
itations including only reflecting recent use, variation in detection
Screening
times, variation in drug levels due to physiologic changes in pregnancy,
not capturing all substances and contaminants/adulterants, and false
Screening is a procedure performed on an unselected population to
positives on immune-assay testing being common.36,37,38 Moreover,
evaluate for a certain diagnosis. Diagnostic testing is a procedure per
criteria for urine toxicology testing have frequently included elements
formed on a population selected because of some increased risk for, or
which do not directly assess for substance use, such as insufficient pre
natal care, psychiatric diagnoses, housing status, dental health, and
Table 1
obstetrical complications.39 As others have noted, “incorporating
Adapted from cooper et al.
screening criteria that is nonspecific to detecting substance use but
Social construction highly correlated with individuals’ socioeconomic status, race, and
Positive Negative ethnicity allows for those who are not impacted by such constraints to be
Political Strong Advantaged Contender overlooked when assessing for perinatal illicit substance use.”23 Simi
power Birthing individuals who Birthing individuals who larly, cannabis use has been cited as a reason to perform toxicology
are white & adhere to social are black, indigenous, testing to assess for co-occuring substance exposures (through contam
norms related to people of color & adhere to inated supply or additional substance use), however the evidence does
motherhood social norms related to
Deserving of motherhood motherhood
not support this practice, as it rarely results in the discovery of other
Motherhood is questioned substances by toxicology testing.40 Use of routine urine drug testing at
Weak Dependent Deviant time of delivery rarely adds new actionable clinical information,
Birthing individuals who Birthing individuals who including when ordered for indications such as a history of substance use
are white & do not adhere to are black, indigenous,
and insufficient prenatal care.41
social norms related to people of color & do not
motherhood (i.e., low adhere to social norms When toxicology tests are obtained, informed consent is best prac
income, substance using, related to motherhood (i.e., tice.30,35 If a clinician’s intent is to assess for and treat substance use
single, and young etc) low income, substance disorder in an evidence-based collaborative, relationship-centered way,
Motherhood is accepted but using, single, and young etc) anything other than an informed consent conversation would fail to
may need supervision Not deserving of motherhood
serve that purpose. One ethics perspective states, “Biomedical

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S. Ostfeld-Johns Seminars in Perinatology 49 (2025) 152009

surveillance should be conducted only for clinical purposes having to do different care settings, and their knowledge of local supports and re
with ensuring access to and delivering quality health care.”42 In fact, sources for people affected by substance use disorders.
toxicology testing during pregnancy has been deemed unconstitutional The process of identifying and treating opioid use disorder during
if it is ordered without medical purpose but instead as a search for ev pregnancy may result in an unchanged risk for NOWS if the appropriate
idence of a crime, without specific informed consent to do so.43 Toxi medical response to opioid use during pregnancy is the prescription of
cology tests do not provide information about a person’s ability to be a medications for opioid use disorder (MOUD). From a clinical standpoint,
safe parent.44 Toxicology test ordering on pregnant patients has the relative characteristics of NOWS when it is caused by use of fentanyl
consistently been shown to be inequitable, with more tests ordered (for in the setting of uncontrolled substance use disorder through the time of
the same list of indications) on people of color, indigenous people, and delivery compared to that of NOWS caused by prescription of a stable
people in poverty,41,45,46,47,48 indicating incorrect assumptions and dose of methadone or buprenorphine are significantly different. The rate
biases related to rates of substance use in different populations.4 of severe symptoms, the potential need for medications to treat NOWS,
and the potential for additional complicating medical factors (including
Populations with existing diagnoses of substance use or substance use risk of prematurity and complications thereof, the risk of vertical
disorder infection transmission, and the risk of other medical complications of
the newborn period including feeding challenges) are higher in the
Screening is, by definition, not necessary for the population of people setting of uncontrolled opioid use disorder. If screening for opioid use
who become pregnant with a known active diagnosis of substance use or during pregnancy results in the identification of opioid use disorder and
substance use disorder. For people in this situation, goals include use of MOUD result in remission during pregnancy, the risk of NOWS
engagement with prenatal care, support for substance use cessation, remains, but this vastly changes the potential medical, social, emotional,
treatment for substance use disorder, social support through referral to behavioral, and overall life course for the child that may be born of the
services, treatment of co-occurring psychiatric diagnoses if present, and pregnancy.
education and support for ongoing or new parenting roles. People who A particular time for screening and testing pregnant patients that
have not been able to achieve remission from opioid use may find deserves separate mention is the delivery hospital stay. There are no
pregnancy a time when this can be achieved, with a compassionate and national guidelines for screening and testing of the birthing person
supportive team.19,20 Health risks related to the illegal drug supply must during the delivery hospitalization. Birthing settings may serve patients
be considered, with current focus on xylazine,49 and patients provided from multiple outpatient prenatal sites with different policies who have
with education, harm reduction tools and strategies that consider and thus experienced variable screening and testing. Hospitals have indi
incorporate pregnancy.50 vidual policies that may include universal screening and testing or tar
Another group requiring a specific management approach is the geted/triggered screening and testing during the delivery
population of people who are pregnant and have a history of substance hospitalization.39
use disorder in sustained remission or recovery.51 Screening for sub It is also worth mentioning the potential for co-exposures that are
stance use in this population may warrant particular attention, and the associated with worse NOWS symptoms: cigarette smoking,57 benzodi
use of screening tools may be different. Toxicology testing in this pop azepine use,58 and the use of medications for depression or other psy
ulation should be directed by the team or clinician providing treatment chiatric conditions, particularly selective serotonin reuptake inhibitors
for substance use disorder, and may not require adjustment or additional (SSRIs).59 Tobacco cessation should be pursued with maximal vigor
testing by the obstetrical clinician.35 Recognizing pregnancy as a time during pregnancy not only because it has significant health outcomes for
when treatment for substance use disorder may require adjustment and the birthing person and fetus, but also to mitigate neonatal withdrawal
possible intensification, particularly medication dose changes such as symptoms, and post-natal risks of ongoing parental tobacco use. Medi
split-dose methadone due to the changed pharmacokinetic environment cations to treat psychiatric illness during pregnancy should, in general,
of pregnancy, is of primary importance.52,53,54,55 It should additionally be addressed with shared decision making between prenatal clinicians
be recognized that the post-partum period is a time requiring additional and the birthing person; withdrawal symptoms for the newborn are not a
support, and that providers caring for post-partum patients should reason to discontinue antidepressant use during pregnancy.
routinely be assessing for return to substance use, a process that may or In addition, given that part of the motivation for screening for sub
may not involve toxicology testing.35 Given the rise in maternal mor stance use during pregnancy is to mitigate risks related to ongoing
tality in the late post-partum period (42 days - 1 year) attributable to parental substance use post-natally, it is curious that there are no
complications of substance use disorder, this is a significant area of need guidelines recommending screening of the non-birthing parent. One
for optimal clinical guidance.56 might suggest that the developmental/cognitive/behavioral conse
quences of the in utero exposure are a reason for this, however, some
Goals of screening and testing evidence suggests that substance use by the non-birthing parent has
similar downstream consequences.60 The role of the father is consis
The primary goal of screening and testing during pregnancy is to tently identified as a strength and benefit to children, we should honor
assess for substance use, and if identified, evaluate for substance use this by subjecting their health to surveillance equally to mothers.
disorder, connect with appropriate services and treatment, and identify
and respond to social needs related to substance use. When we put this Screening and testing of the newborn for prenatal substance
goal in the context of NOWS, we are specifically addressing opioid use exposure
during pregnancy. In our current national landscape this means the use
of non-prescribed, or the misuse of prescribed, opioids including fenta Screening
nyl, heroin, oxycodone, morphine, hydromorphone, methadone, or
others. The populations served by individual clinics providing preg Screening of the newborn is better conceptualized as re-screening of
nancy care may have highly variable rates of opioid use and opioid use the parents during the delivery hospital stay by the pediatric provider.
disorder. From a clinical reasoning standpoint, being aware of the local Unlike screening during pregnancy, there is no standard questionnaire
rate of opioid use disorder may influence the screening methods used in or other instrument that is utilized to facilitate these conversations. The
the clinical environment, because the positive predictive value of AAP’s recommendations related to this situation recognize the role of
response to screening will be different. The local rate of opioid use the pediatrician as a care partner to families as they negotiate the role of
disorder should also influence the knowledge and skill of obstetric cli parenting, and the reality that “engagement depends on the confidence
nicians in providing care and treatment for opioid use disorder in the family has that the health care providers meeting them at the intense

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S. Ostfeld-Johns Seminars in Perinatology 49 (2025) 152009

period of birth will continue comprehensive care and that their issues no clinical question in mind, no plan for interpretation, and erroneous
will be incorporated into a care plan.” Recommended conversational use as a test for environmental safety or parenting ability. They are also
strategies include engaging parents on broad topics related to their frequently ordered due to clinician deference to social services providers
health before narrowing to ask about specific substances, including who are used to receiving the results of these tests and request results as
inquiring about how the pregnancy affected their substance use: “After part of their safety evaluations (without clinical expertise in test result
you knew of your pregnancy, how would you describe your use of interpretation).
alcohol?” allows the parent to discuss changes made and provides in For all test modalities, it is important to define the two-layer
formation to the pediatrician about harm reduction strategies, either mechanism of testing that is available for most modalities. The “pre
self-initiated or in collaboration with a health professional.6 liminary” level of testing is by immunoassay and the second, “confir
Another approach to screening of newborns for NOWS is our routine matory” testing, is by mass spectography which can detect low levels of
clinical assessments during the newborn hospital stay when we observe analyte with high reliability.65 Immuno-assay, as mentioned above, is
for signs or symptoms of withdrawal. This is one rationale, among many, highly susceptible to cross-reactivity and thus has a high false positive
for the current expected minimum duration of 24hrs for the newborn rate.66 False negative rates have many potential factors, including that
hospital stay, specifically that the “clinical course and physical exami metabolites tested are based on adult metabolic pathways which differ
nation reveal no abnormalities that require continued in the fetus and newborn, and metabolite excretion or deposition in the
hospitalization.”61 test matrix may be low, among others.64 Therefore, if newborn toxi
cology testing is used, confirmatory testing should be ordered. Based on
Toxicology testing current laboratory practices, the turnaround time for confirmatory
testing of LWOD methods is days, making them useless for clinical
To be quite clear, newborn toxicology testing is the use of a decision-making related to withdrawal management.
biochemical sample obtained from the infant as a surrogate for infor Toxicology testing is currently used frequently in birthing hospitals,
mation collected from the birthing person. It is a reflection of a trans at highly variable rates in different health care settings and in different
placental exposure, in the absence of any medication being administered geographic locations. There is a paucity of evidence about test ordering
to the infant. practices across the United States. There are care settings that perform
While toxicology testing for pregnant patients is typically urine toxicology tests on all newborns with a method that captures a long
testing, there are a number of modalities available for newborn testing. window of detection. Some care settings have specific protocols for
The most common are urine testing, meconium testing, and umbilical toxicology test ordering based on certain clinical triggers, such as any
cord testing, and key features of these tests are summarized in Table 2. known substance use during pregnancy, a history of substance use dis
Meconium and umbilical cord testing capture substance exposure over a order in the birthing person, or other factors; these protocols may direct
long window of detection (LWOD), many months of pregnancy. providers to order urine testing and/or a LWOD method. In attempting
If you are using toxicology testing to evaluate risk of withdrawal, you to improve protocols, some researchers have found that existing (ineq
need to know what the recent or current exposure is, and the only way to uitable) patterns of newborn toxicology test ordering are challenging to
do that is to use a test method with a short window of detection, e.g. change.67 On the other hand, within the author’s healthcare system, a
urine testing. Urine toxicology testing is the gold standard to evaluate protocol developed through significant interprofessional collaboration
for the cause of withdrawal in adult patients, if biochemic testing is which specified the need for a clinical question prior to ordering a
utilized.62 The difference in the window of detection makes the com newborn toxicology test was instituted and resulted in decreased rates of
parison of test results – “concordance”63 – between maternal urine testing overall, flattened existing disparities in rates of testing, and did
toxicology testing at the time of delivery and newborn umbilical cord or not result in adverse events.68
meconium testing a useless one – there are many instances in which
newborn LWOD testing may be positive and maternal urine testing at Historical context
delivery negative due to a change in pattern of substance use, or the
other way around. Fundamentally, the question of the clinical utility of It is helpful to take a trip down memory lane, to what, in my review
newborn toxicology testing has not been clearly defined or evaluated. In of the literature, is the first paper that evaluated the effectiveness of
a recent literature review entitled Drug testing in support of the diagnosis of toxicology testing of the newborn. Here is the abstract, published in
neonatal abstinence syndrome: The current situation, the authors concluded 1988:
with an important statement: that the studies reviewed “did not try to We compared results of urine drug analysis with clinical data and
answer the fundamental questions of whether drug testing adds any history to test the usefulness of peripartum drug screening and to
value to these clinical tools, and what, if any, standardized list of drugs establish guidelines for optimal testing. Urine from 28 mothers and
or metabolites should be tested to assist in the diagnosis of NAS [my 52 babies was analysed. Drugs not suspected by history were found
italics].”64 This is because toxicology tests are frequently ordered with in 10 mothers and six babies. Results assisted in the management of
neonatal withdrawal in three babies. Drugs suspected by history
Table 2 were not found in 11/22 mothers and 23/35 babies. About half of
Newborn toxicology testing modalities.63,64,65, 69,103(adapted from Colby&Cotten)
these results were associated with delayed urine collection. In 12/28
Urine Umbilical Cord Meconium mothers, drugs administered in hospital could have confused inter
Year developed n/a 2006 1989 pretation of screen results. We conclude that urine drug screening
Typical turn- <4hrs 1–4d 2–5d without strict protocols for specimen collection is of limited useful
around time ness for management of drug abuse in pregnancy and neonatal drug
Collection Urine bag Specimen collected at First stool or
withdrawal. We favour testing of maternal urine obtained before
(first void, up delivery and kept prior to stool
to 4 days after refrigerated for 1 week transition
drugs are administered in hospital. Neonatal urine, if used, should be
delivery) or until test ordered collected in the first day of life.69
Window of Short Long Long
detection (days prior to (20wks gestation) (14wks While first acknowledging that many hospitals continue to use un
delivery) gestation) examined protocols with similar levels of effectiveness, I would draw
Drug Moderate Low High several lessons from this paper that we would do well to follow today.
concentrations First, the authors do not provide information about how screening took
detected
place to determine who would receive testing – we have improved

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S. Ostfeld-Johns Seminars in Perinatology 49 (2025) 152009

significantly in this area with the evidence base cited above. Relatedly, it exposure, given the better test characteristics of toxicology testing of the
is unclear why some patients with no history of substance use during birthing person, this would be the preferred sample from a clinical
pregnancy were tested and thus found to be positive – this affects the reasoning standpoint in terms of evaluation for risk of withdrawal in the
interpretation of the rate of discovering new actionable clinical infor newborn. Differing standards exist for consent for parental vs newborn
mation. Second, many toxicology tests (two thirds!) were negative for testing – national guidelines for toxicology testing of pregnant patients
known substance use, making these tests useless or if they were inter recommend informing the birthing person of testing and obtaining
preted as indicating no recent exposure would adversely affect newborn consent30,35; there is no such national standard for consent for newborn
care targeted at observing for and managing withdrawal symptoms. toxicology testing. Newborn toxicology testing should not be viewed as
Collecting urine specimens earlier (in the first 24hrs) may or may not an “easier to obtain” sample if biochemical testing of the birthing person
alleviate this problem, but regardless, the advancement in limit of is desired but not consented to. Newborn toxicology testing as a diag
detection of substances in the intervening 35 years can accommodate a nostic tool for risk of withdrawal or the etiology of potential withdrawal
longer distance between time of exposure and time of detection.70 And symptoms represents a failure in the effectiveness of compassionate
third, the rationale the authors give for obtaining toxicology testing is to communication by healthcare providers with the birthing person. If
adjust treatment for withdrawal symptoms – our current guidelines do newborn toxicology testing is deemed important to the clinical care of
not support the necessity of toxicology tests in making a diagnosis of the newborn, all available evidence suggests that parents desire an open,
opioid withdrawal symptoms71 or in treating them.72,73 Again, to quote transparent, and informative conversation about the indications for the
from a recent review of studies of toxicology tests in the diagnosis of test, the potential use of the results, and who will have access to the
withdrawal: “At present it would appear that clinical tools and estab results of the test. With this information, the vast majority of surveyed
lished diagnostic signs and symptoms remain adequate at establishing parents would consent to such testing.75,76 On the other hand, surveys
the diagnosis of NAS.”64 have also shown that parents are not interested in universal screening
for alcohol use during pregnancy with meconium testing, likely due to
Indications for newborn toxicology testing unrelated to diagnosing NAS the failure to demonstrate what positive result would come of this type
of screening.77 Therefore, parents should always be informed of the plan
Other indications for newborn toxicology testing including research for specimen collection, and should always be asked for their consent for
and public health are not addressed in this article. The potential for use toxicology testing. When a mutual agreement cannot be achieved
in these venues may guarantee privacy or anonymity in the interest of through excellent communication, and infant health is at risk, there are
population based data collection.74 always exceptions. From an ethical perspective we, as a society, assign
In addition, it is not known on an individual level what the diagnostic greater weight to the right of a child to safety and health than we assign
or therapeutic benefit of newborn toxicology testing related to devel to parental rights,78 therefore, if consent is not provided but the test is
opmental/cognitive/behavioral conditions would be to a child; I am deemed necessary to preserve the life or health of the newborn, it should
aware of no literature that addresses the population of children in whom be performed regardless. Such cases, in the author’s clinical experience,
newborn toxicology testing is the first or only piece of information that are exceedingly rare.
identifies prenatal substance exposure or what the outcomes are for If tests are ordered, it is relevant, given the above information related
these children compared to children identified by prenatal screening. to windows of detection, confirmatory testing, potential for and causes
Similarly, it is unclear how toxicology testing (when performed in the of false positives and false negatives, iatrogenic positive results79 etc to
setting of prenatal substance exposure known by report or testing of the be deliberate in the appropriate interpretation of test results. 24% of
birthing person) would or could inform developmental/cognitive/ perinatal clinicians, however, when surveyed, scored “poor” on their
behavioral screening, diagnosis, or treatment, even if it discovered an ability to correctly interpret the results of toxicology tests ordered
unknown co-exposure. A major concern for this latter population would during the perinatal period, and only 28% had “good” proficiency.80 If
be false negative testing inappropriately interpreted as representing no there is future evidence that supports newborn toxicology testing’s
exposure and/or no need for intensive screening; or positive testing clinical utility, it will be essential to improve education in its interpre
resulting in premature closure of an evaluation for the myriad of causes tation. A particular misinterpretation of newborn toxicology testing, in
of development/cognitive/behavioral challenges. Work in the sphere of particular with LWOD methods, is that substance exposure represents
developmental behavioral pediatrics may ultimately answer these child abuse and that parents who used substances during pregnancy are
questions. not good parents. This is entirely inappropriate; newborn testing should
The use of toxicology testing in children to evaluate for environ be interpreted narrowly, as described in a recent review of the clinical
mental exposure to substances or in the setting of emergency evaluation use of these tests: “We must remember that the ultimate purpose and
for signs or symptoms consistent with potential substance exposure is goal of neonatal drug testing is to support the diagnosis of NAS in order
clinically well-founded. to provide the appropriate follow-up and treatment for the neonate
through clinical laboratory support of the mother-neonate dyad, and not
Testing context and interpretation to identify a condition that may exist in the mother (i.e., maternal
substance use disorder).”64
From a clinical reasoning standpoint, we often say “only order a test Like toxicology testing in pregnant patients, toxicology testing of
if it is going to change your actions,” and newborn toxicology testing newborns has consistently been shown to be ordered at inequitable rates
rarely meets this bar. One must ask: What is my pretest probability for in ways that are not reflective of true substance exposure rates.48,81,82
NOWS in this infant? How certain am I in that probability? Do I need to
do additional tests to increase or decrease the probability so that I can Legal situation related to prenatal substance use and perinatal
make appropriate clinical decisions? The answer to these questions for toxicology testing
the vast majority of infants before we, as the caregivers for the newborn,
even enter the room, is that we usually have a reasonable understanding Federal policy affirmed in 2022 that prenatal substance use is not
of the risk and do not need additional information. child abuse.16 This recent executive branch statement was preceded by
If information about substance use during pregnancy is not clear at existing legislation: The Child Abuse Prevention and Treatment Act, as
the time of delivery, there has been a breakdown in the screening pro updated by the Comprehensive Addiction and Recovery Act of 2016
cess during pregnancy. This should be remedied first by attempts at (which will be referenced as CAPTA/CARA henceforth).83 This legisla
compassionate history-taking from the birthing person. If toxicology tion requires each state to develop a protocol for and produce annual
testing is determined to be necessary to identify prenatal substance reports to the federal government detailing (1) the numbers of newborns

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“affected by” substance use during pregnancy, (2) that CPS systems are NOWS, as will be delineated in subsequent chapters. If the expectation of
notified of delivery of such newborns, (3) that these newborns have NOWS is present, for example, in the setting of known use of MOUD
Family Care Plans, and (4) what is in these plans.84 The legal re throughout the pregnancy, optimal clinical care for the newborn can
quirements of CAPTA/CARA can be viewed as mapping on to the tenets take place. Similarly, if the expectation of NOWS is present in the setting
of optimal clinical care. The legal intent is to identify substance use of known uncontrolled substance use persisting throughout the preg
during pregnancy, develop substantive and beneficial Family Care Plans, nancy, optimal clinical care for the newborn can take place. And again,
collect and send anonymized information to the state during the similarly, if the expectation of NOWS is not present in the setting of
newborn hospital stay, and ultimately support families going home known absence of exposure to substances during the pregnancy, optimal
together. Optimal clinical care is to serially screen for substance use clinical care for the newborn can take place.
during pregnancy, match with appropriate treatment and services dur What currently presents a barrier to our understanding of substance
ing pregnancy, verify appropriate services are in place during the exposure and risk for NOWS is fear.94 Fear that prevents pregnant pa
newborn hospital stay, and ultimately support families going home tients from participating in prenatal care95 (one of the best predictors of
together. healthy pregnancy outcomes96) and substance use treatment97 (strongly
Many states interpreted CAPTA/CARA as a mandate to expand and associated with positive pregnancy outcomes for people with opioid use
authorize surveillance of families affected by substance use through disorder98). Fear of surveillance, judgement, and racism.99 Fear of
interaction with CPS agencies.85 Currently 27 states and the District of having their children taken away.100,101 In our current punitive system,
Colombia consider substance use during pregnancy to be child abuse in fact, “to expect people to be forthcoming about sensitive and poten
and this number has been rising in recent years.86 5 states (Minnesota, tially catastrophic information under such circumstances is
Oklahoma, North Dakota, South Dakota and Wisconsin) consider sub irrational.”102
stance use in pregnancy as grounds for civil commitment.87 The entire history of mechanisms of diagnosing substance exposure
Toxicology tests are more frequently used than other forms of diag in utero that do not start with screening questions, i.e. universal toxicology
nostic information as substantiating evidence in legal claims of harm testing in pregnant patients, or any toxicology testing in newborns –
related to substance use in pregnancy,88 despite rarely offering new acknowledges this fear. From the introduction of the paper first intro
clinical information. CAPTA/CARA does not, nor does any other federal ducing meconium testing as a modality in 1989 we hear that: “Maternal
law, require newborn toxicology testing under any circumstances.84 admission of drug use may not always be obtained because of fear of the
Newborn toxicology tests under certain circumstances are legally consequences.”103 But instead of responding to the knowledge that fear
required by state law in 4 states (Louisiana, Minnesota, North Dakota, is what prevents us from consistently knowing about substance exposure
Wisconsin), although several other states require a positive test result to during pregnancy with attempting to dismantle the harms we in the
warrant a mandated report to CPS related to prenatal substance expo medical community have contributed to this legitimate and
sure.89 Some services, including developmental screening or support for evidence-based panic, instead we have focused on coming up with new
children with a history of prenatal substance exposure, are only avail and increasingly technical ways to document objective evidence of pre
able if positive toxicology testing is present. In many areas even when natal substance exposure in ways that contribute to punitive legal re
there is no specific relationship between toxicology test results and state sponses. Take, for example, this quote from a review of the technical
law, CPS legal action, or service connection, there remains an expecta aspects of newborn toxicology testing: “Confirmation testing…is even
tion from CPS workers and/or law enforcement that these tests are more important when considering that newborn biological tests repre
obtained. sent a once in a lifetime opportunity to protect and enrich the life of the
The designation as child abuse, and the establishment of mandated neonate. The use of a screen and confirm strategy while maintaining a
reporting to CPS for prenatal substance use even in states where it is not documented chain of custody ensures the integrity of the identity of the
designated child abuse, has led to significant surveillance of families in specimen and ensures the accuracy of the result, thereby protecting the
this situation. Mandated reports, when they come from healthcare maternal-child dyad from erroneous results. These are the cornerstone
professionals, tend to be fully investigated based on the concept of principles of producing a forensically defensible result.”65 This state
“mutual deference”,90 even when at the population level, mandatory ment posits that resources, services, family placement, among other
reporting is not associated with improved child health.91 Connecticut protective actions, are reliant upon the results of newborn toxicology
has been a leader in this area, with the use of an anonymous online testing, in a “once in a lifetime” way. This is simply not the case in any
portal for CAPTA/CARA notifications, separate from CPS reporting kind of universal manner, and where it is the case it should not be – the
systems, which has led to the diversion of over half of notifications from provision of resources and decisions related to family separation should
CPS investigation.92 This system of dual reporting would have been be made in a comprehensive and holisitic manner and newborn toxi
federally required based on a draft CAPTA reauthorization bill which cology testing – a poor surrogate for biochemical testing of the pregnant
has not yet been passed.93 person, and an even poorer correlate to true prenatal substance exposure
The political reality of what the response is to newborn toxicology or ongoing risk from parental substance use – should not be considered a
testing is not a fixed entity. We all have the potential to change the weighty factor. They go on to describe testing in “forensic” terms,
system that exists outside of our local zones of influence within the defined as “relating to or denoting the application of scientific methods
clinical care sphere and our healthcare systems. The knowledge and and techniques to the investigation of crime” (Oxford English Dictio
expertise of the lawmakers who enacted clinical care and reporting re nary). Again, newborn toxicology tests, if they are positioned by the
quirements related to prenatal substance exposure is not superior to the healthcare community as a search for evidence of a crime, serve only to
evidence collected and presented here. entrench existing stigma attached to prenatal substance exposure and
perpetuate the failures of the current system in which people who are
Punitive responses to substance use in pregnancy: the impact on pregnant avoid prenatal care altogether and/or avoid sharing with
prenatal care prenatal clinicians information about substance use during pregnancy. If
our medical approach to prenatal substance exposure suggests that we
One of the most important questions in the care of newborns is: how view it as a crime, we have failed our patients. Breaking through this
can care take place such that clinicians have a good understanding of the wall of stigma and bias is the only way forward to allow pregnant people
substance exposure, if any, that took place during the pregnancy? What to safely seek and be provided with treatment and support during
is important for clinicians taking care of the infant during the newborn pregnancy to reduce the rate of fetuses being exposed to substances and
hospital stay is knowledge of the risk for NOWS—that is what allows for children being born into families affected by uncontrolled substance use.
optimal clinical care, including monitoring for, diagnosing, and treating

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Challenges and solutions promoting engagement, and supporting people with reaching the
end of their pregnancy in a manner where the newborn can be well
We have perpetuated non-evidence-based claims about the effect of supported. Therefore,
substance exposure in utero, and delivered inequitable and racist out a. Serial screening with a validated questionnaire starting at the first
comes to families, which perpetuates the very problem: fear. Fear is the prenatal visit and continuing through the delivery hospitalization,
barrier to the ultimate goal, which is not, at this current point in the via electronic interface or by a compassionate individual, should
opioid use pandemic, to decrease the total population of newborns at risk be prioritized.
of developing NOWS. The goal is to shift the group at risk from uncon b. Follow up with service connections, substance use disorder
trolled substance use throughout pregnancy to being part of the group at diagnosis and/or treatment including gold standard use of medi
risk from exposure to MOUD. The identification of substance use during cations for opioid use disorder (ideally by a team familiar with
pregnancy is the starting point to mitigate harms to the pregnant person substance use disorder management in the setting of pregnancy),
and harms to the fetus. This goal can only be achieved by compassionate, and family care plan establishment is essential.
evidence-based, individualized, and responsive screening for substance c. For parents with a history of substance use disorder, screening for
use during pregnancy. If, instead, toxicology testing is ordered without return to use throughout the first year postpartum can support
the knowledge or consent of the birthing person, and they are con ongoing engagement in care and identify patients with a need for
fronted with information they did not willingly share, the clinician is treatment adjustment and social support.
limited in the compassion they can demonstrate in that situation, and d. Pediatric providers, particularly those caring for infants during
the relationship may instead be harmed. The question then arises – what the newborn hospitalization, should familiarize themselves with
would the results of these toxicology tests help to clarify? Do they the practices of substance use screening and taking a compas
identify a substance in a bodily fluid? Yes. Do they clarify the potential sionate, trauma-informed substance use history. They should
diagnosis of substance use disorder? No, this is done by history- evaluate their institutional policies for the potential to perpetuate
gathering and specific criteria not including biochemical evidence of stigma and bias and move toward best practices in managing
substance.104 Do they clarify the impact on the fetus of the substance families affected by substance use disorder. They should famil
exposure? No, this is highly variable and very much dependent on the iarize themselves with their local legal landscape (CAPTA notifi
timing, amount, legal status of the substance, co-exposures to tobacco cations, mandatory reporting, and the designation of prenatal
and alcohol, social stressors during pregnancy, continuation of parental substance exposure as child abuse) and work with local partners
substance use after pregnancy, and nature of the postnatal home envi to move these systems toward justice as well.111
ronment.6-15,60 Do they clarify how we can support the pregnant person, 2. The way we enact biochemical specimen toxicology testing for sub
and ensure that they are able to successfully parent after their child is stance use during pregnancy and in newborns within our extant
born? No, certainly this is dependent on local treatment availability, system frequently works to increase stigma, reduce engagement, and
social services, and other social factors. Thus, it becomes clear there is destabilize people leading to disengagement from care and contin
limited clinical utility of toxicology tests during pregnancy, and no role uation of uncontrolled substance use up until delivery such that the
for toxicology tests separate from their use in a non-pregnant adult to newborn may not be able to be well supported in the family envi
diagnose or adjust treatment for substance use or substance use disorder. ronment. These effects are inequitably distributed, leading to worse
To quote again from Appropriate Use of Drug Testing in Clinical Addiction outcomes for families of color and families living in poverty.
Medicine, “While it can be a powerful tool, a drug test is designed to Therefore,
answer a rather narrow question: is substance X detected in sample a. Toxicology testing in pregnant patients should only be ordered
Y?”35 Ultimately, toxicology tests are best conceived of as communica with the goal of accessing substance use treatment, assessing the
tion tools, and when ordered, interpreted, and communicated about effectiveness of substance use disorder treatment, or adjusting
with patients, can be effectively employed to engage patients with treatment for substance use disorder.
substance use disorder in treatment, as well as in assessing and adjusting b. All birthing persons in whom a toxicology test is desired should be
treatment plans.35 informed and give consent before the test is ordered.
Increasing the number of pregnant people in whom we are able to c. The parents of all newborns in whom a toxicology test is desired
identify and engage with treatment for opioid use disorder must involve should be informed and give consent before the test is ordered. If
a change in the relationship between prenatal substance use and CPS consent is not provided and the test is deemed clinically neces
reporting. States that continue to require mandatory reports to CPS sary, it should be performed regardless.
agencies for use of MOUD during pregnancy are missing a substantial d. All toxicology tests sent in the perinatal period should include
opportunity to support families affected by substance use disorder. confirmatory testing (i.e. gas chromatography).
There are safe and effective systems that divert families from unnec e. Given the current level of evidence and the inequitable conse
essary and harmful interaction with family policing systems in ways that quences specific to newborn toxicology testing, ordering them in a
can more effectively lead to family stabilization and ongoing engage universal fashion is not recommended. Ordering them when there
ment in care.92,105,106 is no known substance exposure and no symptoms of NOWS is not
Systemic racism has been particularly effectively actuated through recommended. Ordering toxicology tests when there is already
inequitable policies related to substance use, and prenatal substance use knowledge of prenatal opioid exposure has no benefit related to
is a harrowing example of this.107 Racial and ethnically minoritized NOWS care, and likely harms. Toxicology tests should be sent only
groups and people living in poverty experience significantly different when the result would clarify a suspected diagnosis of NOWS or
outcomes in ways that are not explained by the clinical, medical, or change clinical management of NOWS; this is rare. The author’s
pathophysiologic effect of substance exposure. Inequity occurs in institution’s publicly available clinical care pathway specifies
screening and testing and at every step after that – reporting to CPS, such situations.112 To fulfill this clinical need, the only appro
action taken by CPS (i.e. family separation), duration of family separa priate test is urine toxicology. These tests should be sent only
tion, and chance of termination of parental rights.4,108,109,110 when attempts to obtain information from higher quality sources
To return to the framework previously expressed, the conclusions I (parental report, toxicology testing of the birthing person) have
posit are that: been exhausted. LWOD methods have no role in the diagnosis or
clinical management of NOWS.
1. The way we enact screening for substance use during pregnancy 3. Care that results in a good understanding of substance use during
within our healthcare systems can work by decreasing stigma, pregnancy allows the delivery hospitalization to be a time when the

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S. Ostfeld-Johns Seminars in Perinatology 49 (2025) 152009

family unit can be the focus. They can rest, recover from the delivery, 6. Smith VC, Wilson CR, , COMMITTEE ON SUBSTANCE USE AND PREVENTION,
Ryan SA, Gonzalez PK, Patrick SW, Quigley J, Siqueira L, Walker LR. Families
and bond. The healthcare team can confirm the plan enacted during
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use disorder (OUD) after monthly long-acting buprenorphine treatment: 12-month
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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Hospital sequelae, discharge, and early interventions in infants with

Neonatal Opioid Withdrawal Syndrome
Frances Y. Cheng *
Department of Pediatrics, Yale University School of Medicine, New Haven, CT

Introduction Feeding and weight management challenges in infants with

opioid exposure
Over the past two decades, the opioid crisis has rapidly escalated in
the United States, impacting a growing number of pregnant women and Feeding is a complex process for young infants, and it is well
their infants.1 Neonatal Opioid Withdrawal Syndrome (NOWS) is char established that those exposed to opioids can experience significant
acterized by symptoms affecting four main organ systems: central ner obstacles.22 Infants with NOWS are reported to experience feeding
vous, respiratory, gastrointestinal, and autonomic systems.2 problems during hospitalization at a rate of nearly three times more than
Traditionally, the management of infants with NOWS has relied on those without NOWS.23–26 Feeding difficulties can lead to longer hos
pharmacologic treatments; however, the Eat, Sleep, Console (ESC) pital stays, poor growth, delayed neurodevelopmental outcomes, and
approach emphasizes nonpharmacologic strategies. This approach has increased healthcare costs.27,28 Additionally, early healthcare utiliza
shown substantial and sustained reductions in average length of stay, the tion29 and complications such as failure to thrive, hyperbilirubinemia,
percentage of infants requiring morphine treatment, and overall hospital hypernatremia, and dehydration contribute significantly to neonatal
costs, without an increase in adverse events.3 Many hospitals have morbidity.30 One study examining a geographically diverse cohort in the
successfully adopted the ESC approach, reporting similar decreases in US found that infants with NOWS had nearly double the all-cause
medication needs and lengths of stay.4,5 A recent stepped wedge cluster- readmission rates within their first year, with these readmissions
randomized control trial conducted across 26 hospitals in the United being longer, more expensive, and more likely to require ICU care and
States showed a significant reduction in time to medical readiness for mechanical ventilation compared to infants without NOWS.31
discharge by 6.7 days and a decrease in length of stay by 6 days for the Withdrawal signs associated with NOWS can significantly disrupt
ESC cohort compared to those using prior standard of care.6,7 Addi feeding, manifesting as weak, excessive, or dis-coordinated sucking and
tionally, there are currently 15 quality improvement projects imple swallowing.32–34 Studies have shown that infants with NOWS consume
menting the ESC approach with comparable outcomes.5,8–21 less milk per suck, exhibit a faster swallow rate, and experience
Despite these promising results, infants with NOWS still may increased episodes of apnea during feedings.32 Furthermore, these in
encounter significant challenges during their hospital stay, at discharge, fants may demonstrate prolonged sucking, increased spitting up, refusal
and during subsequent outpatient visits. This chapter examines to feed, and heightened arousal compared to their non-opioid exposed
comprehensive care strategies aimed at improving feeding and weight counterparts.35 Maguire et al. found that infants with NOWS display less
management, fostering maternal-infant bonding, and implementing distinct feeding cues,36 such as more dis-coordinated movements, less
early interventions both during and after discharge. By focusing on these engagement with the caregiver’s face, and fewer signs of satiation.37
critical areas, healthcare providers can enhance their advocacy and Additionally, a prospective observational study revealed that the
support for infants with NOWS and their families across the spectrum of swallow-breath interaction in infants with NOWS is similarly immature
care. to that seen in preterm infants.38 Collectively, these feeding difficulties
can limit caloric intake for infants with NOWS.
In addition to restricting intake, withdrawal signs can lead to
increased energy expenditure.39 Motor disturbances such as hypertonia,

* Corresponding author at: Department of Pediatrics, Yale University, 333 Cedar St, New Haven, CT, 203-785-4651, 475-355-4483, Private Mailing Address: 289
Willow Street, New Haven, CT 06511
E-mail address: [Link]@[Link].

[Link]
Received 26 September 2024; Received in revised form 10 November 2024; Accepted 16 November 2024
Available online 17 November 2024
0146-0005/© 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Downloaded for ilgar ervanli (bektash_tabriz@[Link]) at [Link] [CK] from [Link] by Elsevier on
February 19, 2025. For personal use only. No other uses without permission. Copyright ©2025. Elsevier Inc. All rights reserved.
F.Y. Cheng Seminars in Perinatology 49 (2025) 152008

tremors, and hyperactive Moro reflexes are commonly observed and environment with little stimulation, and rooming-in (Table 1). A study
contribute to calorie expenditure, with one study indicating that they by Maguire et al identified several key themes for successful feeding:
account for 55 % of withdrawal signs.34 Disruptive behaviors during responding to the infant’s cues, maintaining a calm environment, and
feeding, including fussing–resisting feeds, grimacing, hyperextension or fostering the caregiver-infant relationship. Additional techniques iden
flailing of extremities–and crying can occur for up to 52 % of the tified by nursing and speech therapists include feeding in a flexed "C
attempted feeding period.36 Moreover, vomiting and diarrhea associ position," finding the "sweet spot" on the infant’s palate to encourage
ated with withdrawal can further deplete caloric stores, leading to sucking, vertical rocking, and experimenting with different bottle nip
dehydration and electrolyte imbalances.40 ples.57 Early verbal interactions are crucial for stimulating attention and
The combined effects of limited intake and increased calorie fostering social-emotional development in young infants. Frequent,
expenditure can impact weight management for infants with NOWS. responsive verbalizations by mothers support cognitive growth.
Studies demonstrate that these infants experience greater weight loss Furthermore, collaborative, multidisciplinary support between nurses,
compared to their non-opioid exposed peers.41,42 Studies examining providers, and speech-language pathologists can facilitate discussions
weight loss in infants managed using modified FNASS and modified about infant cues, enabling mothers to identify and respond to their
Lipsitz scoring protocols found median maximal weight losses ranging baby’s signals.55
from 4 % to 9.7 %.41,43–45 Infants managed with the Eat, Sleep, Console Breastfeeding enhances maternal-infant bonding and is associated
(ESC) approach similarly showed a median maximal weight loss of 8.5 % with milder withdrawal signs,58 reduced need for pharmacologic treat
from birth weight, but reach that maximal weight loss more quickly, ment,42 and shorter hospital stays compared to formula-fed infants.59,60
closer to the weight trajectory of non-opioid-exposed infants. Notably, Despite generally low breastfeeding rates among these infants,47 pro
the median day of maximal weight loss for this cohort was 3.0 days, moting breastfeeding, unless contraindicated, is crucial given its
comparable to non-pharmacologically treated infants in an earlier numerous benefits.61,62 The Academy of Breastfeeding Medicine
study41 yet occurring earlier than the 5 to 7 days reported in other recently updated its SUD clinical protocol to endorse breastfeeding
published studies of infants with NOWS.44,46 Percentile curves devel initiation, rather than discourage it, for mothers who stop
oped for this cohort indicate a significant portion (27 %) may lose more non-prescribed substance use either before or during delivery.63 Some
than 10 % of their birth weight, significantly higher than the 0.1 % theories suggest benefits of breastmilk may stem from a healthier
observed in non-opioid-exposed infants.47 These percentile curves pro microbiome,64 small amounts of opioid in breastmilk,65 and its easy
vide valuable guidance for weight management during withdrawal digestibility, which improves reflux and digestive issues compared to
when using the ESC approach. formula.42 Challenges to breastfeeding include issues such as poor
Despite initial weight loss, some infants exposed to opioids in utero weight gain, which can be mistaken for inadequate lactation, inconsis
may show increased appetite by 2 weeks of age.46,48 Studies report hy tent guidance from healthcare providers, and limited financial resources
perphagia- defined as intake over 200 cc/kg/day- in 56-65 % of infants or social supports.62 Additionally, a recent study showed that infants
with NOWS within their first two weeks,46,49 potentially due to neuro with NOWS who experienced feeding issues had lower odds of being
modulatory effects of opioids on brain development.50 While it has been offered lactation services than infants without NOWS diagnosed with
suggested that hyperphagia can lead to irregular growth patterns,50,51 similar feeding problems.25 Despite a strong willingness and positive
preliminary studies have not identified significant differences in weight outlook towards breastfeeding among pregnant women with substance
gain between infants with NOWS with hyperphagia and those without.48 use disorder, a recent study revealed that less than 50 % of respondents
Additionally, no notable differences in body composition or growth were aware of breastfeeding recommendations and its associated health
curves up to one year have been found between infants with opioid benefits.66 To address this gap in knowledge and concerns reported by
exposure and their non-exposed counterparts.51,52 Further research is patients, it is crucial to implement comprehensive prenatal and post
essential to determine the implications of growth restriction in infants natal education programs. These initiatives should cover breastfeeding
with NOWS on their long-term growth and development. guidelines, hospital policies supporting rooming-in, and accessible
Feeding challenges in infants with NOWS extend beyond withdrawal lactation support services, all aimed at increasing breastfeeding
signs, impacting caregivers as well. Many caregivers report experiencing rates.42,66 Additionally, there has been a growing trend in the use of
stress and frustration during feeding due to challenges in interpreting donor breast milk for newborns exposed to opioids in hospital
and responding to their infant’s cues.37,53,54 Qualitative analyses have nurseries.56
highlighted maternal concerns about feeding volume, pace, and poten For formula-fed infants with NOWS, there is currently no consensus
tial adverse outcomes,55 which may lead them to engage in excessive on the optimal formula type. One study indicated that low-lactose for
feeding as a means to soothe their infant’s irritability and atypical mula does not offer advantages over standard formula in terms of
sucking patterns.51 The lack of clarity in feeding cues can contribute to treatment length or weight change.67 Similarly, a double-blind ran
decreased maternal sensitivity,37 creating a cycle of stress for both domized trial found no differences in cumulative morphine dose,
caregiver and infant. duration of pharmacologic treatment, or length of stay between
To support this population, there is a need for educational and lactose-free and lactose-containing formulas.68 A retrospective review
counseling programs that assist parents and caregivers in recognizing comparing partially hydrolyzed to standard formula also reported no
and effectively responding to the unique feeding patterns observed in significant differences in morphine requirements, treatment duration, or
infants with NOWS. Furthermore, additional research is warranted to length of stay.69 Taken together, these studies suggest that use of
identify infants most at risk for feeding difficulties in an effort to facil low-lactose or hydrolyzed formulas have not shown meaningful differ
itate targeted interventions that can improve outcomes for this at-risk ences in hospitalization outcomes.67–70
population. Regardless of feeding method, infants should be fed on-demand
rather than on a schedule to avoid exacerbating withdrawal symp
Approaches for feeding and weight management in infants with toms.71 Multiple QI initiatives have successfully included on-demand
NOWS feeding as part of a QI bundle of interventions in an effort to decrease
pharmacologic use, reduce length of stay, and reduce hospital costs for
Currently feeding practices for infants with NOWS vary widely in the infants with NOWS.3,72 Infants with significant weight loss or feeding
US;56 implementing strategies to optimize the nutritional needs of in difficulties may benefit from nasogastric tube feedings rather than im
fants with NOWS is critical given the feeding and growth challenges they mediate pharmacological interventions, a practice that is supported by
face. Management of feeding should emphasize non-pharmacological current literature.28,47,73,74 Early caloric supplementation could also aid
strategies, including swaddling and holding, maintaining a quiet weight gain in these infants, considering their increased caloric needs

Table 1
Feeding and weight management strategies during birth hospitalization.
Non-pharmacologic strategies: swaddling and holding, low stimulation environment, rooming-in, parental presence, skin-to-skin contact
Speech/OT/PT Support
Lactation Support
Encouraging Breastfeeding
On-Demand Feeding
High Calorie Supplementation
Consider: Nasogastric Tube Utilization

and risk for limited intake.43,47,62 A recent randomized controlled trial evaluate the effectiveness of these methods continuously and make
demonstrated feasibility of high calorie formula in infants managed by a informed decisions about their infant’s care. Family engagement in the
modified Finnegan approach even though it was not powered to detect care team can be facilitated by open communication between healthcare
significant differences in outcomes between the high and standard cal providers and parents.82
orie groups.46 Additionally, a multicenter quality improvement initia Mothers of infants with NOWS often express feelings of guilt,61,76,81
tive indicated that using higher calorie formula resulted in reduced but as they become more involved in their infants care, they report
weight loss, need for additional medications, and length of hospital mutual benefits for their infants and themselves.83,86 By actively
stays.70 participating in their infant’s care, parents can gain a sense of agency,
Further investigation into optimal feeding strategies for infants with empowering them to lead care for their infant.87,88 Bonding can also be
NOWS is essential, as prioritizing early evaluation and intervention can strengthened by a low stimulation environment and intermittent vital
improve nutrition, enhance oral feeding skills, and reduce the risk of signs by reducing disruptions and allowing for undisturbed rest for the
long-term feeding difficulties in this high risk population.22 Addition infant. Breastfeeding also plays a well-documented role in fostering in
ally, there is a need to establish interventions specifically targeted to fant attachment.58
wards weight management in hospitalized infants with NOWS.75,76 Interventions after discharge aimed at enhancing maternal-infant
bonding can be particularly beneficial for women with SUD and their
Promotion of maternal-infant bonding in NOWS infants.42 As demonstrated by a randomized clinical trial,
attachment-based parenting therapy programs can effectively improve
The well-being of the maternal-infant dyad is central to the care of early parenting experiences.80 To foster positive interactions, in
infants with NOWS. Fostering bonding between dyads can reduce the terventions should address the mutual distrust that often exists between
likelihood of adverse outcomes, have a lifelong impact on health, and healthcare providers and parents with SUDs. Many postpartum mothers
enable mothers to adhere to health-promoting activities such as with SUDs have reported a preference for a normal parenting experience
compliance with SUD treatment and self-care.77,78 However, state level without excessive medical oversight, reflecting previous experiences
approaches to pregnancy and SUD vary significantly, from expansion of where their parenting abilities were questioned by healthcare pro
medication assisted treatment programs to implementation of punitive viders.89 Emphasizing supportive attachment and promoting parent
measures. Some states go so far as to consider both prescribed and self-efficacy is essential, rather than increasing surveillance by health
non-prescribed maternal substance use as child abuse. It remains unclear care providers.89 Furthermore, clinicians should advocate for and sup
how these policies can improve outcomes for children prenatally port mothers in building their confidence and connection with their
exposed to substances.79 infants. A recent study indicated that mothers whose infants needed
Mothers with SUDs face many barriers in the process of bonding with pharmacological treatment for NOWS are at higher risk for depression.90
their infants. Mothers’ own experiences with past attachment or stress Addressing maternal mental health through support and medical treat
can result in insecure attachment with their infant, as can the effects of ment is crucial, as untreated mental health conditions in mothers are
opioids on brain reward pathways.80 Physical separation, which can associated with reduced maternal-infant bonding91 and adverse neuro
occur even during birth hospitalization as part of the FNASS approach, developmental outcomes in infants.92
remains a significant barrier. Many institutions do not support
rooming-in after maternal discharge, and mothers may need to leave the Safe discharge processes and early interventions after discharge
hospital daily to obtain their SUD treatment. Stressors related to
perceived judgment from clinicians and Department of Children and Ongoing, multidisciplinary outpatient care that addresses the unique
Families involvement and custody can affect the mother’s ability to be medical and social needs of infants with NOWS is essential for lasting
emotionally available to bond with their infant.81,79,82 Mothers’ own outcomes. Infants with NOWS often face higher rates of missed ap
experiences with past attachment or stress can result in insecure pointments, emergency room visits, hospital readmissions,93 early
attachment with their infant, as can the effects of opioids on brain childhood mortality,94 foster care placement, and involvement with
reward pathways.80 For instance, Cleveland et al. noted that every child protective services95 compared to unexposed infants. Despite the
mother involved wanted to be recognized as their infant’s mother, and rising incidence of NOWS, funding for social service systems has
voiced frustration when they felt their role was not acknowledged by remained stagnant,96 exacerbating health disparities and highlighting
staff.83 Communication inconsistencies, especially around breastfeed the challenging socioeconomic conditions these infants face.
ing, further exacerbated these difficulties.84 Similarly, NOWS itself can In the United States, infants with NOWS can benefits from resources
affect bonding as autonomic pathways are dysregulated, impeding the under the Child Abuse Prevention and Treatment Act (CAPTA), which
infant’s ability to communicate their needs effectively.85 requires safe discharge procedures and access to appropriate outpatient
Active involvement from parents in caring for infants with NOWS care. Effective discharge planning should include caregiver education on
during hospitalization is crucial when possible. Comprehensive and withdrawal signs, provision of social support, emphasis on early hospital
consistent prenatal education on NOWS signs can help caregivers bond follow-up, and access to rehabilitation services.28 Given the increased
with their babies by preparing them to anticipate and meet their infant’s risks of adverse cognitive, psychomotor, and behavioral outcomes in
needs.85 The non-pharmacological interventions for NOWS support early childhood, early intervention services and development clinics are
maternal-infant bonding. These include breastfeeding, skin-to-skin recommended.97 Weight monitoring, psychosocial support, and care
contact, rooming-in, maintaining a low stimulation environment, and navigation services through home-based nursing assessments can help
encouraging family participation. With rooming-in, parents are able to improve healthcare utilization (Table 2). Specialized outpatient clinics

Table 2
Discharge considerations for infants with NOWS.
Consider: Clinical parameters and timing of discharge
Anticipatory Guidance
Pediatrician Follow-up
Lactation Support
Early Intervention Services
Developmental Clinic Referral
Visiting Nurse
Care Navigation Services
Connection through Social Work or OB: Maternal Behavioral Health and Recovery Services; consider peer support specialists, harm reduction strategies

for infants with NOWS could better address their complex medical, so Summary
cial, and developmental needs while providing support to caregivers.
While long-term outcomes for infants treated under the ESC Over the past 20 years, there has been a notable increase in the
approach are still pending, data from our hospital indicates no rise in prevalence of NOWS. The ESC approach prioritizes nonpharmacologic
readmission rates or adverse events.98 Research on neurodevelopmental techniques such as rooming-in, creating low stimulation environments,
outcomes after hospital discharge presents varied results. Early studies increasing family support, with medication reserved for short-term use
linked opioids such as methadone and heroin to potential impairments when necessary. Inpatient care should address not only the infant’s
in intellectual, language, and motor development; however, many of feeding, weight management, and bonding with caregivers, but also
these studies did not have control groups or account for confounding provide support for postpartum care for the mother. After discharge, it is
variables.99 More recent research, which has adjusted for socioeconomic essential to continue monitoring the infant’s development and to pro
factors, found no significant cognitive differences,99 except that boys vide integrated care that includes maternal behavioral and recovery
exposed to multiple substances had lower intellectual development services to ensure positive outcomes. Expanding support systems to
scores on the Bayley Scales of Infant Development.100 Additionally, encompass social and environmental factors that impact both maternal
comparisons between infants exposed to buprenorphine vs methadone well-being and child development is crucial for improving outcomes for
revealed minimal differences in neurodevelopmental outcomes.101,102 A families affected by opioid exposure.
recent prospective study showed that infants who received pharmaco
logical treatment for NOWS had lower Bayley Scales of Infant Devel Funding/Support
opment scores at age one,103 and another study noted lower scores at age
2 compared to the general population, though these scores remained No external funding for this manuscript.
within one standard deviation of the mean.104
Research on long-term cognitive outcomes in children exposed to CRediT authorship contribution statement
prenatal opioids beyond the age of 2 similarly remains inconclusive.
Some studies have identified differences in IQ, neurological develop Frances Y. Cheng: Writing – review & editing, Writing – original
ment, and language skills, particularly in boys,105 but these findings are draft, Conceptualization.
not consistent. Behavioral issues, such as aggression and symptoms of
ADHD, are more reliably associated with prenatal opioid exposure, Data availability
whereas results for executive functioning and visual-motor skills are
mixed.99 The challenge in establishing conclusive evidence stems from No data was used for the research described in the article.
difficulties in isolating the specific effects of maternal opioid use from
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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Comparisons of management approaches in neonatal opioid withdrawal

syndrome: The eat, sleep, console approach vs. the Finnegan approach
Kia Johnson * , Adam Berkwitt , Lyubina Yankova , Rachel Osborn
Yale School of Medicine, New Haven, CT, USA

A R T I C L E I N F O A B S T R A C T

* Corresponding author.
E-mail addresses: [Link]@[Link] (K. Johnson), [Link]@[Link] (A. Berkwitt).

[Link]
Received 2 October 2024; Received in revised form 26 November 2024; Accepted 17 December 2024
Available online 18 December 2024
0146-0005/Published by Elsevier Inc.

Fig. 1. ESC Implementation Goals.

Fig. 2. NOWS Clinical Pathway featuring ESC.

Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Beyond a simple cause and effect relationship: Exploring the long-term

outcomes of children prenatally exposed to opioids and other substances
Ekaterina Burduli a,b, Hendrée E Jones c,*
a
Washington State University, College of Nursing, Spokane, WA, USA
b
Washington State University, Department of Community and Behavioral Health, Elson S. Floyd College of Medicine, Spokane, WA, USA
c
University of North Carolina at Chapel Hill, UNC Horizons, Department of Obstetrics and Gynecology, Chapel Hill, NC, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The long-term outcomes of children exposed to opioids and other substances in utero, specifically those diag
Neonatal abstinence syndrome nosed with Neonatal Abstinence Syndrome (NAS), present a complex interaction of different factors. First, NAS
Neonatal opioid withdrawal and its clinical presentation will be defined, then summarized will be an overview of NAS prevalence, recent
Opioid use
trends, and significance of NAS in the context of the rising synthetic opioid and polysubstance use. Highlighted
Perinatal, Long-term outcomes
Child
will also be the identified risk factors for NAS, especially regarding the role of environmental and psychosocial
Pregnancy stressors during pregnancy. Finally, reviewed will be the existing NAS literature, including its gaps and limita
tions, and suggested recommendations for future research and policy considerations for improving care for
children and families impacted by NAS.

Introduction noted in the opioid agonist medication labels that it is possible, yet rare,
that NAS could lead to infant death. Based upon ways NAS is addressed
Definition of NAS, definition of NOWS, how they are distinct and treated, extended hospital stays after birth may occur. Symptoms
usually emerge within 2-7 days of delivery and can last from several
NAS refers to a group of substance withdrawal signs and symptoms days to several weeks post birth.1,2,9 Most recently, a new standardized
experienced by newborns that were exposed to substances, including clinical definition of opioid withdrawal in neonates was published. This
opioids, in utero. Although the term Neonatal Opioid Withdrawal Syn new definition aims to advance clinical care, quality improvement,
drome (NOWS) has been recently used, NOWS specifically refers to research, and public policy for this patient population. This new clinical
opioid-only related withdrawal and can be conceptualized as a subset defined opioid withdrawal in neonates as needing both in utero opioid
NAS. NAS may manifest following chronic in utero exposure to multiple exposure (identified by history, not requiring toxicology testing) with or
substances, often including opioids (either illicit or prescribed medica without the presence of other psychotropic substances, and the presence
tion for opioid use disorder).1,2 Infants with NAS experience signs and of at least two of the most common clinical signs characteristic of
symptoms related to abrupt post-partum discontinuation of opioid withdrawal (excessive crying, fragmented sleep, gastrointestinal
exposure, including autonomic and neurobehavioral dysfunction, dysfunction, increased muscle tone, and tremors). For the first time,
potentially due to uteroplacental insufficiency and intrauterine growth such a clinical definition was grounded in a set of bioethical founda
restriction.1-6 NAS is characterized by changes in the central nervous tional principles to specify uses for the definition. These principles both
system, gastrointestinal tract, and/or autonomic nervous system and can aim to prioritize the dyad, and avoid misuse of the clinical definition.
result in a wide range of withdrawal signs and symptoms in any of four Specifically, the principles note that the definition should not be mis
areas: state control and attention, motor and tone control, sensory construed as evidence of harm or used to prosecute, punish, or remove
integration, and autonomic functioning,1,2 as well as birth complications neonates from parental custody.10
including but not limited to: low birth weight, preterm, sepsis, feeding
difficulties, increased irritability, tremors, seizures, jaundice, breathing
problems.1,7,8 If fully untreated, the Food and Drug Administration has

* Corresponding author at: 410 North Greensboro Street, Carrboro, NC 27510.

E-mail address: hendree_jones@[Link] (H.E. Jones).

[Link]
Received 1 October 2024; Received in revised form 23 November 2024; Accepted 2 December 2024
Available online 7 December 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

NAS prevalence and perinatal substance use trends in the US over the last severe cases, seizures typically occurring around the third day after
few decades birth. Many of these infants did not survive, as the cause of their
symptoms was unknown at the time.7,16 By 1901, researchers deter
Substance use and substance use disorders (SUDs) during pregnancy mined that the infants were experiencing withdrawal from opioid
remain a widespread concern, with significant implications for both exposure in- utero, and small doses of opium were found to relieve their
maternal and neonatal health. In 2020, between 8 percent and 11 symptoms. The cluster of withdrawal symptoms in infants, now referred
percent of pregnant women aged 15 to 44 reported using illicit drugs, to as NAS, was first explicitly documented in the scientific literature in
tobacco products, or alcohol in the past month.11 Recent studies have Dr. Loretta Finnegan’s seminal work in 1975.19,20 Fast forward to the
highlighted the rising incidence of opioid use during the general popu 21st century, NAS has become a growing issue due to the continued
lation as well as in pregnancy, contributing to an increase in NAS cases. evolution of the opioid crisis and steady increases in opioid use in the
For instance, between 2010 and 2017, opioid use among pregnant in general population that is also mirrored in the perinatal population. In
dividuals surged by 131%, while the rate of NAS increased by 82%.12 2020, more than 6% of US pregnant women self-reported prenatal
The most recent data from the Transformed Medicaid Statistical Infor opioid use. Also in 2020, West Virginia reported the highest rate of NAS
mation System Analytic Files13 showed that while the estimated US rate in the United States, with 68 cases per 1,000 live births.13 While opioid
of NAS has decreased by 18% between 2016–2020, the rate of prenatal withdrawal signs and symptoms have been recognized for over 100
substance exposure rose by 3.6% during the same time, reflecting sig years, and NAS as a syndrome for nearly 50 years, the past century has
nificant variation across states. From 2016 to 2020, 38 states saw an seen significant shifts, including a sharp rise in its prevalence and
increase in prenatal substance exposure, while 10 saw a decline. At the notable changes in both the substances involved in prenatal exposure
same time, NAS rates declined in 28 states and increased in 20, varying and approaches to clinical management.
from 3.2 per 1,000 births in Hawaii to 68.0 in West Virginia in 2020.13
This growing trend underscores the urgent need for targeted in Why NAS is a significant issue in neonatal care, the increasing incidence of
terventions that address both substance use during pregnancy and the NAS in the context of the opioid/fentanyl/methamphetamine epidemic
broader socio-environmental factors that exacerbate these outcomes.
The variation in NAS rates across states points to underlying disparities The ongoing opioid crisis in the United States has caused widespread
in access to healthcare and social services. harm to families and society as a whole and has continually raised sig
nificant concerns about the short and long-term consequences of pre
Brief history of NAS and substance use during pregnancy natal opioid exposure. The rise in the use of powerful synthetic opioids
like fentanyl, along with the concurrent use of opioids and substances
Opium use dates back over 6,000 years, initially used for its euphoric such as methamphetamine21 has heightened concerns about the impact
effects and later for medical purposes such as pain relief, respiratory of fentanyl and stimulant use on the assessment, treatment, and
issues, and mental health disorders. The isolation of morphine in 1803 long-term outcomes for children and families affected by NAS. In 2019,
marked the start of widespread medical use, but also led to growing 51.7% of pregnant individuals using heroin also reported metham
addiction issues.14,15 In 1827, the pharmaceutical company Merck phetamine use.22 Additionally, mortality rates linked to fentanyl and
began marketing morphine for the treatment of pain, as well as to help stimulant use among pregnant and postpartum individuals more than
with opium addiction and alcoholism. Interestingly, morphine use was doubled between 2017 and 2020.23 Emerging research suggests that
disproportionately higher among women, particularly those from mid fentanyl use during pregnancy may have more severe and prolonged
dle- and upper-middle-class backgrounds, who were twice as likely as effects on neonates than traditional opioids and could be terato
men to use the drug in the US. By 1898, heroin, a more potent derivative, genic.24-26 Some case studies further indicate that fentanyl and poly
was introduced and falsely believed to be non-addictive.14-16 In 1906, substance use during pregnancy may lead to unique withdrawal patterns
the American Medical Association approved heroin for general medical not typically observed with NAS.27 However, current research is limited
use and recommended it as an alternative to morphine. This led to its to animal models and human case reports only. The extreme potency of
widespread use, including as a recreational drug. In the U.S., heroin was fentanyl, especially when combined with stimulants like methamphet
sold over-the-counter to remedy common conditions (such as flu, colds, amine, can also worsen the harms of addiction in parents. Limited access
sore throats, pneumonia, and tuberculosis) until the early 1900s, to treatment options for pregnant individuals experiencing substance
including for pregnant women and infants. Addiction soared, particu use adds another layer of difficulty and constitutes a barrier28-30 for
larly among women prescribed opioids for various ailments. This lack of parents to engage in care of their newborns. The lack of care access, in
regulation led to the Harrison Narcotic Act of 1914, which sought to turn, can often result in more prolonged NAS signs and symptoms and
control narcotic distribution.7,14,15 The modern opioid epidemic evolved worse outcomes for newborns, beyond what might be expected from
with the introduction of synthetic opioids like oxycodone, methadone, fentanyl and stimulant exposure alone.
and buprenorphine, which became common in pain management and
addiction treatment in the 20th century. Historically, treatment for Risk Factors: Maternal substance use, socioeconomic factors, racism and
opioid use disorder in pregnant women has focused mainly on heroin discrimination, access to prenatal care, and co-occurring mental health
addiction. With the growing prevalence of opioid pain reliever misuse disorders
since the 1990’s, including medications like oxycodone, treatment
strategies have shifted.7 Opioid agonist therapy intervention, that in The severity and duration of NAS can be influenced by multiple
cludes methadone and buprenorphine, has been a central element of factors, including prenatal exposure to various substances (i.e., poly
care for OUD in pregnant women.17,18 Despite these advancements, substance use), co-occurring mental health conditions, and a myriad of
opioid use, especially among pregnant women, remains a significant external environmental stressors.7,31-35 Perinatal individuals with
public health issue. opioid use disorders (OUD) are at a heightened risk for using additional
In 1875, symptoms that constitute the condition now known as NAS substances, such as alcohol, tobacco, marijuana, and stimulants, which
were first recognized under the term Congenital Morphinism in Ger can further complicate fetal development.5,36-39 These additional sub
many.7,16 At that time, it was mistakenly believed that opioid use in stance exposures may either intensify the risks or interact with opioids in
pregnant women had no impact on their newborns, as morphine was ways that alter the developmental trajectory of the fetus. For example,
associated with female sterility and diminished sexual desire. This view tobacco smoking during pregnancy is a significant contributor to
changed when multiple cases of infants born to mothers using morphine adverse neonatal outcomes, as it can disrupt fetal brain development by
prenatally began exhibiting symptoms such as persistent crying and, in affecting key regulatory genes, leading to increased risks for conditions

such as ADHD, bipolar disorder, and depression.39,40 Additionally, changes that can be passed down through generations. External in
co-using opioids with alcohol or benzodiazepines can enhance euphoric fluences, such as socioeconomic status, the quality of caregiving, and
effects while exacerbating respiratory depression, whereas the use of exposure to environmental toxins, often have significant implications on
stimulants in conjunction with opioids may obscure sedative effects, a child’s cognitive and emotional development. For instance, children
leading to serious cardiovascular complications.5 Certain combinations raised in poverty or exposed to chronic stress may face additional
can also have unique biochemical impacts on the fetal brain, potentially challenges beyond the direct effects of prenatal substance exposure.66-69
resulting in poor fetal growth. Patrick et al. (2015)41 found, through a Emerging research also highlights the role of epigenetics, where pre
retrospective chart review, that prenatal exposure to nicotine, different natal stressors—both psychosocial and physical—can leave lasting
types of opioids, and selective serotonin reuptake inhibitors (SSRIs) "imprints" on the developing brain, affecting everything from stress
increased the likelihood of NOWS. response systems to emotional regulation.70-74 These epigenetic markers
Opioid use during pregnancy, especially OUD that is untreated with may also be influenced by paternal factors, such as substance use, diet,
medications often results in lack of engagement in prenatal care services and stress levels, which further complicates the developmental
thus increasing the risk of complications such as fetal growth restriction, picture.75,76
placental abruption, fetal death, and preterm labor.42-45 These birth Moreover, internal maternal conditions, such as nutrition, obesity,
complications, independent of prenatal substance exposure, are linked and mental health disorders like depression and anxiety, contribute to a
to poorer developmental outcomes in children.46,47 Environmental higher risk of developmental delays.32,67,77-81 For example, maternal
stressors, such as poverty and systemic discrimination, also contribute to obesity is linked to increased risks of adverse outcomes such as stillbirth,
the challenges families impacted by SUDs face, particularly when they preterm birth, congenital anomalies, and neonatal intensive care unit
are unable to access adequate prenatal care. Pregnant individuals with admissions.82 Inadequate maternal nutrition during pregnancy has been
OUD/SUDs, especially from minoritized and marginalized populations, linked to unfavorable birth outcomes and long-term negative effects on
are at increased risks of violence, child protective services referral and fetal development in several trials and cohort studies.83-86 Moreover,
involvement, family separation, and criminal justice system involve maternal mental health and co-occurring psychiatric disorders directly
ment.48-52 These individual and combined socioeconomic stressors and indirectly influence birth outcomes and eventual infant develop
negatively affect the mental and physical health of pregnant women, ment. For example, maternal stress during pregnancy has been associ
limiting their access to quality prenatal care.28 Together with substance ated with delayed motor and cognitive functions in children,
exposure, these factors significantly influence neonatal and develop underscoring the interconnected nature of internal and external fac
mental outcomes in children. tors.67,69 Given these diverse and overlapping influences on children’s
Pregnant women with OUD encounter significant challenges in long term outcomes, it is essential to adopt a holistic approach when
accessing and maintaining effective OUD care during the perinatal assessing the neurodevelopmental outcomes of children exposed to
period, with these barriers being even more pronounced for marginal opioids in utero. This approach must consider not just the prenatal
ized groups.30,48,53-55 For example, research shows that white exposure itself but also the cumulative effects of environmental condi
non-Hispanic women are more likely than Black and Hispanic women to tions, parental care, and broader socio-economic circumstances.
receive MOUD during and after pregnancy.30,53-55 Non-Hispanic Black
women often face both overt and implicit biases in healthcare, along Neurobiology: The neurodevelopmental implications of in-utero exposure
with societal obstacles like lack of insurance and discrimination. and NAS
Structural racism results in inadequate care, limited treatment options,
and increased legal repercussions for women of color, particularly Black Prenatal exposure to opioids and other substances can significantly
women, who are more frequently reported to child welfare services and disrupt the developing brain, with far-reaching implications for neuro
subjected to drug testing.49-51 This scrutiny can discourage disclosure of development.87,88 These disruptions manifest as withdrawal signs and
substance use and rapport with healthcare providers, further reducing symptoms in newborns, but also can result in impaired neurological
SUD treatment access and as a result, worsening outcomes for children. function, with potential long-term effects on cognitive, motor, and
Those with OUD also often require support for co-occurring mental behavioral outcomes.1,8,9,89 Children exposed to opioids in utero are at
health conditions such as depression, PTSD, and anxiety, with studies greater risk for developmental and behavioral challenges, including
showing that women with OUD have higher rates of postpartum difficulties with learning, attention, cognitive and motor skills, as well as
depression and nearly a third of pregnant women in SUD treatment delayed educational progress. They are also more likely to develop
report moderate to severe depression.32,56 These co-occurring mental conditions like attention deficit hyperactivity disorder and autism
health and psychiatric conditions that perinatal individuals with OUD spectrum disorder.87,90-94 In-utero opioid exposure can interfere with
experience further hinder their access to SUD treatment and negatively the normal development of the central nervous system, altering the
impact NAS/NOWS symptoms and infant outcomes.57-59 The frag trajectory of brain growth and organization. Opioids can affect neural
mented healthcare system in the US and the resulting lack of access to pathways related to pain regulation, stress response, and emotional
comprehensive both mental health services and substance use treatment regulation.90,95 Chronic opioid exposure can dysregulate the
are particular barriers for perinatal individuals with SUDs, which con hypothalamic-pituitary-adrenal (HPA) axis, which governs the body’s
tributes to worse infant and child outcomes via multiple epigenetic and response to stress. This dysregulation can lead to heightened stress
environmental pathways.33,60-62 reactivity in infants, increasing their vulnerability to emotional and
behavioral disorders as they grow.67 Research also suggests that NAS
Long-term outcomes and prognosis may alter synaptic connections, delay myelination, and disrupt neuro
transmitter systems, particularly dopamine and serotonin, which are
Multiple factors influence developmental outcomes essential for emotional regulation and learning.96-99 These neurobio
logical changes contribute to the developmental delays and behavioral
Developmental outcomes in children exposed to substances prena challenges commonly seen in children with a history of prenatal opioid
tally are shaped by a range of complex and interconnected factors. While exposure. Structural abnormalities in brain regions like the basal
prenatal opioid exposure has been studied for its direct effects on neu ganglia, cerebellum, and corpus callosum have also been observed in
rodevelopment, the child’s broader environment, genetic makeup, and imaging studies of infants exposed to opioids.96,100-102 These areas of the
parental behaviors play equally critical roles in shaping long-term out brain are crucial for motor coordination, emotional control, and exec
comes.63-65 Key factors influencing development include genetic pre utive function, all of which can be impaired in children with NAS.
dispositions, the impact of environmental stressors, and epigenetic However, the full extent of the neurodevelopmental impact of NAS

varies greatly, influenced by factors such as the duration and severity of conditions can impact neurodevelopment in children. For example,
opioid exposure, co-occurring substance use, and the quality of post maternal obesity has been linked to long-term health issues in children,
natal care. Children with NAS are not uniformly affected, and many such as asthma, heart disease, type 2 diabetes, and neurodevelopmental
show significant recovery with the right support, highlighting the disorders like cerebral palsy.77 Stress during pregnancy has also been
importance of early intervention and supportive environments in miti connected to delays in motor and cognitive development.69 Adequate
gating long-term deficits. maternal nutrition is another key factor, as deficiencies in important
A combination of physical and socio-economic environmental fac nutrients, such as fatty acids, vitamins, and minerals, have been asso
tors, including maternal age, overall health,103 exposure to toxins, ciated with developmental disorders, including ADHD and autism.112
poverty, climate change, and systemic discrimination, have been shown Furthermore, maternal infections, like Zika, rubella, and herpes virus,
to significantly impact birth outcomes and neurodevelopment in chil can lead to serious complications such as miscarriage or congenital ab
dren. Pregnant women who use opioids often face compounded chal normalities, potentially affecting the child’s neurodevelopment.113
lenges such as inadequate nutrition, limited access to healthcare, and a These risks are heightened when micronutrient deficiencies, like inad
higher likelihood of experiencing violence.52 Many also have a history of equate folic acid, are also present.114 These internal factors are often
physical, sexual, or emotional abuse and trauma,28 which can contribute intertwined with external challenges like poverty, stress, physical and
to neuroendocrine imbalances,104 further exacerbating the negative ef social environment, and limited access to healthcare, which can exac
fects on both maternal and child health. Exposure to environmental erbate the risks to both the mother and child. Recognizing the inter
toxins, including pesticides and lead, has been linked to various devel connected nature of these influences is essential when examining the
opmental challenges. Pesticides are associated with cognitive delays, neurodevelopmental outcomes of children, particularly those exposed to
attention problems, and an increased risk of developing ADHD,105 while opioids in utero.
even low levels of lead can adversely affect both physical and mental Pregnant women with OUD also frequently experience high rates of
health, leading to long-term cognitive and behavioral issues.106 These co-occurring mental health conditions like depression, PTSD, and anx
risks are further amplified by structural inequalities, where historically iety,32,34,56 which can further hinder access to SUD treatment and
marginalized communities are more likely to be living in substandard negatively impact NAS symptoms and long-term infant outcomes.57-59
housing and in impaired air quality, are more vulnerable to toxic envi The combination of stress, anxiety, and depression during pregnancy has
ronmental exposures and the negative impacts of climate change.107,108 been tied to negative neurodevelopmental outcomes in children,
The effects of climate change on health, specifically, the impact of including behavioral issues, smaller head size, and impaired cognitive
ambient air quality and wildfire smoke on neonatal outcomes has been abilities.67 For example, research shows that maternal depression is
the focus of ample recent research, highlighting that these environ intricately linked to various neurodevelopmental challenges in children.
mental exposures, exacerbated by climate change, are linked to serious Studies indicate that pregnant women living with depression face an
negative pregnancy outcomes across the United States, particularly elevated likelihood of having a child diagnosed with autism spectrum
impacting minority populations.109 For example, a cohort study of disorder, regardless of whether they are treated with depression medi
n=628 low-income pregnant Hispanic women assessed the relationship cations.78 Depression is particularly common among pregnant women
between specific windows of air pollution exposure during pregnancy with OUDs, likely stemming from exposure to trauma and unstable en
and birth weight, while also examining the influence of individual- and vironments.115 A recent study found that 25% of mothers with infants
neighborhood-level stressors.110 The main finding revealed that expo diagnosed with NAS or exposed to opioids without a NAS diagnosis were
sure to particulate matter and nitrogen dioxide from early to also diagnosed with depression.35 The symptoms associated with NAS
mid-pregnancy was linked to lower birth weight, with the effects being can further disrupt the mother-infant attachment, particularly for
more pronounced in mothers experiencing higher levels of personal women with SUDs, who may struggle to respond to their infants’ cues
stress and living in neighborhoods with greater environmental due to existing psychiatric comorbidities. This disruption can potentially
stressors.110 Studies on environmental disasters such as hurricanes, increase the risk of worsening psychological conditions for mothers
floods, wildfires, as well as extreme temperatures, show that in some postpartum, such as depression and anxiety, as well as contribute to
cases, communities of color—including Black, Latinx, Native American, relapse or discontinuation of treatment. For the newborn, this impaired
Pacific Islander, and Asian populations—face a higher risk of bond can result in poorer health and developmental outcomes.116,117
climate-related health impacts compared to White populations.111
Furthermore, specifically for pregnant and parenting populations, racial Developmental outcomes: Current data on potential cognitive, behavioral,
and socioeconomic disparities frequently intersect with such environ and motor development issues in children with NAS
mental risks, creating disproportionate impacts on child development. A
systematic review examining the effects of prenatal exposure to fine The evidence on the effects of prenatal opioid exposure and its link to
particulate matter, ozone, and heat on preterm birth, low birth weight, adverse developmental outcomes in children is inconsistent and reflects
and stillbirth, revealed that among the 68 studies analyzed, a significant a broad spectrum of outcomes.63,74,118 Some studies found neuro
association was found between air pollution and heat exposure with behavioral abnormalities in newborns and children exposed to opioids
adverse birth outcomes, particularly increased risks of preterm birth and in utero, such as difficulties with autonomic nervous system regulation,
low birth weight, with heightened vulnerability observed in populations and muscle tone, along with deficits in attention processing and higher
with asthma and among minority groups, especially Black mothers.109 In rates of conditions like ADHD and oppositional defiant
addition, a systematic review assessing the role of race as a risk factor in disorder.87,91,93,94,119-122 Other systematic investigations suggest a more
air pollution-related adverse pregnancy outcomes revealed that Black nuanced picture, with developmental outcomes influenced by environ
and Hispanic mothers experience a higher incidence of adverse out mental factors and the potential for recovery.123-125 Some research
comes, such as preterm birth, low birth weight, and stillbirth, due to air suggests that while early developmental delays are common among
pollution compared to non-Hispanic White mothers, with the disparities prenatally substance-exposed children, they may experience develop
largely driven by social and economic factors.108 Additionally, poverty mental normalization by toddlerhood.124 Collectively, these studies
significantly influences child development by increasing exposure to emphasize the complex and multifaceted nature of prenatal opioid ex
adverse childhood experiences, poor health, and a higher likelihood of posure’s impact on early childhood development. In a recent systematic
behavioral problems and lower academic achievement.66 These inter review by Carter et al., (2024)118, researchers aimed to clarify the mixed
related environmental challenges reflect the complex means by which literature and explored the complex relationship between prenatal
structural inequalities and neurodevelopment intersect. opioid exposure and early childhood cognitive, motor, and psychosocial
In addition to environmental factors, a range of maternal health developmental outcomes, as assessed primarily using the Bayley Scales

of Infant and Toddler Development, while examining studies that methadone or buprenorphine, with developmental outcomes aligning
controlled for known confounding variables. This review concluded that with population norms, despite the absence of a separate control
the adverse outcomes often attributed to prenatal opioid exposure are group.65 Additionally, a large retrospective analysis found no general
not statistically significant after controlling socio-environmental factors correlation between fetal opioid exposure and neurodevelopmental
such as family dynamics and socioeconomic status. Findings under disorders, although a specific subgroup of infants born to mothers on
scored that developmental delays are more closely linked to environ higher doses of prescription opioids for longer durations did exhibit
mental influences—like poverty, caregiving quality, and numerous some associations.133 Overall, the majority of studies that accounted for
other environmental stressors—than to opioid exposure itself. While confounding variables indicated no significant differences in infant
previous studies have shown mixed results regarding long-term out neurodevelopment linked to prenatal opioid exposure.63,64,90,118,134-136
comes, with some children recovering by toddlerhood, the need for Determining the exact effects of prenatal opioid exposure on neu
further research is highlighted to clarify these associations and disen rodevelopment remains a challenge, mainly because many studies have
tangle the effects of prenatal exposure from confounding small sample sizes and fail to consider important confounding factors,
socio-environmental variables. The Carter et al. review emphasizes the such as maternal psychological health, polysubstance use, nutrition, and
importance of shifting policy focus towards strengthening socioeconomic conditions. In studies that do control for these variables,
socio-environmental supports to enhance developmental outcomes for opioids often appear to have less significant effects. Additionally, very
children affected by prenatal opioid exposure. few studies have thoroughly examined the impact of multiple substance
In summary, while prenatal opioid exposure may correlate with exposures. This makes it difficult to pinpoint whether neuro
developmental challenges, the child’s environment plays a critical role developmental problems stem from opioid use specifically or from other
in determining outcomes. The developmental outcomes for children factors like polysubstance use (e.g. nicotine) or the myriads of envi
exposed to opioids prenatally are shaped by a wide array of factors, with ronmental stressors. Larger, more comprehensive studies are required to
research showing mixed results. Some studies have documented neu untangle the specific effects of opioid exposure on neurodevelopment
robehavioral abnormalities, such as deficits in attention processing, from those of other substances and related stressors.63
motor skills, and higher rates of conditions like ADHD. However, other
research suggests that these developmental challenges may be more Future directions
closely linked to environmental influences, such as caregiving quality
and socioeconomic conditions, rather than opioid exposure alone. This Research gaps: Areas where further research is needed
research highlights the need for nuanced, long-term studies that can
disentangle the effects of prenatal substance exposure from the socio- The direction of research must necessarily shift to emphasize the
environmental contexts in which children are raised. Importantly, not various factors that can reduce risk and promote positive outcomes for
all children with NAS experience long-term deficits, as early in children and families impacted by opioid and substance use. Histori
terventions and supportive environments can promote recovery and cally, studies have focused on singular prenatal exposures or stressors,
developmental improvements by toddlerhood. Comprehensive ap but future research should investigate the collective impacts of multiple
proaches addressing socio-environmental risk factors for perinatal in substance exposures and prenatal psychosocial and environmental
dividuals and families impacted by substance use are necessary to strains on neonatal stress response and regulation, incorporating both
support children’s healthy development. maternal and paternal physiological and behavioral influences on chil
dren’s long-term outcomes.
Research on long-term child outcomes: What recent research says Research on predicting neurodevelopmental outcomes in infants
exposed to opioids during pregnancy that account for maternal factors
Research from meta-analyses has shown that children who experi like mental health, trauma history, and detailed substance use, are still
enced prenatal opioid exposure—whether through the use of illicit very limited. Studies must not only focus on the direct impact of opioid
substances by their parents or through prescribed agonist therapies for exposure but also account for socio-environmental factors that influence
OUD—tend to have lower cognitive, language, and motor skills outcomes. Developing methods to clearly differentiate opioid-related
compared to those not exposed.87,119,121,122,126 Nonetheless, the effects from other influences is crucial. Future studies can address this
strength of these conclusions is compromised by the inclusion of studies gap by incorporating comprehensive maternal assessments, including
with flawed designs or statistical methods, such as differences in the nutrition, poverty, substance use and mental health histories as well as
types of opioids investigated, varied definitions of exposure categories, physiological stress responses that may predict the severity of NAS and
small participant samples, no comparisons of long term outcomes be moderate long term child outcomes. Since polysubstance use with OUD
tween infants that developed NAS/NOWS and those who did not, no is so common, studies must control the influence of other exposures,
accounting of gender differences in long term outcomes, and a limited such as nicotine and methamphetamines. Further, a complete bioethical
scope focused only on early developmental stages. Furthermore, analysis of the risks and benefits of the study design and methods must
important confounding factors—including a comprehensive maternal be completed to ensure that such studies provide more benefit than
mental health and substance use history, nutrition, polysubstance use, harm to the parent-child dyad. Meaningful participation in the study
experienced stress, racism in healthcare, genetic and epigenetic factors, design and methods of those who are or have been pregnant while
and the overall quality of the home environment—are often having an OUD and those prenatally exposed to opioids will also benefit
overlooked.51,64,74,88,127 Recent studies focusing on children with future research.
NAS/NOWS have called for a strong emphasis on the necessity for larger, A standardized definition of prenatal opioid exposure is necessary, as
well-designed prospective studies that rigorously assess these various current studies lack consistency. Women engaged in MOUD only and
influences in child outcomes.74,128,129 receiving integrated care during pregnancy tend to have better birth
Several cohort studies have attempted to clarify the intricate con outcomes, which can positively influence child development even with
founding factors associated with prenatal opioid exposure, yet many opioid exposure, highlighting the importance of clearly defining the
have reported effect sizes that were inadequate to fully address these study population. Research should clearly specify the type, source, and
complexities.120,130 One substantial prospective study found that opioid frequency of opioid use (e.g., fentanyl, oxycodone, buprenorphine),
use during pregnancy had no significant effect on language or commu differentiating between prescribed, illicit, and MOUD sources. This will
nication skills in children by age three.131 In a follow-up to the MOTHER enable a more accurate understanding of opioid exposure’s impact on
study132, which tracked 96 infants to 36 months, researchers found no child development.
notable differences between infants born to mothers treated with The long-term neurodevelopmental effects of opioid exposure

remain unclear, particularly when comparing infants who develop NAS/ exposure from other medical, genetic, and environmental factors re
NOWS to those who do not, or when comparing outcomes by infant mains challenging, as studies have yet to establish a clear cause-and-
gender. Including well-defined comparison groups (e.g., infants with effect relationship between opioid exposure or NAS and adverse neu
NAS diagnosis vs. infants without, infants exposed to MOUD only vs. rodevelopmental outcomes. A multifaceted approach is required to fully
infants exposed to illicit fentanyl, etc.), and incorporating participants understand the interplay of interpersonal, intrapersonal, and environ
from several and diverse demographics and socioeconomic statuses is mental factors that shape children’s long-term development.
necessary to expand our understanding of neurodevelopmental out Addressing NAS and its associated outcomes requires an integrated
comes among children exposed to substances prenatally. strategy that emphasizes ongoing research, policy reform, and
Finally, current research is limited by small sample sizes and several compassionate care. Future research should go beyond investigating the
methodological and design flaws, leaving gaps in our understanding of direct effects of prenatal substance exposure and explore the broader
both short- and long-term effects on infants with prenatal opioid and socio-environmental factors influencing child development. Policy
substance exposures. Future research would benefit from longitudinal makers must move away from punitive approaches and instead focus on
designs, diverse populations, and advanced statistical approaches to supportive frameworks that help families overcome poverty and gain
better isolate these effects and focus on causal factors. Prospective access to comprehensive care. Collaboration between researchers,
recruitment during the perinatal period, especially starting in early healthcare providers, and policymakers is critical to ensure that in
pregnancy, is also vital for effective long-term monitoring of NAS and terventions are both compassionate and evidence-based, ultimately
child outcomes. Employing appropriate and robust statistical methods, leading to better outcomes for children affected by NAS.
such as adjusting for multiple comparisons, multiple imputations for
missing data, propensity scoring and causal inference, will also neces Encourage continued research, policy advocacy, and compassionate care
sarily enhance the rigor of data analysis, especially when the gold to address NAS and its consequences
standards of blinding and randomization cannot be achieved due to
ethical and feasibility concerns. Furthermore, maintaining participant In conclusion, addressing NAS and its consequences requires a ho
retention while avoiding coercion is crucial for the accuracy of longi listic, multifaceted approach that prioritizes continued investments in
tudinal studies, as attrition often correlates with socioeconomic chal research, compassionate care, and evidence-based policy advocacy. The
lenges. Lastly, given that admitting substance use during pregnancy can research community must bridge existing gaps by investigating both the
lead to punitive legal consequences, researchers must develop method causal factors in opioid and psychoactive substance exposure and the
ologies that safeguard participants from mandatory reporting to child collective effects of prenatal substance exposure alongside psychosocial
protective services. and environmental stressors. This includes a more inclusive study design
that examines diverse populations, incorporates longitudinal method
Policy recommendations: Recommendations for improving NAS outcomes ologies, and considers the role of both maternal and paternal histories in
through policy changes, healthcare reform, and better resource allocation child development. Expanding research to account for socio-
environmental influences on child outcomes will offer a clearer under
To create effective policies and to enhance intervention strategies, it standing of the true impact of prenatal opioid exposure.
is critical to thoroughly assess the multifaceted impacts of prenatal From a policy perspective, it is essential to move beyond punitive
substance use, particularly in relation to both child development and approaches and instead promote supportive, family-centered in
maternal health. This requires a comprehensive understanding of how terventions. Federal and state policies should focus on reducing poverty
prenatal exposure interacts with broader socioeconomic and environ and enhancing early intervention programs and access to comprehen
mental influences. As emphasized in this chapter, socioeconomic status sive addiction and mental health services, especially in-home services
and environmental conditions are pivotal in shaping child outcomes. for families facing socioeconomic risks. By reallocating resources to
Therefore, it is imperative to establish supportive measures that help preventative care and early support, we can meaningfully promote and
families overcome poverty while also reforming punitive policies that improve healthy child and family development.
disproportionately target prenatal substance use. If research demon Ultimately, to create lasting change, collaboration between re
strates that socio-environmental factors exert a more profound influence searchers, policymakers, and healthcare providers is essential. This
on long-term child outcomes than prenatal substance exposure alone, collaborative effort must prioritize the ethical treatment of vulnerable
federal initiatives should incentivize states to adopt holistic early populations, with an emphasis on reducing stigma, fostering trust, and
intervention programs. These programs should include wrap-around ensuring that policies and interventions are grounded in compassion and
services tailored to children and families facing socioeconomic and robust scientific evidence. Through these combined efforts, we can
environmental challenges. By making strategic investments in these better understand NAS, improve outcomes for affected children and
approaches, we can not only improve maternal-infant bonding but also families, and promote a more equitable and humane approach to sub
promote the healthy development of both children and families, ulti stance use during pregnancy.
mately reducing long-term disparities.
Financial support
Conclusion
This work was supported by funding from the National Institute on
Summary of key points Drug Abuse (K01DA051780, PI; Burduli; 1R01DA047867, PI: Jones).
This funding source had no other role other than financial support.
Prenatal opioid exposure is often mistakenly seen as the sole or main
cause of neurodevelopmental issues, leading to the assumption that all CRediT authorship contribution statement
affected neonates require specialized services. However, this chapter
demonstrates that neurodevelopmental challenges stem from a variety Ekaterina Burduli: Writing – review & editing, Writing – original
of interconnected factors, with robust data suggesting that differences draft, Methodology, Conceptualization. Hendrée E Jones: Writing –
between children with and without prenatal opioid exposure are likely review & editing, Writing – original draft, Validation,
due to multiple causes. This complicates efforts to address these in Conceptualization.
fluences, making it essential to consider the broader context when
assessing developmental outcomes in children and adolescents exposed
to opioids prenatally. Distinguishing the direct effects of prenatal opioid

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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Treatment and decriminalization of the mother-infant dyad in perinatal

opioid use disorder
Erinma P. Ukoha, Assistant Professor a,1, Mishka Terplan, Medical Director b,1,*
a
Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, USA
b
Friends Research Institute, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Treatment of perinatal opioid use disorder should center the mother-infant dyad, the needs of both entities, and
Pregnancy preservation of the relationship. The criminalization of pregnancy and substance use in pregnancy through
Opioid use disorder punitive policies and legislation and the involvement of the family policing system are in direct opposition to
Dyad
compassionate, person-centered care and lead to worse maternal and neonatal outcomes. In this chapter, we
child welfare
Carcerality
review the history and ongoing criminalization of pregnancy and perinatal substance use disorder, explore
carcerality as a barrier to dyadic care that disproportionately targets Black, Brown, and Indigenous birthing
individuals, and propose solutions to decriminalize care based in abolition medicine and reproductive justice
frameworks.

Introduction dysfunction within the dyad. Numerous factors during pregnancy, the
birthing experience, and postnatally influence the dyadic relationship
Understanding the Dyad and eventual mother-infant attachment style. For example, prenatally
the maternal response to the metabolic and physiologic changes of
The mother-infant dyad represents a dynamic relationship that be- pregnancy as well as genetic and environmental factors affect the
gins in pregnancy and is the foundation of long-term health and well- mother-baby attachment.6,7 Additionally, postpartum maternal depres-
being of both entities. The dyad refers to the interconnectedness of the sion has been shown to be an indicator for poor maternal-infant
shared biological, psychological, and social relationship between the attachment.8 As health care providers, our role is to effectively eval-
parent and infant. Human newborns are unique when compared to other uate for such risk factors and provide appropriate support to both the
species given their immaturity and complete dependence on their mother and infant.7
caregiver’s actions, behaviors, and environments.1 Early parent-infant
interactions play a critical role in shaping developmental outcomes,
future relationships, and physical and psychological health.2 Addition- The Dyad and Perinatal substance use
ally, the parent’s response to the infant’s needs is important in deter-
mining adaptative emotional, cognitive, and social abilities and The intersections of substance use, pregnancy, and parenting create
regulation.3,4 Maternal emotional availability, sensitivity, and respon- landscapes of opposition. As clinicians, we encounter them in practice:
siveness are all integral to the quality of the attachment and the infant’s fetus versus pregnant person, child versus parent, pediatrician versus
learned behavior.5 The importance of attachment is bidirectional. Both obstetrician, doctor versus nurse, social worker versus doctor. These
form and inform each other’s response, and infants who receive secure dichotomies are narrow, false, and misleading. In order to improve
responses more often display more engagement with their caregiver and outcomes for pregnant individuals who use substances and their infants,
less resistant behavior.4 a more comprehensive, holistic approach is needed that focuses on the
An understanding and appreciation of the mother-infant dyad is mother-infant dyad as an inextricably linked unit, rather than creating
necessary to appropriately identify and address potential causes of harmful divisions.
Mother-infant interactions may be complex and multifaceted in

* Corresponding author.
E-mail address: mterplan@[Link] (M. Terplan).
1
Mailing Address: FRI, 1040 Park Ave, STE 103, Baltimore, MD 21,201, USA

[Link]
Received 30 September 2024; Accepted 16 November 2024
Available online 17 November 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

individuals who use substances, yet remain the cornerstone of the dyad. prosecution, and made federal grant funds contingent upon State pro-
Substance use does not negate the care capabilities the mother brings to cedures for reporting abuse and neglect.19 In short, CAPTA created the
the dyad, and the dyad still remains the appropriate subject of care.9 The administrative and legal means and time frames for reporting and
care needs and outcome of the mother-infant dyad as a single unit should responding to reports of child abuse, but for almost 30 years, parental
be prioritized. With this understanding and framework in mind, our substance use or newborn substance exposure were not indications for
goals as providers should focus on preserving and maximizing the dyad CAPTA reports.20 It was only in 2003 and in reaction to the frank racist
in line with an individual’s desire to parent. This shift requires a and scientifically flawed “crack baby” hysteria that CAPTA required
collaborative, integrative approach from obstetricians, pediatricians, states to arrange “plans of safe care” for infants affected by “illegal”
social workers, institutions, and care delivery models alike. The dyadic substance use.21 Subsequent CAPTA reauthorizations in 2010 and 2016
approach both in clinical practice and from a policy and research expanded the lens of substance reporting when the language of “illegal”
standpoint highlights the interdependence of mother and infant and was removed and MOUD was understood as reportable.22
recognizes the importance of this dyad in a manner that benefits both There is no evidence that mandated reporting for suspected child
entities. abuse or neglect keeps children safe. In fact, states that expanded what is
reportable as well as who is legally required to report neither are asso-
Treatment of opioid use disorder ciated with improvement in the detection of children at risk of
harm.23,24 Mandatory reporting laws disproportionately and systemat-
Treatment of opioid use disorder rests on the dyad and reflects the ically target poor, immigrant, and Black and other families of color, and
age-old adage “healthy mother equals healthy baby.” Chronic disease in fact make families less safe by discouraging parents from seeking care
management in pregnancy improves birth outcomes, but, as Loretta or supportive services.25-28
Finnegan demonstrated in early 1970s, engagement in prenatal care Because CAPTA was designed to respond to child abuse, family
alone also improved birth outcomes for people with opioid use disorder policing agencies have an administrative urgency to respond to reports.
(OUD).10 Today, we understand the primary risk to the fetus to not be But in the context of a positive drug test, such an administrative urgency
the opioid per se, rather the repeated cycles of withdrawal that are the is false and misleading. Mandated reporting for substance exposure at
common feature of untreated OUD. Repeated cycles of withdrawal birth contributes to the overuse and misuse of drug testing. Finally,
“stress the fetal brain,” prematurely activate the hypothalamic pituitary mandatory reporting offsets responsibility for care from health systems
axis, and lead to a cascade of events that can culminate in preterm birth which contain the resources and expertise to assess and treat substance
and low birth weight.11,12 Methadone and buprenorphine are the safest use disorder, to the family policing system, which is primarily a sur-
and most effective medications for OUD in pregnancy. These medica- veillance agency that does not directly provide care.
tions are long acting and when administered correctly, people experi-
ence neither withdrawal nor euphoria – they feel normal.13 When the Carcerality of care
pregnant person is stable, so too is the pregnancy, and the fetus can grow
normally, deliver at term. In other words, medications for OUD (MOUD) Mandated reporting for substance exposure is one of the primary
do not just treat the pregnant person. MOUD also treats the fetus. MOUD ways that carcerality enters clinical care.29 As the American College of
benefits the dyad. Obstetricians and Gynecologists (ACOG) stated, “The laws, regulations,
Postpartum infants exposed in utero to opioids may develop with- and policies that require health care practitioners and human service
drawal. Infant withdrawal, or neonatal abstinence syndrome (NAS), can workers to respond to substance use and substance use disorder in a
develop among infants of people with untreated OUD, treated OUD, or primarily punitive way, require health care providers to function as
among people without OUD who are receiving opioids for chronic pain. agents of law enforcement.”30
In the language of the “sufficient causes, component causes” theory of Health care providers and institutions alike participate in the crim-
causality coined by Rothman, opioids are a necessary but insufficient inalization of individuals seeking care, functioning as yet another facet
cause of NAS.14 Every infant with NAS was opioid exposed, but not every of mass incarceration. From physicians and nurses to social workers and
infant with opioid exposure will develop clinically significant NAS. The security personnel, health care professionals can easily find themselves
expression, severity, and duration of NAS are impacted by both the in- willfully acting as agents of the state. The carceral complicity of health
trauterine and extrauterine environments. Dyadic disruptions worsen care professionals is often a reflection of biased perspective and privi-
NAS, especially postpartum.15,16 Infants that are separated, placed in the leged socioeconomic status.29 For example, health care providers
neonatal intensive care unit (NICU), or not breastfed, experience worse criminalize patients by performing drug testing and screening on peri-
withdrawal.17,18 natal people and their newborns without informed consent, calling the
Though dyadic care is biologically, socially, and ethically parsimo- police, immigration, or family policing system on individuals seeking
nious, many barriers exist to its realization. Access to MOUD, prenatal care, or sharing information with authorities.31,32 This repeated policing
care, and birthing hospitals is inequitable and uneven geographically. and criminalization perpetuates harm and violence by systematically
Uncoupled maternal and infant hospital discharge, especially for infants subjecting poor communities of color to state surveillance.
with NAS, disrupt attachment. Insurance churn and welfare re- Criminalization refers to “the social and political process by which
alignment postpartum interferes with addiction chronic disease man- society determine which actions or behaviors and by who are punishable
agement and is associated with medication discontinuation. However, by the state.”33 In addition to the passage and enforcement of legislation,
the greatest barrier to dyadic care is the family policing system (also criminalization also encompasses the social constructs at play in deter-
known as the child welfare system), specifically mandated reporting and mining who in fact is a “criminal.”33 This determination hinges on an
how reporting mandates for infants born with prenatal substance individual’s race, gender, sexuality, disability status, and socioeconomic
exposure have led to an increased carcerality of care during the birthing class and is fueled by anti-Black, classist, misogynistic rhetoric. The
hospitalization. prosecution of pregnant individuals, specifically Black individuals,
increased drastically in the 1980s during the “war on drugs” in response
Mandated reporting to the state-manufactured “crack cocaine epidemic.”34 This punitive
climate was driven by media depiction of the “pregnant addict,” “wel-
Mandated reporting is organized federally under the Child Abuse fare queen,” and “crack baby.”35,36 These sensationalized, racist narra-
Prevention Treatment Act (CAPTA). Signed into law in 1974, CAPTA tives laid the groundwork for the criminalization of pregnancy which
established a national clearinghouse for child abuse and neglect data, disproportionately affected and targeted Black, Brown, and Indigenous
created mechanisms for funding both prevention programs and criminal individuals and their reproductive decisions.36,37 This agenda has been

furthered by ongoing attacks on sexual and reproductive rights and substance use causes pregnant individuals to not seek or disengage from
bodily autonomy. all forms of care, including prenatal care, substance use treatment,
mental health care, or other ancillary services, due to substantiated fear
Criminalization of pregnancy of arrest, punishment, or child separation.43-45 States with laws allowing
for child abuse charges for substance use in pregnancy had decreased use
Pregnancy-related criminalization is increasing and takes many of MOUD despite this being the standard of care.44 Qualitative and
forms.37 Pregnant individuals are vulnerable to criminalization when quantitative data alike show that fear of being reported to the family
they seek abortion care, miscarriage care, or engage in activities deemed policing system and losing their children presents a common and sig-
“dangerous to the fetus.”35 From 2006 to 2022 there have been almost nificant challenge to presenting for prenatal care.43,46,47 Criminaliza-
1400 cases of pregnancy criminalization across the U.S. and compared to tion, from the criminal justice and family policing systems, creates an
previous years this represents an overall significant upward trend. The additional barrier to dyadic care in this already stigmatized population,
vast majority of cases are related to “fetal personhood,” which allows for which leads to worse maternal and neonatal outcomes.
a fertilized egg, embryo, or fetus to be equated as a distinct entity with
rights separate from the pregnant individual.37 As of 2023, at least 11 Decriminalization of care
states have incorporated broad “fetal personhood” into all of their state
laws, and every state has statutory or case law that considers fetuses to In order to shift the narrative from criminalization of substance use
be a person at some point during pregnancy.38 Through “fetal person- in pregnancy to integrative care for the mother-infant dyad, an approach
hood” legislation, pregnant individuals, especially those from margin- that centers reproductive justice and abolition medicine should be
alized backgrounds or who use substances, are subject to arrest, employed. Reproductive justice is defined as “the right to not have a
prosecution, and criminal charges for “perceived risks during pregnancy child, but also the right to have children, the right to raise them with
and actions that endanger the fetus.”35,38 Under the false pretext of dignity in safe, healthy, and supportive environments, and the right to
protecting the fetus, “fetal personhood” measures have been used time bodily autonomy.”48,49 Polices and legislation that criminalize perinatal
and time again to restrict the constitutional rights of pregnant substance use infringe on reproductive self-determination, autonomy,
individuals.37 and rights. This restriction of bodily autonomy is disproportionately
Anti-abortion rhetoric intersects with all aspects of sexual and seen in Black and Brown, economically disadvantaged communities who
reproductive care. With the June 2022 Supreme Court Dobbs v. Jackson have long been over-policed and hyper-surveilled.
Women’s Health Organization decision, which overturned Roe v. Wade, An abolition medicine framework stems from the understanding that
the overcriminalization of pregnancy has only been worsened. Roe v. health care facilities are sites of racial oppression with health care
Wade, to a certain extent, provided the constitutional right to abortion professionals complicit in the subjugation of Black individuals.50
and rejected the premise of “fetal personhood.”37 Since the Dobbs ruling, Activist, author, and organizer Mariame Kaba states, “white supremacy
14 states have total abortion bans, and 27 states have abortion bans is maintained and reproduced through the criminal punishment appa-
based on gestational duration.39 The state’s attack on bodily autonomy ratus;” this applies to the carceral care seen in the management of
through such restrictions and pregnancy criminalization has substance use in pregnancy.51 Professor and scholar Angela Davis ex-
far-reaching implications, and we have seen time and time again sys- pands on this even further by describing abolition as “a process of
tematically affects poor, Black, Brown, and Indigenous communities of decriminalization, recognizing that threats to safety, threats to security,
color. In the aftermath of the Dobbs decision, all pregnancy outcomes come not primarily from what is defined as crime, but rather from the
and actions of pregnant individuals, not just abortion, will be under failure of institutions in our country to address issues of health, violence,
increased scrutinization and subject to criminalization. education, etc.”52 The “war on drugs” is a prime example of this short-
coming. The punitive measures target marginalized, racialized com-
Criminalization of substance use in pregnancy munities and conflate drug use with criminality.53 Health care providers
participate in anti-Black state sanctioned violence in a myriad of ways.
The legal expansion of “fetal personhood” and broad interpretation This complicity is evident through discriminatory practices of urine
of risk to the “unborn child” allows for the prosecution of actions, like toxicology testing in perinatal settings. Data show Black birthing in-
substance use, alcohol or tobacco consumption, or even skiing or poor dividuals and their newborns are more likely to have urine toxicology
nutrition, that otherwise would not have been criminalized outside of performed than White individuals and in fact individuals of all other
pregnancy.37,38 Twenty-four states and D.C. consider substance use races, despite being less likely to test positive for drugs.54-57 Such
during pregnancy child abuse or neglect under civil child welfare violence also extends to the racism in disproportionate mandatory
statues, and at least 3 states consider prenatal substance use grounds for reporting to government authorities. Studies demonstrate providers are
civil commitment.38,40 Substance use in pregnancy leads to the majority up to ten times more likely to report Black individuals to family policing
of cases of criminalization in pregnancy and serves as the point of entry than White individuals, in spite of similar rates of drug use.54,58 Thus,
to continued state surveillance either from the criminal justice or family abolition medicine calls for an interrogation of the carceral health care
policing systems.37 Pregnant people who use drugs find themselves at structures in place that create racial inequities and reimagining creative
increased risk for criminalization due to their reproductive choices and solutions founded in mutual aid and decriminalization.52,59,60
the intersection of racist, sexist, and classist reproductive and Reproductive justice and abolition medicine represent harmonious
substance-related polices.29,41 approaches to ensure that pregnant individuals who use substances have
Furthermore, data shows that such punitive policies in fact do not the ability for self-determination, receive care founded in dignity, and
improve neonatal outcomes. A 2019 retrospective, cross-sectional experience care delivery without oppression.61,62 Our recommenda-
analysis of almost 4.6 million live births in 8 states compared 1) states tions, listed in Table 1, provide concrete examples of how to decrimi-
without punitive or reporting polices that criminalized substance use nalize care within each level of the health care system and highlight
during pregnancy, considered it grounds for civil commitment, or actions that can be taken by health care providers, institutions and
considered it child abuse or neglect to 2) states with policies before and policymakers. These recommendations stem from the published work of
after policy enactment. This study found that odds of neonatal absti- abolitionist scholars, organizers, reproductive justice advocates, and
nence syndrome in the immediate aftermath and longer term were impacted community members, such as Movement for Family Power,
significantly greater after enactment of such punitive policies when Interrupting Criminalization: Beyond Do No Harm Network, and Preg-
compared with states that did not have such policies.42 These findings nancy Justice.31,37,41 Table 2 provides a non-exhaustive compilation of
are in line with previous studies that show the criminalization of partner organizations and resources.

Table 1
Recommendations to decriminalize care of pregnant individuals who use substances.
At the Bedside

• Create more welcoming and accepting care environments. The inherent power dynamics within medicine coupled with the stigma and prejudice that pregnant individuals who use
drugs face can make traditional care facilities and interactions intimidating and often times inaccessible.64,65 Health care professionals must take deliberate action to unlearn internal
biases and negative attitudes towards individuals who use substances.66
• Provide collaborative, non-judgmental care. Programs with integrated obstetric care, substance use disorder treatment, and wraparound services, including case management,
behavioral health, and peers or coaches with living experiences exemplify trauma-informed models that are more inviting and personal.67
• Ensure care is transparent, reflective, and proactive.
○ Transparency is key in building trust in patient-provider interactions. One step towards transparent, therapeutic care is performing explicit informed consent prior to drug

screening or toxicology testing given the social and legal ramifications of a positive result.31,32,68 This change in practice ensures that patients are informed the clinical indication,
potential consequences of a positive test, their right to refusal as well as implications of refusal, and have the opportunity to obtain legal advice or support prior.41
○ We should be critical of decisions to involve family policing. The false sense of urgency created by the family policing system contributes to unnecessary, unsubstantiated reports.

An example of a reflective practice is the “Pediatric Care Coordination Time Out” utilized at a public hospital in San Francisco.69 Similar to a time out or safety pause performed
pre-operatively, this care coordination time out allows for collaboration amongst pertinent patient-care team members and the family, and includes discussion of strengths,
resources, and social support for a patient as well as an assessment of biases and privilege that may be at play prior in the decision to report.
○ As health care professionals pushing back against criminalization and the family policing system, it is our responsibility to partner with social services and family legal aid for

patients who have a high likelihood of family policing system involvement. This proactive approach ensures that patients are prepared for potential surveillance, aware of their
rights, and have needed resources available.
• Do not collaborate with the criminal legal or family policing system. For example, this can mean limiting unnecessary documentation in medical records, not providing evidence for
state surveillance agencies, or not allowing use of confidential information obtained from health care settings against patients in family policing cases or legal prosecution.31,70

Institutional Policies

• Identify and de-implement punitive polices. Such polices can take many forms, such as urine toxicology testing or restrictive visitation policies for patients receiving substance use
disorder treatment.
• Codify informed consent for substance use screening and biological testing into policy.
• Provide evidence-based guidelines for when biological drug testing should be performed on perinatal individuals and their newborns to restrict the use of drug testing, combat the
misinterpretation of results, and mitigate racial disparities in testing.71
• Collect and make data public on testing and reporting to evaluate and address inequities.
• Interrogate and end the use of police and governmental authority response within care settings, including in response to drug use or possession. Health care institution response to
such situations should be based in de-escalation, providing services and support, and addressing unmet needs.31
• Provide comprehensive social services and resources for perinatal patients and families. Resources, support, and wraparound services can be provided in hospital-setting to ensure
that people have their needs addressed (for example, more stable housing or a reasonable plan of safe care in place) prior to discharge.29
• Reframe institutional vulnerabilities from a risk management standpoint. Hospital stakeholders and their legal teams should acknowledge that their complicity with state
surveillance exposes their institutions to additional risks and potential lawsuits. Therefore, ensuring equitable, person-centered care becomes not just a moral calling, but also has a
financial incentive to protects the economic viability and image of the institution.

Legal Reform

• Repeal the Child Abuse Prevention and Treatment Act (CAPTA) and end mandated reporting.
• Eliminate civil and criminal prosecution for pregnant individuals who use drugs, as well as broader penalties for drug use and possession.72
• End “test and report” practices of performing drug testing and screening on perinatal individuals and their newborns and then reporting the co-occurrence of substance use and
pregnancy to the family policing system. Federal law does not require drug testing nor reporting of positive results to the family policing system, and additional legal provisions
should be enacted to prevent “test and report” on a state level as well.32,37,41,70
• Pass legislation requiring informed consent prior to drug screening or testing of perinatal individuals and their newborns. Currently, advocacy groups in New York, California, and
Maryland are working to pass informed consent legislation.41
• Expand Health Insurance Portability and Accountability Act (HIPAA) protections in order to limit information sharing with state agencies.37
• Provide funding for individuals, communities, and social services agencies outside of carceral systems.29 Financial investments should be provided directly to community-based
initiatives and efforts to keep families together. Furthermore, financial assistance and benefits should be provided for impacted families at risk for family policing involve-
ment/separation or working toward reunification.41
• Protect abortion and reproductive rights. Given the intersection of abortion bans and criminalization of pregnancy, codifying abortion and repealing fetal personhood laws is needed
to ensure the constitutional rights and reproductive freedom of pregnant individuals.37

Table 2 Conclusion
Partner organizations and resources.
Abolitionist Organizations In order to achieve decriminalized, person-centered care, changes
must be made from an individual, institutional, and legal standpoint. For
Movement for Family Power [Link]
upEND Movement [Link] people who use substances in pregnancy, the carceral logic that per-
Just Making a Change for Families [Link] meates our health care infrastructure remains a significant barrier to
Reimagine Child Safety Coalition [Link] dyadic care of the mother-infant. The current punitive policies and
Drug Policy Alliance [Link] legislation place the patient and provider at odds, fracturing the patient-
Operation Stop CPS [Link]
provider relationship. The forced entanglement of law enforcement, the
Reproductive Justice Organizations family policing system, and state surveillance into our current systems of
Physicians for Reproductive Health [Link] health care is in direct opposition to our principles of care provision.41
SisterSong Women of Color Reproductive Justice [Link] Trust, privacy, and confidentiality are the foundational aspects of the
Collective
patient-provider relationship, which the criminalization of substance
New York Informed Consent Coalition [Link].
com
use in pregnancy completely erodes. From an ethical standpoint, our
If/When/How: Lawyering for Reproductive Justice [Link] obligation and mandate as providers is to “do no harm.”31 How can we
Pregnancy Justice [Link]. begin to mitigate the harm caused by the current structures in place and
org go beyond this calling to provide anti-racist, healing spaces that promote
Resources the health and preservation of the dyad? We must radically reimagine
Interrupting Criminalization [Link] health care, safety, support, family structures, and how we meet the
Doing Right By Birth [Link] needs of the dyad as a unit.41,63 As we strive towards decriminalized care
Academy of Perinatal Harm Reduction [Link] centered around reproductive justice and abolition medicine

frameworks, it is imperative we place impacted individuals and com- 17. Wine O, McNeil D, Kromm SK, et al. The alberta neonatal abstinence syndrome
mother-baby care improvEmeNT (NASCENT) program: protocol for a stepped wedge
munities at the center of this work.
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September 20 [Link]
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CRediT authorship contribution statement 20. Children’s Rights. 50 Years of CAPTA: what you need to know about this harmful law.
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Erinma P. Ukoha: Conceptualization, Writing – original draft, ://[Link]/news-voices/50-years-of-capta-what-you-need-to-kno
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Contents lists available at ScienceDirect

Seminars in Perinatology
journal homepage: [Link]/locate/semperi

Review of parent and healthcare provider experiences based on approach to

managing Neonatal Opioid Withdrawal Syndrome (NOWS)
Lisa M. Cleveland *
The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1132, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Neonatal Opioid Withdrawal Syndrome (NOWS) is a group of clinical withdrawal signs occurring in prenatally
Neonatal Opioid Withdrawal Syndrome opioid-exposed newborns and manifesting as neurobehavioral dysregulation, including extreme irritability such
(NOWS) as excessive crying, rigid muscle tone, and difficulty feeding and sleeping. One U.S. infant experiencing NOWS is
Neonatal Abstinence Syndrome (NAS)
born every 25 min. Clinical management of these infants has traditionally occurred in the high-acuity envi-
Finnegan Neonatal Abstinence Scoring Tool
(FNAST)
ronment of a neonatal intensive care unit (NICU), which contributes to separation of infants from their parents
Eat, Sleep, and Console (ESC) and increases the likelihood of pharmacological intervention to manage withdrawal. Over the past decade, more
Parent experience holistic approaches, such as the Eat, Sleep, and Console method, have focused on parents’ active participation in
Healthcare provider experience care, rooming-in, and implementation of non-pharmacologic soothing techniques to reduce medication use,
hospital length of stay, and healthcare expenditures. These distinctly different management approaches have
contributed to unique experiences for parents and healthcare providers involved in infants’ care; therefore, the
purpose of this paper is to review the experiences of parents and healthcare providers as they relate to man-
agement approaches for infants with NOWS.

Introduction result, these lengthy hospital stays, and high-acuity care have contrib-
uted to annual healthcare costs that surged from $61 M in 2003 to $316
Neonatal Abstinence Syndrome (NAS) is a group of clinical with- M in 2012.8 In response, newer care approaches, such as the Eat, Sleep,
drawal signs experienced by newborns who have been prenatally and Console (ESC) method,9 have evolved to be more holistic and
exposed to opioids and other substances.1,2 Between 2013 and 2016, the centered on engaging the infants’ caregivers in non-pharmacologic
U.S. Food and Drug Administration introduced new terminology to more management techniques like rooming-in with parents, skin-to-skin
specifically define newborn opioid withdrawal, renaming it Neonatal holding or kangaroo care, and breastfeeding. The ESC approach has
Opioid Withdrawal Syndrome (NOWS).2 Over the past several decades, contributed to a reduction in pharmacologic intervention, shorter length
the United States has experienced an increased incidence of NOWS, with of hospital stays, and lower healthcare costs.9
one infant now born every 25 min experiencing the syndrome.3,4 This These unique approaches have been met with differing responses
rise corresponds with the 333 % increase in opioid use during pregnancy from both the infants’ caregivers and the healthcare teams. As a result,
that occurred between 1999 and 2014.5 an increased interest in parents’ and healthcare providers’ experiences
Infants with NOWS demonstrate neurobehavioral dysregulation that with NOWS care is contributing to a growing body of literature10-15 that
manifests in extreme irritability such as excessive crying, rigid muscle improves our understanding of this often emotionally charged and so-
tone, and difficulty feeding and sleeping.6,7 Traditional approaches to cially nuanced diagnosis. Therefore, the purpose of this paper is to re-
NOWS care have typically involved the transfer of infants to a higher view and summarize the literature on parent and healthcare provider
acuity setting, such as a special care unit (SCU) or neonatal intensive responses to NOWS care approaches.
care unit (NICU), and management with short or long-acting opioids and
other adjunctive medications.4 Initiation of medications is often asso- Early attachment and bonding
ciated with long weaning protocols, extended hospital stays, and sepa-
ration of infants from their parents or other primary caregivers. As a The importance of early infant-caregiver attachment and bonding

* Corresponding author at: Associate Dean of Nursing Science and Professor of Graduate Studies, 301 University Blvd, Galveston, TX 77555-1132.
E-mail address: lmclevel@[Link].

[Link]
Received 15 October 2024; Accepted 4 November 2024
Available online 5 November 2024
0146-0005/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

was described in the seminal works of Klaus and colleagues in the want to be around that nurse because she made me so uncomfortable
1970′s. Through their work, they explained the critical importance of (p. 324).
extended mother-infant physical contact during the early postpartum
Statements like these are particularly notable since even when in-
period and the role this plays in the formation of attachment.16 As
fants require pharmacologic management of NOWS symptoms, parental
hormonal and instinctive changes following birth promote initial
presence (typically the mother) at the infant’s bedside is associated with
bonding,17 early and uninterrupted skin-to-skin contact enhances
fewer days on medication and a shorter length of hospital stay. Further,
bonding over the weeks that follow and helps establish breastfeeding
maternal absence from the infant’s bedside is a significant predictor of
and the development of secure attachment at 12 months.17 In contrast,
increased medication needed to manage withdrawal.25
separation of mothers and infants during this time can have a lasting
These issues of stigma, bias, and discrimination have also been re-
negative impact on their relationship, even after the first year.18 Mothers
ported by mothers who take prescribed opioids during pregnancy and
who have immediate and unlimited contact with their infants after birth
for those receiving evidence-based treatment for opioid use disorder
and room-in during their hospital stay demonstrate greater maternal
(OUD). Although prescribed, the use of these medications may still
sensitivity and responsiveness to their infants after 12 months compared
result in NOWS. For example, O’Connor and colleagues conducted a
to mothers who were separated from their infants and only reunited
content analysis of qualitative data from an open-ended prompt about
intermittently for feedings.18
opioid use in pregnancy that was included in the Pregnancy Risk
Assessment Monitoring System (PRAMS).12 They discovered five unique
Traditional NOWS care approach
themes, one of which was experiences of discrimination and stigma around
the time of delivery. Data supporting this theme focused on negative
For decades, the care of infants with NOWS has been provided in
health care provider interactions, being misunderstood, being treated
SCUs and NICUs where infants are regularly monitored and assessed for
poorly, and being made to feel like a bad or negligent parent. One
the onset of opioid withdrawal4,9 in an environment separated from
mother responded:
their primary caregivers. The American Academy of Pediatrics recom-
I had some issues after my son was born at the hospital … I had
mends in-patient monitoring of prenatally opioid-exposed newborns for
narcotic medicines that I was told I had to take during my pregnancy by
up to 7 days following birth.1,19 If signs of withdrawal develop, length of
my doctor and it was in my medical records that I had to take them.
hospital (LOS) stay can vary widely depending on management
When the baby was born … they treated me like a drug addict. They
approach, with a range of 12–44 days.20 Scoring instruments, such as the
wouldn’t let my baby come home and they made me leave [12, p. 7].
Finnegan Neonatal Abstinence Syndrome Scoring System (FNASS)21 and
Another woman wrote:
later adaptations like the Finnegan Neonatal Abstinence Scoring Tool
(FNAST),22 have been used by healthcare providers to quantify A nurse treated me very poorly at the hospital because of the Subutex
observable withdrawal signs in the newborn and to determine when (medication for opioid use disorder). She made me think that my
initiation of pharmacologic treatment is warranted. Using the FNASS or baby would go to the NICU if she had withdrawals. She scared me
its adaptations, infants are generally assessed every three to four hours, and made me feel like a bad mom. I was doing the right thing for my
and pharmacologic interventions are initiated following three consec- baby. I got off of heroin and got into treatment. Apparently, that
utive scores of eight or two consecutive scores of 12.9 Likewise, these woman has never walked in my shoes, and has lived a perfect life
scores are used to guide the slow weaning of medications, which can also [12, p. 7].
contribute to prolonged hospital LOS.9
In a different study,13 women described how these types of negative
interactions with healthcare providers could place new mothers at risk
Parent and caregiver experience
for a return to opioid use and prevent them from spending time with
their infants: “The attitude from the nurses may make some moms
The early separation of infants from their primary caregivers that
relapse and not come back to the [hospital]. If they are not mentally
often occurs when NOWS care is provided in the high-acuity environ-
strong enough, they might be scared away” (p. 19). In contrast, care
ment of an SCU or NICU can place additional burdens on families
provided in a non-judgmental and supportive manner left mothers
already managing the complicated chronic health condition of a sub-
feeling accepted and welcomed.11 One mother recalled a NICU nurse
stance use disorder (SUD). Due to the stigma surrounding issues of
saying to her, “I don’t know what you’ve been through, girl, so I’m not
mental and behavioral health and SUDs, mothers of infants with NOWS
gonna sit here and judge you” [11, p. 325].
often encounter stigma23,24 and discrimination, which may result in
feelings of shame and guilt,10 particularly when interfacing with the
healthcare system. In a qualitative study that explored the NICU expe- Infant feeding
riences of mothers of infants with NOWS,11 one mother explained, “I
don’t think [the nurses] really understood. They just saw the baby and Breastfeeding/human milk feeding is recommended for infants with
what I did … which is understandable. They just saw a heroin addict and NOWS,26-28 and in a recent meta-analysis of breastfeeding effects on
that’s it.” (p. 323). At times, these emotions can be powerful, particu- NOWS, 11 studies (including 6375 infants) were reviewed. Researchers
larly when coupled with insensitive and judgmental healthcare provider found that breastfeeding reduced the need for pharmacological man-
interactions that may create barriers to parental involvement in infant agement of symptoms, duration of pharmacological treatment, and
care and potentially jeopardize those crucial opportunities for early length of hospital stay.29 However, successful breastfeeding can be
mother-infant attachment and bonding. In this same study,11 a mother jeopardized when care is provided in an SCU or NICU due to the sepa-
described overhearing one nurse talking to another about her infant and ration of mother and infant, which has been positively correlated with
her emotional response to that conversation: an increased need for pharmacological intervention to manage NOWS
symptoms30 and a prolonged hospital stay.
‘You’re going to have a lot of problems with that little baby because
In general, infants with NOWS are nearly three times more likely to
he’s real jumpy and jittery. His muscles are locking up because of his
experience feeding difficulties during hospitalization than infants
junkie mom.’ I didn’t want to visit. I would call [ahead] and if [that
without NOWS,31 with the most reported issues being gastrointestinal
nurse was working], I wouldn’t even go. And [Child Protective Ser-
disturbances. However, some inconsistencies in the evidence exist. For
vices] was like, ‘well you’re not even acting like you care about [your
example, in a recent integrative literature review, researchers uncovered
baby]. You’re out using still.’ I [wasn’t] out using, it was that I didn’t
an overall lack of consistency in the way feeding behaviors in infants
with NOWS are characterized. They concluded that sucking and

behavioral states may be different in infants with NOWS and recom- scoring instruments, such as the FNASS, which is a common component
mended further examination of effective assessment methods and the of traditional NOWS management.9 In one qualitative study, researchers
categorization of infant feeding behaviors.32 found that parents were frustrated by the FNASS and the variability
These observable feeding difficulties may be challenging for parents, involved in the scoring process. One mother explained how she felt the
leading them to question their ability to care for their infants. For scoring was unclear and too subjective to accurately capture the clinical
example, mothers of infants with NOWS who are cared for in the NICU picture of her infant [10, p. e186]. Another qualitative study found that
expressed concerns about the volume their infants were feeding. Some some mothers even believed these scores could be negatively impacted if
also misinterpreted their infant’s feeding cues, continuing to coax intake the nurse assigning the score liked or disliked them, “…when [a nurse
despite their infant’s disengagement or satiation cues. While most who liked me] was on shift, I would notice that his scores were better.
mothers were encouraging and supportive during feedings, researchers When the nurses that used to whisper about me were on, his scores were
concluded that mothers of infants with NOWS may need additional worse” [39, p. 203]. Mothers also believed that these scores were
support from nurses to include education about withdrawal signs and dependent upon how well the nurses knew their infants. One mother
feeding cues, such as hunger, disengagement, and satiation.33 recalled a nightshift nurse, who had never cared for her infant before,
assigning a high score and why this was so significant, “Oh my God. [The
Healthcare provider experience nurse has] the score real high, where I can’t even take my baby home,
and I’m supposed to take her home tomorrow” (p. 203). Finally, mothers
Healthcare provider attitudes and beliefs surrounding substance use shared their belief that their presence at their infant’s bedside positively
have historically been negative, laden with judgement, and generally impacted their infant’s scores. One mother said, “I feel like when you’re
lacking understanding and compassion.34 These negative attitudes and there more, they score better, and they get out quicker—even when
beliefs are often amplified in the case of perinatal substance use and the they’re sick” (p. 203).
resulting prenatally substance exposed newborn,35 which is contrary to Nurses have also questioned the reliability of NOWS scoring in-
initiatives and recommendations that support nonpunitive approaches struments. In a study of 41 nurses in a northeastern hospital, 100 % felt
for pregnant women with SUD. Postpartum nurses have described an the FNASS was somewhat to very subjective, and more than half felt it
awareness of their own personal biases and prejudices related to sub- was somewhat to not at all accurate and a new scoring instrument
stance use: “I just think…staff members stereotype, and I just think it’s needed to be developed.40 Infants are often awakened to perform the
who they are…I can’t say that 100 % of us don’t stereotype” [36, p. scoring, which many of the nurses felt was counterproductive, particu-
605]. In another study,14 nurses and midwives shared statements such larly when infants were rooming in with their mothers and the primary
as, “I must admit my personal experience when I first started looking treatment goal was to minimize disturbances and maintain a low stim-
after [NOWS] babies. I used to find myself feeling quite angry at the ulation environment. One nurse explained, "It’s hard … to carry out NAS
parents” (p. 7) and “I think a lot of neonatal nurses see [NOWS] parents scoring … these kids are withdrawing less [while rooming-in], and they
as more of a hindrance than a help” (p. 8). Another nurse explained, are a lot happier … but we are unwrapping them … we are doing
“[The parents] are really good at over-handling the baby and unsettling nothing with the score" [40, p. 604].
them again. They often undo all the work that you’ve already done” (p. Researchers have also found that the subjective nature of scoring
8). Several nurses discussed the potential impact of their fellow nurses’ instruments like the FNASS may lead to implicit bias among nurses
personal biases on the infants’ families: based on infant race. In a study of 70 NICU nurses from a large tertiary
hospital in the eastern region of the U.S., nurses received three vignettes
So even when [the parents] are trying to do the right thing, they’re
describing infants experiencing clinical signs of NOWS.41 The nurses
always being judged based on other experiences that nurses and
were randomized to receive an accompanying photo of either a White or
midwives have had, which I think is sad because it makes them stop
Black infant. Younger, less experienced nurses were more prone to im-
trying. You’re not supporting them and going… ‘good on you, you’re
plicit bias based on the infants’ race, routinely scoring Black infants
doing so well’ rather than being always suspicious of them [14, p. 8].
lower. These lower scores may be of clinical significance since as little as
Since substance use is often closely tied to a history of trauma, a truly a one-point variation in an infant’s score could translate to the difference
comprehensive approach to the care of families impacted by NOWS is between rooming-in or the initiation and/or weaning of medications,
needed, and many healthcare providers may not feel prepared to deliver which contributes to an infants’ length of hospital stay and separation
this type of care. In a study conducted by Salameh and Polivka,37 NICU from parents.
nurses demonstrated low to moderate knowledge about and perceived
competence in trauma-informed care. As a result, they demonstrated Care environment and adequate staffing
more judgmental attitudes towards mothers of newborns with NOWS.
Their level of knowledge about mothers with SUDs and perceived Nurses have shared their thoughts about the care environment for
competence in trauma-informed care was associated with their atti- infants with NOWS and the impact it has on their outcomes. In one
tudes. These NICU nurses described difficult interactions with mothers study, researchers found that most (60 %) maternal-newborn nurses
with SUDs: "It is still difficult to work with many of these families. The believed the NICU was an inappropriate environment for infants with
main reason is manipulative behavior and mistruths" [37, p. 382]. NOWS,42 and almost all (98 %) nurses in the study implemented
Further, the nurses felt that prenatal substance use was a form of child non-pharmacologic comforting techniques. Less than half (48 %) of the
abuse, and a perceived lack of commitment to the newborn played a role nurses reported that their facility had developed adequate practice
in shaping their attitudes toward the mother. This is worth noting guidelines, and only 33 % felt their facility had succeeded in creating an
because mothers with SUDs often experience self-criticism, negative appropriate environment for infants with NOWS and their families. Most
experiences, previous trauma, and fear of judgement from nurses. While nurses (57 %) stated they did not blame the mother for her infant’s
a common ground between the nurses and mothers may be difficult to NOWS but still expressed frustration with mothers’ lack of participation
establish, it is also seen as critical for establishing a therapeutic in their infants’ care. In addition to the care of the infant, 70 % of nurses
nurse-parent relationship and sense of unity as a team.38 stated they also felt responsible for the care of the mothers.
In another study,43 Australian nurses and nurse midwives described
NOWS assessment “Scoring” instruments the complexities of NOWS care and how they believed it was best pro-
vided by more experienced nurses; yet most infants with NOWS were
In addition to issues surrounding bias, stigma, and judgement, par- assigned to new or agency nurses, which brought into question conti-
ents and nurses alike questioned the dependability and practicality of nuity of care. The nurses also discussed the high stress associated with

caring for infants with NOWS and their relief at the end of a shift14: delivered a common message to parents that they were their infant’s
“We’re looking after them and after eight hours if you have a baby that’s treatment and were expected to be present as much as possible during
really withdrawing, you’re going oh God I’m glad I’m going to go home” their infant’s hospital stay.46
(p. 5). The nurses felt that existing care models were inadequate in The infant’s environment was also controlled to reduce stimulation
supporting them and in some cases resulted in compassion fatigue and from noise and light, and breastfeeding/human milk feeding was
moral distress: strongly encouraged unless otherwise contraindicated.45 The assessment
of infants was simplified to focus on three important infant behaviors,
[The baby] just would sometimes cry and cry, and nobody could get
the infant’s ability to a) eat effectively, b) sleep uninterrupted for at least
to him, and he would just give up. He would just have this sort
an hour, and c) be consoled within 10 min. Additionally, rather than the
of—sometimes he’d just be there with this sort of look. I don’t know.
slow medication weaning protocols used in traditional NOWS manage-
Maybe it was in my head, but it just seemed like he had given up—it
ment approaches, medication was weaned more quickly and/or given
was like crying is not working, so I’m just going to lie here, you
only on an as-needed basis to reduce withdrawal symptoms. Finally, the
know? [14, p. 6].
practice of directly admitting infants with NOWS to the NICU was dis-
In another study, several nurses explained how hospital management continued and instead only utilized if a medical concern arose or if beds
lacked understanding and basic knowledge about NOWS and how much were unavailable on the in-patient unit. Following implementation of
time was required to care for these infants and their families, which the ESC approach to care, infants’ hospital LOS decreased from an
resulted in management questioning unit staffing ratios.44 These nurses average of 22.4 days to 5.9 days, the use of medication was reduced from
felt that managerial support was needed to ensure appropriate staffing, 98 % of infants to 14 %, and the total cost of care was reduced from $44,
especially during night and weekend shifts. One nurse said, “I would say 824 to $10,298. No infants were readmitted to the hospital for treatment
the hospital approving more nurses to take care of these babies and of NOWS and there were no reports of adverse events.45
understanding that sometimes they can be a one on one if they have to
be, and supporting that, I would say that’s currently not there. So as far Parent experience
as I’m concerned, there really isn’t a lot of hospital support at this time”
[44, p. 459]. In general, the response to a more holistic and patient-centered
approach to NOWS care has been positive, with parents expressing a
Parental participation in infant care greater sense of empowerment and self-efficacy in their ability to com-
fort their infants.15 In one study, researchers found that ESC reinforced
Nurses believed that lack of parental participation was a barrier to the importance of parents in their infant’s care.15 When comparing ESC
parental education and a source of stress for the nursing staff. In one with traditional NOWS care, they found that the greatest differences
study, nurses described external factors, such as the need for mothers to were parents’ perceptions of fewer interruptions to bonding due to
regularly access substance use treatment services, their physical dis- scoring and less immediate initiation of medications based on reaching a
tance from the hospital, needing to care for other children, and certain score threshold. Parents also shared how they appreciated fewer
employment, to be barriers to effective bonding and being present at the interventions and normalization of their infant’s care. One mother said,
hospital to care for their infant.44 One nurse stated, “I think because the “…the doctor’s message had been…always holding [my baby] and
parents can’t be there 24/7 because they usually have other kids at trying to comfort him and swaddling him…. He likes that. Just rocking
home so it’s hard, your baby changes every day and it’s hard for them to him and singing to him. Stuff like that. Nursing him when he would
really get to know them, so I do feel like it’s hard for them to bond (p. nurse” [15, p. 362].
452). Additional perceived barriers included the initiation of medica- This greater emphasis on non-pharmacologic interventions, which
tions to manage the infant’s withdrawal, visitation requirements of may include skin-to-skin care, where parents hold their unclothed infant
Child Welfare, or other complex social issues. skin-to-skin on their bare chests, was also valued by parents. In a study
While mothers acknowledged the importance of being present for that implemented skin-to-skin care (SSC) for infants with NOWS, re-
their infants, day-to-day life and other responsibilities often interfered, searchers discovered benefits for mothers as they explained the recip-
which left them trying to be in two places at once and resulted in feelings rocal nature of their relationship with their newborn. The mothers
of judgement and guilt. One mother, who needed to care for two of her described needing to be with their newborns as much if not more than
other young children, described how her inability to be at her infant’s their newborns needed to be with them. Participating in SSC helped the
bedside as often as she wanted became an additional source of judge- mothers achieve this closeness, as one mother explained:
ment for her, which led to her negative perceptions of the healthcare [SSC] felt good. [When we were separated], it felt like a part of me
team. Other mothers described being in a no-win situation. One mother was missing and, when I held her, it felt like [she] was the part that
expressed feeling guilty for being away from her newborn to care for her was missing. It was just like a weird connection. I can’t explain it. It
other children, while another experienced guilt for not caring for her was amazing; like a bond. It was like a good bond. I love my baby,
other children so she could be with her newborn.10 you know. And holding her, I loved—I loved her more [13, pp.
18–19].
Eat, sleep, and console (ESC)
This closeness also helped alleviate some of the shame and guilt
experienced by the mothers and elicited a sense of healing and self-
Due to limitations described with the traditional approach to NOWS
forgiveness. Another mother stated:
care, over the past decade, Grossman and colleagues have sought to
develop and implement a simpler and more holistic approach.9,45,46 To Skin-to-skin allowed us to heal together, recover together. [My
accomplish this, they focused their attention on four key drivers of in- daughter] helps me to forgive and forget and move forward. Skin-to-
fants’ hospital length of stay (LOS): a) non-pharmacologic interventions, skin helped get rid of the guilt of using [substances]. That one-on-one
b) a simplified approach to assessment, c) reduction in medication use, time with me and her was so special to me because I felt like she was
and d) improved communication between hospital units. They began by
standardizing nonpharmacologic interventions across hospital units and

telling me that it was okay. You know? Like because, she was so calm Services providers who have familiarity with NOWS management. These
[13, p.19]. researchers also recommended that team members have specialized
training in recognizing and managing withdrawal, implementing non-
However, while the ESC approach, with its emphasis on non-
pharmacologic management, and the science of addiction. In this study,
pharmacologic interventions, may support early bonding between par-
physicians and nurses emphasized the importance of interprofessional
ents and infants, researchers have found that it may not be enough to
and volunteer staff, such as nutritionists, lactation consultants, and
completely alleviate the feelings of guilt, fear, and stress that can be
cuddlers, who are instrumental in caring for infants with NOWS. They
inherent for parents of infants with NOWS. Parent statements such as,
also stressed the important role obstetricians and family practitioners
“Watching her suffer was the worst thing that I’ve ever seen in my life”
play in setting expectations prenatally for hospitalization and orienta-
[15, p. 362] serve to further illustrate this concern.
tion of families to hospital policies.

Healthcare provider experience Staff education

The shift in NOWS care management to the ESC approach has also Another general topic of agreement is the overall need for more in-
had an impact on healthcare providers’ perceptions of patient care. Prior depth education on NOWS and skills training for front-line healthcare
to implementation of ESC in a community-based hospital, researchers providers. In one study, nurses discussed how little education and
found that nurses (68 %) were overall satisfied with the traditional training they received on caring for families impacted by NOWS and
management approach for infants with NOWS.47 However, following recalled that most of this training, which was specific to using the
the implementation of ESC, most nurses (68 %) believed that ESC was FNASS, had been received during new-hire orientation.38 They shared
best for the families, and nearly all nurses (97 %) felt this approach that little to no time was spent learning about maternal OUD and
improved the parents’ engagement in their infants’ care. The nurses (78 evidence-based NOWS treatment approaches. One nurse said, “When I
%) also felt that parents were well supported and had adequate re- was first hired in the NICU, we were shown an assessment video to show
sources for managing their infants at home. However, these same nurses how they assess early withdrawal babies, but that’s all” (p. 489). More
were somewhat neutral when asked if they felt ESC improved breast- experienced nurses believed that new nurses were inadequately pre-
feeding rates, with 46 % stating rates had increased. pared to provide quality NOWS care, especially as it pertained to
Even in care settings where the ESC approach had not been maternal OUD and evidence-based treatment, and the social and family
completely implemented, nurses expressed greater satisfaction than dynamics that often accompany this condition. Some nurses said they
with the traditional approach to care. In one study,36 researchers relied on the internet to learn more about caring for patients with NOWS
described two New England hospitals where infants roomed-in with even though they knew the internet could be unreliable. For nurses who
their parents and non-pharmacological interventions were implemented did have experience caring for families with NOWS, they felt their
to include environmental control of light and noise. Use of the FNASS to experience was insufficient. They wanted more formalized education
score infants’ withdrawal remained part of the unit practice, and infants from the hospital about maternal OUD, NOWS outcomes, and engaging
requiring medication were transferred to the in-patient pediatric unit. In with mothers. One nurse summarized, “I just think [perinatal nurses]
these hospitals, nurses were satisfied with the new rooming-in care need the whole opioid addiction education…we just don’t get any of it
compared to previous care in the NICU. One nurse said, " … they are all really.” (p. 489)
out with the moms so … [the moms] are keeping them calmer, and the This lack of NOWS education is concerning and unnecessary since
withdrawing process is a lot easier" [36, p. 604]. Overall, the nurses quality and impactful training programs have been developed and
believed that rooming-in and having parents be the first-line treatment implemented with relatively good success, resulting in increased
had resulted in better management of infants’ withdrawal. One nurse knowledge and confidence in nurses. For example, following a brief in-
shared, " … the last few babies that I’ve had, the moms really assumed person educational intervention delivered by a nurse for nurses, par-
full care" (p. 604). ticipants demonstrated a statistically significant (p < 0.001) improve-
This reliance on parents as the primary caregivers of their infants ment in NOWS knowledge.49 Participants (96 %) were also able to
also came with some challenges including managing the expectations of correctly identify three clinical skills they could implement with
anxious parents.36 Once nurse said, " … the parents, they’re not calm mothers with SUD, and 84 % were able to identify two personal
people, and when they see the baby … having shivers, they get more strengths and two personal weaknesses that could negatively impact the
nervous" (p. 603). Nurses also explained that with mothers who smoked quality of care they provided for families with NOWS. However, the
tobacco, they felt challenged to convince them not to leave the unit to author concluded this improvement in knowledge may not necessarily
smoke and had to reiterate the importance of staying with their infant. translate to improved nursing attitudes and patient outcomes and that
One nurse shared her experience, " … many times you are peeling [the more research is needed.
mothers] off the wall or telling them they can’t leave the floor for a Another group of researchers drew similar conclusions upon
cigarette" (p. 603). Regardless of management approach or parent completing and evaluating a web-based NOWS educational curricu-
involvement in care, some nurses remained concerned about how fam- lum.50 Following completion of the curriculum, participants demon-
ilies impacted by NOWS would cope following discharge, "It’s scary on strated substantial increases in NOWS knowledge and care practices.
our part of what we’re discharging home sometimes with families and While most participants agreed with the positively worded attitude
wondering, ’I hope that baby is going to be okay"’ (p. 605). items at pretest and posttest, a small number expressed negative atti-
tudes about parents of infants with NOWS at pre-test. The training
Interdisciplinary care coordination curriculum appeared to have no impact on those negative attitudes at
post-test. In general, however, participants felt the program was effec-
Considering both the traditional management approach for NOWS tive in reducing stigma and improving provider/staff interactions with
and ESC, there seems to be consensus that Interdisciplinary, team-based patients. The researchers recommended incorporating the core concepts
care (TBC) coordination is essential for impacted families. In one study, of trauma-informed care and self-regulation into future revisions of the
researchers investigated the important structures and processes of TBC curriculum to address negative staff attitudes and improve the care of
for infants with NOWS.48 Recommendations from this study were the families with NOWS.
establishment of a team that includes infants’ parents; healthcare pro-
viders with specialized expertise in caring for infants with NOWS, such
as nurses, physicians, dedicated social workers; and Child Protective

Summary and conclusions 10. Buczkowski A, Avidan O, Cox D, Craig A. The parental experience of newborns with
neonatal abstinence syndrome across inpatient care settings: a qualitative study.
J Addict Med. 2020;14(5):e183. -e7.
The increased incidences of NOWS occurring over the past several 11. Cleveland LM, Bonugli R. Experiences of mothers of infants with neonatal
decades has contributed to improved knowledge and experience in the abstinence syndrome in the neonatal intensive care unit. J Obstet Gynecol Neonatal
therapeutic care of infants and families impacted by NOWS. Stigma and Nurs. 2014;43(3):318–329.
12. O’Connor M, Czarnik M, Morrow B, D’Angelo D. Opioid use during pregnancy: an
judgement toward individuals with mental and behavioral health con- analysis of comment data from the 2016 pregnancy risk assessment monitoring
ditions have been common in healthcare settings and serve as barriers to system survey. Subst Abus. 2022;43(1):649–656.
individuals accessing needed healthcare and other supports. The high- 13. McGlothen-Bell K, Recto P, McGrath JM, Brownell E, Cleveland LM. Recovering
together: mothers’ experiences providing skin-to-skin care for their infants with
acuity environment of an SCU or NICU can be difficult for parents, NAS. Adv Neonatal Care. 2021;21(1):16–22.
challenging their ability to provide the one-on-one nonpharmacological 14. Shannon J, Blythe S, Peters K. The complexities associated with caring for
care their infants need. Further, this environment may exacerbate hospitalised infants with neonatal abstinence syndrome: the perspectives of nurses
and midwives. Children (Basel). 2021;8(2).
withdrawal in newborns with NOWS. A more holistic approach to care, 15. McRae K, Sebastian T, Grossman M, Loyal J. Parent perspectives on the eat, sleep,
such as the ESC model, supports active parent participation in infants’ console approach for the care of opioid-exposed infants. Hosp Pediatr. 2021;11(4):
care and is preferred by healthcare providers. This approach has 358–365.
16. Klaus MH, Jerauld R, Kreger NC, McAlpine W, Steffa M. Kennel JH. Maternal
contributed to less need for medication to manage withdrawal, shorter attachment. Importance of the first post-partum days. N Engl J Med. 1972;286(9):
hospital LOS, and a reduction in cost to the healthcare system. However, 460–463.
the ongoing educational needs of parents and healthcare providers 17. Stevens J, Schmied V, Burns E, Dahlen H. Immediate or early skin-to-skin contact
after a Caesarean section: a review of the literature. Matern Child Nutr. 2014;10(4):
related to perinatal OUD and NOWS care, adequate unit staffing to meet
456–473.
the needs of infants and their families, and interdisciplinary care coor- 18. Bystrova K, Ivanova V, Edhborg M, Matthiesen AS, Ransjö-Arvidson AB,
dination must be supported for ESC to positively impact NOWS care and Mukhamedrakhimov R, et al. Early contact versus separation: effects on mother-
outcomes. infant interaction one year later. Birth. 2009;36(2):97–109.
19. Smirk CL, Bowman E, Doyle LW, Kamlin CO. How long should infants at risk of drug
withdrawal be monitored after birth? J Paediatr Child Health. 2014;50(5):352–355.
CRediT authorship contribution statement 20. Slowiczek L, Hein DJ, Risoldi Cochrane Z, Gregory PJ. Morphine and methadone for
neonatal abstinence syndrome: a systematic review. Neonatal Netw. 2018;37(6):
365–371.
Lisa M. Cleveland: Conceptualization, Investigation, Writing – 21. Finnegan LP, Connaughton Jr JF, Kron RE, Emich JP. Neonatal abstinence
original draft, Writing – review & editing. syndrome: assessment and management. Addict Dis. 1975;2(1–2):141–158.
22. Academy of Neonatal Nursing. Finnegan Neonatal Abstinence Scoring Tool (FNAST)
[PDF]. 2007. Available from: [Link]
Declaration of competing interest [Link].
23. Titus-Glover D, Shaya FT, Welsh C, Roane L. The lived experiences of pregnant and
The authors declare the following financial interests/personal re- parenting women in recovery toward medication treatment for opioid use disorder.
Subst Use Addctn J. 2024;45(3):367–377.
lationships which may be considered as potential competing interests: 24. Frazer Z, McConnell K, Jansson LM. Treatment for substance use disorders in
Lisa M Cleveland reports a relationship with The Texas Health and pregnant women: motivators and barriers. Drug Alcohol Depend. 2019;205, 107652.
Human Services Administration that includes: funding grants and 25. Howard MB, Schiff DM, Penwill N, Si W, Rai A, Wolfgang T, et al. Impact of parental
presence at infants’ bedside on neonatal abstinence syndrome. Hosp Pediatr. 2017;7
speaking and lecture fees. If there are other authors, they declare that
(2):63–69.
they have no known competing financial interests or personal re- 26. Breastfeeding recommendations for people who use substances: AWHONN practice
lationships that could have appeared to influence the work reported in brief number 16. Nurs Womens Health. 2022;26(6):e4–e7.
this paper. 27. Management of newborns with in utero substance exposure: AWHONN practice
brief number 18. Nurs Womens Health. 2023;27(2):e8–e11.
28. Taylor K, Maguire D. A review of feeding practices in infants with neonatal
Data availability abstinence syndrome. Adv Neonatal Care. 2020;20(6):430–439.
29. Chu L, McGrath JM, Qiao J, Brownell E, Recto P, Cleveland LM, et al. A meta-
analysis of breastfeeding effects for infants with neonatal abstinence syndrome. Nurs
Data will be made available on request. Res. 2022;71(1):54–65.
30. Scott LF, Guilfoy V, Duwve JM, Rawl SM. Factors associated with the need for
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