Opioid Epidemic: How It Affects Neonates

Emmalee S. Bandstra, M.D. Professor of Pediatrics and OB/GYN

Division of Neonatology Holtz Children’s Hospital

Neonatal Track

September 14, 2016

Neonatal Abstinence Syndrome

NAS is an array of signs and neurobehaviors in the neonate following abrupt discontinuation of in utero exposure to substances of abuse.

The term primarily refers to opioids, such as heroin, methadone,

buprenorphine, and prescription pain medications, for example oxycodone (Oxycontin®), hydrocodone (Vicodin®), Fentanyl.

Withdrawal occurs in 55-94% of neonates with in utero opioid exposure.

However, alcohol, nicotine, benzodiazepines, antidepressants, and

antipsychotics can also produce NAS.

Furthermore, nicotine, cocaine, antidepressants, and polydrugs can potentiate opioid-induced NAS.

Some experts prefer the term NOWS (neonatal opioid withdrawal syndrome), but this may not capture all infants at risk for NAS.

Opioids Opioids are a class of natural, endogenous and synthetic

compounds that activate primarily μ-opioid (but also κ- and δ-opioid) receptors in the CNS to produce supraspinal analgesia.

Acute effects include sedation, euphoria, miosis, respiratory

depression, and decreased gastrointestinal motility.

Acutely, opioids inhibit the release of noradrenaline at synaptic terminals. Chronic exposure to opioids leads to tolerance as the rate of noradrenaline release over time increases toward normal.

Methadone exerts secondary effects by acting as an NMDA (N-methyl-D-aspartate) receptor antagonist, blocking the actions of glutamate, the primary excitatory neurotransmitter in the CNS.

Opiates are a subclass of opioids consisting of alkaloid compounds extracted or derived from opium.

Prevalence of Substance Abuse by Pregnant Women (15-44 Years of Age) National Survey on Drug Use and Health estimates:

15.9% smoke cigarettes 8.5% use alcohol 2.7% binge drink 0.3% drink heavily

5.4% use illicit drugs

National Survey on Drug Use and Health (NSDUH), 2011-2013

Prevalence of NAS In a nationally representative sample of newborns:

From 2009-2012, the incidence of NAS increased from 3.4 to 5.8 per 1000 hospital births overall; reaching a total of 21,732 infants. • By 2012, approximately one infant was born every 25

minutes in the United States with NAS. Inflation-adjusted mean hospital charges in 2012 reached

$66,700 for infants with NAS, $93,400 for pharmacologically treated NAS, and $3,500 for uncomplicated term infants.

NAS incidence varied widely geographically, from 2.6 to 16.2 per 1000 hospital births.

Patrick SW, et al. Journal of Perinatology. 2015;35:650-655.

What is Fueling this Health Crisis? The National Institute of Drug Abuse (NIDA) reports that the increase in prescription drug abuse over the past decade is due to a variety of reasons, including:

Introduction of a powerful new class of time-released opioids – what some addiction specialists have dubbed “heroin in a pill.”

Aggressive marketing strategies by the pharmaceutical industry to promote the widespread use of these new drugs.

Greater social acceptability for medicating a growing number of conditions.

False perception that abusing prescription drugs is inherently less harmful than using “illegal” drugs like cocaine, methamphetamine, and heroin.

Prescription opioid diversion, an illegal activity, has increased.

Prevalence of NAS in Florida

In Florida, the number of newborns discharged with neonatal withdrawal syndrome from 1995 to 2009 increased 10-fold from 0.4 to 4.4 discharges per 1000 live births.

This increase was largely due to the prescription of opiates in pregnant women for acute or chronic pain.

Hudak ML, et al. Pediatrics. 2012;129(2): 540-560.

Prescription Drug Diversion in Florida Florida has been the epicenter of prescription drug

diversion, resulting in more women using or abusing prescription opioid drugs.

More pregnant women abusing prescription drugs leads

to an increase in NAS cases. Determining the exact number of NAS cases is difficult

because of significant variability in hospital policies and practices for both diagnosing and reporting of NAS.

In 2011, the Florida Department of Health reported 1,563

newborn drug withdrawal cases statewide – surely the “tip of the iceberg”. Florida Statewide Task force on Prescription Drug Abuse and Newborns, 2013: 7-51

Prevalence Rate of NAS per 10,000 Live Births in Florida, 2008-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

Prevalence Rates of NAS per 10,000 Live Births in Florida by Maternal Race and Ethnicity, 2011-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

Prevalence Rates of NAS per 10,000 Live Births in Florida by Maternal Age Group, 2011-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

Prevalence Rates of NAS per 10,000 Live Births in Florida by Maternal Education Level, 2011-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

Prevalence Rates of NAS by Maternal County of Residence Per 10,000 Live Births, 2011-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

NAS Frequencies by County Per 10,000 Live Births, 2011-2013

Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From 2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf

NAS Pathophysiology Abrupt discontinuation of exogenous opioids results in supranormal release of noradrenaline and produces autonomic and behavioral signs and symptoms characteristic of withdrawal.

Mechanisms are not fully understood --

• One theory involves cyclic adenosine monophosphate

(cAMP), the intracellular secondary messenger responsible for signal transduction.

• During withdrawal there is overproduction of cAMP. The

resultant flux is a suspect for the intense withdrawal manifestations, in addition to effects from dysregulation of other neurotransmitters.

NAS Clinical Manifestations Presentation is widely variable in timing of onset and severity, likely multifactorial in origin:

• Maternal substances used, dosage and frequency of opioid

use, and timing during gestation

• Maternal factors (e.g., nutrition, infections, stress, comorbid psychiatric conditions)

• Placental opioid metabolism

• Infant factors (e.g., gestational age, infections, metabolism and excretion rates, other neonatal conditions and medications)

• Environmental factors

• Genetics, epigenetics

OPRM1 and COMT Single-Nucleotide Polymorphisms Associated with Treatment of

NAS and Hospital Length of Stay Genetic variations of the mu-opioid receptor (OPRM1) and the

catechol-o-methyltransferase (COMT) gene appear to affect the need for pharmacotherapy and length of stay in neonates with prenatal opioid exposure.

These data are consistent with data from adult studies showing that genetic polymorphisms are associated with variability in adult opioid dependence.

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

These preliminary findings may provide insight into the mechanisms underlying NAS.

Wachman EM, et al. JAMA. 2013;309(17):1821-1827.

Clinical Manifestations

Opioid receptors are concentrated in the CNS and the GI tract.

Thus, the predominant signs and symptoms of pure opioid withdrawal reflect CNS irritability, autonomic over-reactivity and gastrointestinal dysfunction.

Opioid-induced NAS Manifestations

Neurological Gastrointestinal Autonomic

• Irritability • Increased wakefulness • High-pitched cry • Tremor • Increased muscle tone • Hyperactive deep

tendon reflexes • Frequent yawning and

sneezing • Seizures (2-11%)

• Vomiting/diarrhea • Dehydration • Poor weight gain • Poor feeding • Uncoordinated and

constant sucking

• Diaphoresis • Nasal stuffiness • Fever • Mottling • Temperature

instability • Piloerection • Mild elevations in

respiratory rate and blood pressure

Bio LL, et al. Journal of Perinatology. 2011; 31:692-701.

NAS Timing of Withdrawal Varies depending upon type of opioid, the last dose, and the half-life of

drug elimination. Present at birth, may peak at 3-4 days, may not appear until 10-14 days

• Heroin – signs appear within 24 hours of birth • Methadone – signs begin 24-72 hours after birth • Buprenorphine – signs present later than with methadone

Subacute opioid withdrawal may persist for 4-6 months

Neurologic irritability with abnormal Moro reflexes may last 7-8 months

Recommendation: Opioid-exposed infants should be observed in the hospital for a minimum of 4-5 days and should be carefully followed post-discharge.

NAS in Preterm Infants Infants

NAS Differential Diagnosis In the neonatal period other problems may have features similar to NAS. Clinical signs should not be attributed solely to withdrawal without appropriate assessment for other causes, for example:

• Seizures

• Hypocalcemia • Hypoglycemia • Hypoxic-ischemic encephalopathy (HIE)

• Fever and irritability

• Sepsis • Hyperthyroidism

• Poor feeding due to myriad causes, including polycythemia.

NAS - Diagnosis

A history (or suspected history) of maternal

substance abuse Positive maternal or infant toxicology

screening Neonatal findings consistent with NAS

Role of the Physician and Nurse in the Care of Substance-exposed Newborns

• Prevention • Identification of exposure • Recognition of medical issues • Protection and follow-up

There is clear evidence that recognizing the substance-exposed infant and implementing early intervention services for the child and mother are keys to minimizing the acute and long-term effects of prenatal substance exposure.

Even if the infant does not exhibit clinically significant

difficulties in the neonatal period, identification of the substance-exposed infant can improve his or her long-term outcome.

Maternal Screening for Substances of Abuse

The optimal approach to identify drug use is maternal screening

based on developing rapport and using validated screening tools. It is imperative for the examiner to have a nonjudgmental

approach, use open-ended questions, and take time to achieve maternal trust and obtain a full history.

There is no biological specimen that, when obtained randomly,

identifies prenatal drug use with 100% accuracy. • A negative drug screening result does not ensure that the

pregnancy was drug-free.

CAGE Questions Adapted to Include Drugs (CAGE-AID)

1. Have you ever felt you ought to cut down on your drinking or drug use?

2. Have people annoyed you by criticizing your drinking or drug use?

3. Have you ever felt bad or guilty about your drinking or drug use?

4. Have you ever had a drink or used drugs first thing in the morning to steady your nerves or to get rid of a hangover (eye-opener)?

Brown RL, Rounds LA. Wisc Med. 1995;94:135-140

Toxicology Screening Maternal and neonatal urine, meconium, and hair are the most commonly used specimens for drug testing during the prenatal and perinatal period, however none are accepted as a gold standard. Urine has been the most frequently tested due to ease of collection.

• Identifies only recent use • Detects nicotine, opiate, cocaine, amphetamine, and marijuana

exposure

Meconium analysis is sensitive and specific for drugs excreted either in the hepatobiliary system or amniotic fluid via fetal renal excretion.

Hair analysis is used predominantly for research purposes. Umbilical cord tissue assays appear promising, but are not widely available for clinical use.

Newborn Toxicology Screening Guidelines

Institutional guidelines and protocols vary widely Specific clinical conditions for which toxicology

testing is indicated:

• No prenatal care • Abruptio placentae • Preterm delivery • IUGR • Cardiovascular accident of mother or child

Methadone Maintenance Treatment (MMT) for Opioid Dependence in Pregnant Women

Opioid abuse in pregnant women poses risks for the fetus and newborn. Opioids are lipophilic compounds that cross placental and blood brain barriers.

Active or passive maternal detoxification is associated with increased risk of fetal distress and demise.

MMT for pregnant women can sustain opioid concentrations in the mother and fetus in ranges that minimize opioid craving, suppress abstinence symptoms, and prevent fetal stress.

Methadone Maintenance Treatment (MMT) for Opioid Dependence in Pregnant Women Considered standard of care for opiate addiction during

pregnancy

Advantages: • In pregnancy, methadone treatment programs have

successfully decreased use of other opiates and illicit drugs, improved prenatal care, and afforded opportunities to provide psychoeducation.

Disadvantages:

• Detoxification after delivery unlikely • More severe and prolonged course of NAS

Buprenorphine Maintenance Treatment for Opioid Dependence in Pregnant Women

Issues with methadone maintenance therapy encouraged the development of other synthetic opioids as alternative treatments to methadone.

Buprenorphine is increasingly favored by some clinicians and

patients: • Effectively treats opioid dependence • Partial mu-opioid agonist and kappa-opioid antagonist • Less than maximal opioid effect and diminished risk of

overdose due to its low intrinsic receptor efficacy

The Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study

MOTHER Study

International study (US and Austria) Double-blind, flexible dosing, parallel-group randomized clinical trial of the relative maternal and neonatal safety and efficacy of buprenorphine monotherapy vs. methadone for the treatment of opioid dependence during pregnancy 175 mothers randomized 131 neonates (58 buprenorphine, 73 methadone) were followed to study completion

Jones HE, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363:2320.

MOTHER Study Buprenorphine vs Methadone-exposed neonates:

• Showed some improvement in neonatal outcomes • Required less medication (morphine) to treat NAS (1.1 vs 10.4 mg) • Had significantly shorter hospital stays (10 vs 17.5 days) • Had shorter duration of treatment for NAS (4.1 vs 9.9 days)

Follow-up assessments are anticipated to provide comparisons of the effects of in utero buprenorphine vs methadone exposure on early childhood development effects.

ACOG (2012) acknowledged that emerging evidence supports the use of buprenorphine for opioid-assisted treatment during pregnancy.

Jones HE, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010; 363:2320.

NAS Assessment and Management The optimal care of the mother-infant dyad is provided by a nonjudgmental multidisciplinary team

Interdisciplinary collaborative care by health care and social service providers

Goals of therapy:

• Establish consistent weight gain through adequate sleep and nutrition

• Allow the infant to successfully integrate into his or her environment by managing stimuli and educating and empowering caretakers

Every nursery should adopt a standardized protocol for assessing and managing neonates at risk for NAS

NAS Assessment and Management Nonpharmacologic comfort measures and pharmacologic therapy. Pharmacotherapeutic decisions are based on the response to nonpharmacologic measures and the severity of withdrawal signs, typically determined by an abstinence scoring system. Several scoring systems (none universally accepted) are often adapted or modified to meet the needs of the institution.

• Finnegan Scoring System most comprehensive and widely used

• The Neonatal Drug Withdrawal System (Lipsitz tool) • Ostrea criteria • Neonatal Withdrawal Inventory • Riley Infant Pain Scale

Finnegan NAS Scoring System In 1975, Finnegan and colleagues selected the 20 most common signs and grouped them into CNS, metabolic/vasomotor/respiratory, and gastrointestinal subscales.

Signs were ranked according to pathologic significance and assigned scores 1-5.

Total scores ≤7 are considered mild – infants usually do well with nonpharmacologic comfort measures.

Total scores ≥8 indicate need for pharmacologic therapy. Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis 1975; 2:141

Finnegan CNS Subscale

Text/Graphics Start Here

Finnegan Metabolic/Vasomotor/Respiratory Subscale

Finnegan Gastrointestinal Subscale

Nonpharmacologic Treatment of NAS

Initial treatment of early signs of withdrawal is directed at minimizing environmental stimuli (light and sound)

• Placement in a dark quiet environment, careful swaddling • Responding early to the infant’s signals • Adopting appropriate comforting techniques (swaying,

rocking)

Frequent feedings to minimize hunger When possible, mothers who adhere to a supervised drug

treatment program should be encouraged to breastfeed.

• Breastfeeding or human milk feedings have been associated with less severe NAS.

Pharmacologic Treatment of NAS Drug therapy is indicated to relieve moderate to severe NAS signs

• Opioids 1st line: neonatal morphine solution, methadone, tincture of opium, paregoric (2012 AAP guidelines: morphine or methadone preferred NAS treatment)

• Barbiturates (phenobarbital): adjunctive, 2nd line drug • Clonidine: adjunctive, 2nd line drug

• Benzodiazepines (diazepam, lorazepam) not favored due to

adverse side effects on infant suck and swallow and lack of efficacy

• Phenothiazines (chlorpromazine)

Buprenorphine Treatment of NAS

Randomized, open label, active-control trial of buprenorphine in neonates

24 neonates with NAS; 12 in each treatment group

Sublingual buprenorphine 15.9 mcg/kg/day in 3 divided doses vs.

oral morphine 0.4 mg/kg/day in 6 divided doses Length of stay and duration of treatment were significantly shorter

in the buprenorphine vs. morphine group: • Length of stay: 23 vs 38 days, p=0.01 • Duration of treatment: 32 vs 42 days, p=0.05

Buprenorphine is promising but still under investigation

Kraft WK, et al. Addiction. 2011; 106 (3): 574-580.

Clonidine Treatment of NAS Centrally acting alpha 2-adrenergic receptor agonist

Used to suppress opiate withdrawal symptoms in older

children and adults

Provides an alternative to opioids, benzodiazepines and barbiturates in NAS treatment

Reduces symptoms associated with withdrawal and provides a shorter duration with limited adverse effects

Evidence remains limited; only 1 randomized controlled trial (RCT)

No long-term studies currently available

Clonidine RCT for NAS Adjunct Treatment

Double-masked, RCT compared the efficacy and safety of

treating NAS with DTO plus oral clonidine (1 mcg/kg q 3hrs) vs DTO plus placebo

80 neonates exposed in utero to methadone or heroin

Clonidine group had significantly reduced length of pharmacologic therapy (11 vs 15 days) and decreased mean total dose of morphine (7.7 vs 19.2 mg)

No differences in feeding, weight gain, or loss, HR or BP

Agthe AG, et al. Pediatrics. 2009; 123(5): 849-856.

AAP Guidelines Opioid Withdrawal Medical Treatment

Hudak ML, et al. Pediatrics. 2012;129(2): 540-560.

Outcomes Assessment of long-term morbidity specifically

attributable to neonatal drug withdrawal and its treatment is difficult.

Few studies have followed drug-exposed neonates beyond the first few years of life.

Available information suggests that infants prenatally exposed to opiates are at an increased risk for neurodevelopmental impairment.

Confounding variables (environment and dysfunctional caregivers) complicate interpretation of outcomes.

The home environment plays a significant role in modulating developmental outcomes of exposed children.

Need for ongoing longitudinal research in school age and adolescence.

Seizures in Infants with NAS

Doberczak TM, et al. Journal of Pediatrics. 1988; 113: 354-358.

AAP: NAS Clinical Highlights Each nursery caring for infants with neonatal withdrawal

should develop a protocol defining indications and procedures for screening, and evaluation and treatment of infants.

Screening for maternal substance abuse is best accomplished by using history, maternal urine testing, newborn urine/meconium testing.

Drug withdrawal should be considered in the differential diagnosis for infants in whom compatible signs develop.

Nonpharmacologic supportive measures should be the initial approach to therapy.

Signs of withdrawal can be scored by using a published abstinence assessment tool.

The optimal threshold score for initiating pharmacologic therapy is unknown.

Breastfeeding should be encouraged if not contraindicated.

AAP: NAS Clinical Highlights Pharmacologic therapy for withdrawal-associated seizures

is indicated, but other causes of seizures must be ruled out. Vomiting, diarrhea, or other associations with dehydration

and poor weight gain are relative indications for pharmacologic treatment.

Oral morphine solution or methadone should be used when pharmacologic therapy is indicated.

There is emerging evidence for use of clonidine as primary or adjunctive therapy.

Severity of withdrawal signs, including seizures, has not been proven to be associated with differences in long-term outcome and treatment may not alter long-term outcome.

Given the natural history of withdrawal, it is reasonable to observe infants with known antenatal exposure to opioids and benzodiazepines for 4-7 days.

Early follow-up after discharge is advised.

Children’s Hospital of Philadelphia NAS Protocol Hufnal-Miller, et al.

Acknowledgements Special appreciation:

Jackson Hospital Systems Holtz Children’s Hospital

NICU NAS Quality Improvement Group

Research Assistants: Alexandra Fernandez, M.D.

Samantha Langer, B.S.

References • Agthe AG, Kim GR, Mathias KB, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a

randomized, controlled trial. Pediatrics. 2009; 123(5): 849-856. • Bandstra ES, Morrow CE, Mansoor E, Accornero VH. Prenatal drug exposure: infant and toddler outcomes. J Addict

Dis. 2010;29(2):245–258 • Bio LL, Siu A, Poon CY. Journal of Perinatology. 2011; 31:692-701. • Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and drug abuse. Wisc Med J. 1995;94:135-140 • Cabel Huntington Hospital. http://www.ibtimes.co.uk/shocking-video-shows-shaking-baby-born-addicted-drugs-

1532926 • Chasnoff IJ. Prenatal Substance Exposure: Maternal Screening and Neonatal Identification and Management.

Neoreviews 2003;4(9):e228-235 • Children’s Hospital of Philadelphia NAS Clinical Pathway, Hufnal-Miller C, Chuo J, Evans J, Monk H. February 2016.

http://www.chop.edu/clinical-pathway/neonatal-abstinence-syndrome-clinical-pathway • Doberczak, T.M., et al.: 1988, 'Neonatal Neurologic & Electroencephalographic Effects of Intrauterine Cocaine

Exposure', Journal of Pediatrics 113,354-358. • Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management.

Addict Dis 1975; 2:141 • Florida Health Neonatal Abstinence Syndrome Data Summary: Maternal Characteristics Among Live Births From

2011-2013. March 2015. http://www.fbdr.org/pdf/NAS_FLDOH_2011_thru_2013.pdf • Florida Statewide Task force on Prescription Drug Abuse and Newborns, 2013: 7-51 • Hudak ML, Tan RC, COMMITTEE ON DRUGS, COMMITTEE ON FETUS AND NEWBORN, American Academy of

Pediatrics. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540. • Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure.

N Engl J Med 2010; 363:2320. • Kraft WK, et al. Revised dose schema of sublingual buprenorphine in the treatment of neonatal opioid abstinence

syndrome. Addiction. 2011; 106 (3): 574-580

References Continued • National Survey on Drug Use and Health (NSDUH), 2008 • National Survey on Drug Use and Health (NSDUH), 2011-2013 • Patrick SW, Davis MM, Lehman CU, Cooper WO. Increasing incidence and geographic distribution of neonatal

abstinence syndrome: United States 2009 to 2012. Journal of Perinatology 2015; 35: 650-655. • Wachman EM, Hayes MJ, Brown MS, et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with

hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 2013; 309:1821.

Slide Number 1Opioid Epidemic: �How It Affects NeonatesSlide Number 3Neonatal Abstinence Syndrome OpioidsPrevalence of Substance Abuse by Pregnant Women (15-44 Years of Age)Prevalence of NASWhat is Fueling this Health Crisis?Prevalence of NAS in FloridaPrescription Drug Diversion in FloridaPrevalence Rate of NAS per 10,000 Live Births in Florida, 2008-2013Slide Number 12 Prevalence Rates of NAS by Maternal County of Residence Per 10,000 Live Births, 2011-2013NAS Frequencies by County Per 10,000 Live Births, 2011-2013NAS PathophysiologyNAS Clinical ManifestationsOPRM1 and COMT Single-Nucleotide Polymorphisms Associated with Treatment of NAS and Hospital Length of StayClinical ManifestationsOpioid-induced NAS ManifestationsNAS Timing of WithdrawalNAS in Preterm InfantsNAS Differential Diagnosis NAS - DiagnosisRole of the Physician and Nurse in the Care of Substance-exposed NewbornsMaternal Screening for Substances of AbuseCAGE Questions Adapted to Include Drugs (CAGE-AID)Toxicology ScreeningNewborn Toxicology Screening GuidelinesMethadone Maintenance Treatment (MMT) for Opioid Dependence in Pregnant Women�Methadone Maintenance Treatment (MMT) for Opioid Dependence in Pregnant WomenBuprenorphine Maintenance Treatment for Opioid Dependence in Pregnant WomenThe Maternal Opioid Treatment: Human Experimental Research (MOTHER) StudyMOTHER StudyMOTHER StudyNAS Assessment and ManagementNAS Assessment and ManagementFinnegan NAS Scoring SystemSlide Number 40Finnegan �CNS Subscale Finnegan �Metabolic/Vasomotor/Respiratory SubscaleFinnegan� Gastrointestinal SubscaleSlide Number 44Nonpharmacologic Treatment of NASSlide Number 46Pharmacologic Treatment of NASBuprenorphine Treatment of NAS Clonidine Treatment of NASClonidine�RCT for NAS Adjunct TreatmentAAP Guidelines�Opioid Withdrawal Medical TreatmentOutcomesSeizures in Infants with NASAAP: NAS Clinical HighlightsAAP: NAS Clinical HighlightsSlide Number 56Slide Number 57AcknowledgementsReferencesReferences ContinuedSlide Number 61