Treatment and Long-Term Outcomes of Neonatal Abstinence Syndrome (NAS)

1. Treatment and Long-Term Outcomes of
Neonatal Abstinence Syndrome (NAS)
Presenters:
• Jennifer A. Hudson, MD, Medical Director for Newborn
Services, Greenville Health System
• Henrietta S. Bada, MD, MPH, Professor and Vice Chair for
Academic Affairs, Department of Pediatrics, College of
Medicine and Department of Health Behavior, College of
Public Health, University of Kentucky
Treatment Track
Moderator: Carla S. Saunders, NNP-BC, Advance Practice Coordinator, Pediatrix
Medical Group, and Neonatal Nurse Practitioner, East Tennessee Children’s
Hospital, and Member, Rx and Heroin Summit National Advisory Board

2. Disclosures
Henrietta S. Bada, MD, MPH; Jennifer A.
Hudson, MD; and Carla S. Saunders, NNP-BC,
have disclosed no relevant, real, or apparent
personal or professional financial relationships
with proprietary entities that produce
healthcare goods and services.

3. Disclosures
• All planners/managers hereby state that they or their
spouse/life partner do not have any financial
relationships or relationships to products or devices
with any commercial interest related to the content of
this activity of any amount during the past 12 months.
• The following planners/managers have the following to
disclose:
– John J. Dreyzehner, MD, MPH, FACOEM – Ownership
interest: Starfish Health (spouse)
– Robert DuPont – Employment: Bensinger, DuPont &
Associates-Prescription Drug Research Center

4. Learning Objectives
1. Identify reasons and methods for the
increasing rate of diversion and abuse of Rx
narcotics.
2. Evaluate effective law enforcement strategies
for responding to drug diversion.
3. Describe current drug disposal legislation and
regulations.

5. Neonatal Abstinence Syndrome
Physical withdrawal in newborns with in-utero drug exposure
*Does not matter if drug it is prescribed, diverted, misused, or illicit*
Multiple symptoms including:
irritability and high-pitched cry, poor sleep, poor feeds, increase tone/tremors,
hypersensitivity, autonomic instability/tachypnea, sneezing, yawning, fever,
sweating, vomiting, cramping, diarrhea, excessive sucking, skin breakdown
Incidence has increased to 5.8 cases per 1000 inpatient births
~ 1 baby every 25minutes
The total US hospital charges for infants with NAS
is > $1.25 billion
100% Preventable

6. Preventing Neonatal
Opioid Withdrawal:
A Palliative Model
Rachel M Mayo, PhD; Liwei
Chen, MD, PhD; Lori A. Dickes,
PhD; Julie Summey, BS, MAT;
Windsor W Sherrill, PhD
jhudson@ghs.org wsherri@clemson.edu
Jennifer A Hudson, MD
Medical Director for
Newborn Services
jhudson@ghs.org

7. Disclosures
• I have no financial dualities of interest or relevant
relationships to disclose

8. Objectives
• Review national and regional trends related to
neonatal abstinence syndrome
• Discuss the benefits and safety profile of a
model combining early treatment and
stabilization of neonatal opioid dependence in
the low-acuity nursery

9. What We Really Hope You Hear
• Suffering is cruel and unnecessary
• Newborns deserve early and
effective treatment for opioid
withdrawal, just as they do for pain
• Our early treatment model is safe,
effective, cost-saving and feasible
for hospitals to consider replicating

10. Background
Blarney Castle, Ireland
Poison Garden
• Prescription drug abuse is
our nation’s fastest
growing drug problem
• Opiate use in women of
reproductive age is rising
– 5-fold increase in use by
pregnant mothers
– 30% of young Medicaid
women have a current
opiate prescription

11. Current Clinical Challenges
• A majority of birthing centers are not skilled in detecting or
treating NAS
• Lack of knowledge about which newborns are at risk
• Nonspecific symptoms are easy to misinterpret
• Pressure to achieve short length of stay
• Observation and treatment protocols vary by institution, state,
and country
• No formal guidelines for overall management of NAS
• No agreement about which abstinence scoring system should be the
“gold standard”
• Several medications are available to treat, but no standard dosing
approach or clinical care guidelines yet exist in the US

12. Newborns are Dependent, not Addicted

13. Pop Quiz
• How do most physicians learn to manage
neonatal abstinence syndrome?
A. Medical school
B. National conferences
C. Formal professional guidelines
D. Trial and error

14. Patrick SW, et al. Increasing incidence and geographic
distribution of neonatal abstinence syndrome: United States
2009 to 2012. J Perinatol, 2015
Background
• Hospital costs are rising
– $66,700 per withdrawing
newborn
– $93,400 per
pharmacologically-
treated newborn
– 78% Medicaid-funded
Patrick SW, et al. Neonatal abstinence syndrome and
associated health care expenditures: United States, 2000-
2009. JAMA, 2012
Blarney Castle, Ireland
Poison Garden

15. NAS in South Carolina
SC
7.0
births
2014
Mean SC Hospital Charges
(All Payers) per NAS Birth, 2014
Overall $60,176
In NICU $157,912
Total $24,250,928

16. Greenville Memorial Hospital
• Level IV Perinatal Care Center
• 5600 deliveries annually
• 88% of births – Mom/Baby care
• 85-bed NICU
• Baby-Friendly designated

17. • 29yo G1 mother
• Adverse childhood experiences:
Physical, sexual, emotional abuse
• Mental health history:
Anxiety, depression, PTSD, psych admission
age 16
• Drug screens:
Positive for THC, benzo, opioids for 10 years
and in third trimester, but negative at delivery
• Inadequate PNC:
6 visits, left one without being seen
– admits using oxycodone and hydrocodone during
pregnancy
– would take it daily if she could get it
– took methadone 4 months during pregnancy and quit
• In hospital:
Denies current use, last oxycodone “2 weeks
ago”
Photo and videos with written consent by newborn’s
mother for purpose of internal and external education
Our Patients
Picture and video only available for
live educational presentation

18. Wong-Baker facial grimace scale
Oucher real faces pain scale
FLACC scale

19. • Neuroanatomical components and neuroendocrine systems are sufficiently
developed to allow transmission of painful stimuli in the neonate
• A lack of behavioral responses (including crying and movement) does not
necessarily indicate a lack of pain
• Exposure to prolonged or severe pain may increase neonatal morbidity
• Infants who have experienced pain during the neonatal period respond
differently to subsequent painful events
• Neonates are not easily comforted when analgesia is needed
Pain /pān/
noun
1.physical suffering or discomfort caused by illness or injury
Origin of PAIN
Middle English, from Anglo-French peine, Latin poena, Greek
poinē payment, penalty; akin to Greek tinein to pay, tinesthai to
punish, Avestan kaēnā revenge, Sanskrit cayate the revenges
First Known Use: 14th century
AAP Committee on Fetus and Newborn. Prevention and management
of pain and stress in the neonate. Pediatrics, 2000
Prevention and management of pain in the neonate: an update. AAP Committee on
Fetus and Newborn and Section on Surgery, Section on Anesthesiology and Pain
Medicine; Canadian Paediatric Society, Fetus and Newborn
Committee. Pediatrics, 2006

20. AAP Guidance
Stance on Pain
When pain is prolonged, striking changes
occur in the infant’s physiologic and
behavioral indicators.
The prevention of pain in neonates should
be the goal of all caregivers, because
repeated painful exposures have the
potential for deleterious consequences.
AAP Committee on Fetus and Newborn. Prevention and
Management of Pain and Stress in the Neonate.
Pediatrics, 2000
Stance on Withdrawal
…the severity of withdrawal signs,
including seizures, has not been proven
to be associated with differences in long-
term outcome after intrauterine drug
exposure.
Ultimately, withdrawal is a self-limited
process.
Treatment of drug withdrawal may not
alter the long-term outcome.
AAP Committee on Drugs and Committee on Fetus
and Newborn. Neonatal Drug
Withdrawal. Pediatrics, 2012

21. Withdrawal is…
• Stage I: craving, anxiety, irritability, perspiration
• Stage II: add yawning, lacrimation, rhinorrhea, depression
• Stage III: add dilated pupils, pilo-erection (cold turkey), hot/cold
flashes, aches, cramps, anorexia
• Stage IV: add severe cramping, involuntary leg movements
(kicking the habit), loose stool, hypertension, tachypnea,
tachycardia, hyperthermia, nausea, restlessness
• Stage V: add fetal position, vomiting, profuse liquid diarrhea,
leukocytosis, weight loss of 4-12 pounds per day
• Stage VI: transition to normalizing bowel function but ongoing
psychologic symptoms, hypersensitivity to pain, prolonged
hypertension, weight control issues

22. Early Treatment Concept

23. Palliative Hypothesis
• 55-94% of term newborns with chronic fetal exposure to long-acting
opioids develop withdrawal
• Delaying treatment seems to…
• Result in difficulty gaining symptom control
• Lead to excessive weight loss and abnormal suck patterns
• Exacerbate self-inflicted skin injuries and diaper rash
• Increase risk of seizures and fever
• Be cruel and unethical
• Early treatment with low-dose methadone can be considered a continuation
of therapy and might…
• Prevent full-blown symptoms and their complications
• Reduce weight loss levels
• Improve parental engagement and lessen feelings of guilt
• Result in a shorter length of stay than “last resort” treatment
• Therefore, result in lower health care costs
• With an outpatient partner, newborns might be safely weaned at home

24. Research Objective
To describe health outcomes and hospital costs
for newborns with NAS who were treated using
an early pharmacologic treatment model in a
low-acuity care setting, with outpatient weaning

25. Study Population
Target population: All babies born at Greenville Memorial Hospital
and coded for NAS diagnosis between 2006 and 2014
• Inclusion criteria
• Newborns admitted to GMH level I nursery care
• Long-acting opioid-exposed (methadone or buprenorphine)
• Treated with early low-dose methadone therapy (within first 24 hours)
• Exclusion criteria
• NICU admission prior to initiation of medication
• Final sample size: 147 treated newborns
• 30 (20%) transferred to NICU for medical complication (seizure, fever, arrhythmia)
• 117 (80%) treated with complete palliative model

26. Palliative (Early Treatment) Model
• Otherwise healthy newborn identified with chronic fetal exposure to
methadone or buprenorphine
• H&P completed; routine and protocol orders initiated after discussion with
family, unless family is averse to pharmacological treatment
• Protocol orders:
• Start methadone: 0.05mg/kg/dose po q6h for maternal buprenorphine use or low-dose
(<60mg daily) methadone use; 0.1mg/kg/dose po q6h for high-dose methadone use
• Consults to social services/case management, physical and occupational therapy, pediatric
pharmacy
• Urine and meconium drug screens
• Apnea/bradycardia monitoring in mother’s room
• Modified Finnegan abstinence scoring every 4 hours
• Encourage breastfeeding unless contraindicated
• Barrier cream to perianal skin as needed

27. Palliative (Early Treatment) Model
• Stabilization: monitor for evidence of
• Under-treatment (high scores, weight loss, exam-intolerant, feeding problems)
• Stability (stable scores at or under 8, gaining weight, exam-tolerant)
• Over-sedation (very low scores, bradypnea/bradycardia alarms, difficulty awakening)
• Solicit feedback from care team daily: family, nurses, therapists, pharmacist
• Increase methadone in 0.05mg/kg increments (if needed), ideally once per day
• Hold methadone, with input from pharmacy, if over-sedated
• After 36-48h of stability, spread (don’t wean) dosing
• First spread: 24-hour dose divided q8h
• Wait 36-48h, then second spread: 24-hour dose divided q12h
• Wait 36-48h to ensure ongoing stability prior to discharge
• Day before expected discharge: develop weaning calendar and write rx
• Fill in hospital outpatient pharmacy, pre-filled oral syringes
• Maximum 30-day wean allows entire rx to be dispensed
• Wean every Sunday and Wednesday
• PCP visits weekly on Mondays or Thursdays until wean done
• Filled rx is reconciled by unit staff; calendar and medication reviewed with family

29. Methods and Measures
• Retrospective Chart Review
• Primary Outcome Measures
• Hospital length of stay
• Need for adjunctive medication
• Peak abstinence score and weight loss
• Medical complications requiring transfer to the neonatal intensive care
unit (NICU)
• Adverse medication and safety events
• Infant drops, unsafe sleep, over-sedation during treatment
• Emergency department utilization within 30 days of discharge
• Total hospital charges and cost per case

30. Maternal Demographics (N = 117)
Age 33 + 5 years
Caucasian race 95%
Education level < 12 years
High school degree
Some college or associates degree
28%
35%
37%
Marital status Married/separated
Never married
37%
49%
Received prenatal care
(Mean number of prenatal visits 8.3 with SD 3.9)
96%
Mental health issues
(Not mutually
exclusive)
Depression
Anxiety
Bipolar disorder
44%
37%
13%
Opioid used Methadone (Mean dose 96.3 mg/day)
Buprenorphine (Mean dose 12.9 mg/day)
70%
30%
Tobacco use during pregnancy 72%
CPS involved Ante or perinatal
After hospital discharge
No involvement
29%
21%
50%
Feeding method Exclusive breast milk
Exclusive formula
Mixed: breast/formula
8%
61%
31%
39% overall
breastfeeding rate

31. • Gestational age 38.5 weeks
(range: 35-41)
• Peak m-Finnegan
abstinence score 10
(peak on day 2)
• Peak weight loss from birth
7% +/- 2.5% (peak on day 3)
Flaherman V, et al. Early Weight Loss Nomograms for
Exclusively Breastfed Infants. Pediatrics, 2014
Clinical Outcomes

32. Reasons for readmission:
• pertussis
• RSV
• bacteremia
• hypothermia
• fever
• diarrhea
• failure to thrive
• ALTE with reflux
Clinical Outcomes

33. Clinical Outcomes
Methadone Treatment Variables (N=117)
Average discharge methadone dose 0.5 + 0.25 mg/kg/day
0.6 mg every 12 hours
Mean treatment duration (IP + OP) 45 days
Mean amount of methadone dispensed 33 mg
4-week weaning calendar; weekly PCP visits during wean
All doses dispensed to family in prefilled syringes from GMH outpatient pharmacy
Cost to family for medication: $7-15

34. Utilization Outcomes
23
16.9
15
8.4
0
5
10
15
20
25
US 2012,treated US 2012, overall SC 2014,overall GHS 2014,treated
Average Length of Stay for NAS Newborns
Hospital Days
Patrick SW, et al. Increasing incidence and geographic distribution of neonatal
abstinence syndrome: United States 2009 to 2012. J Perinatol, 2015 April
SC Data Courtesy of SC Birth Outcomes Initiative
Data Committee, 2016

35. Cost Outcomes
Newborns
(N=117)
Mean per
case
Total hospital
charges
$10,945
Total hospital costs $5,909
Total reimbursement $5,261
Patrick SW, et al. Increasing incidence and geographic distribution of neonatal
abstinence syndrome: United States 2009 to 2012. J Perinatol, 2015 April
95% of cases were funded
by SC Medicaid

36. Current MAiN Program Model
Prenatal identification of
maternal opioid dependence
Interventions to minimize
NOWS risk for newborn
Care coordination of infant
and mother in low-acuity
nursery
Early treatment to minimize
complications of NOWS
Inpatient symptom
stabilization
Outpatient medication wean
MAiN (Managing Abstinence in Newborns) Program Aim: To provide multidisciplinary, coordinated care to families
with newborns at risk for or diagnosed with neonatal abstinence syndrome, in order to achieve a cost-effective,
family-centered experience with best potential outcomes for mothers with substance use disorders and their exposed
and/or treated infants

37. Obstetrics, ER, Primary Care, Pain Clinics
Screen pregnant women with History, UDS, SBIRT and
Refer to MAiN Case Manager at any gestational age:
1. Chronic short- or long-acting opioid or benzodiazepine
use, for any reason, prescribed or non-prescribed
2. Alcohol or illicit drug use documented during pregnancy
Prenatal Pathway
Documents referral
Contacts mother by phone or in
prenatal office
Offers Phoenix Center Evaluation
Tracks maternal treatment
outcomes during pregnancy
At/after 24 weeks’ gestation
Enrolls mothers on LAO in MAiN
Prenatal Consult
Targeted Education
Level I Newborn
Palliation Care Map
Exposed to methadone or
buprenorphine with early
treatment: 7-10 day stay
Treatment Care Map
Observance newborn
develops severe NAS:
8-14 day stay
Observance Care Map
Exposed to short-acting
prescription drug, alcohol or
illegal drug: 3-5 day stay
Routine Care
Drug-free at birth: 2-day stay
MAIN Case Manager
(Phoenix Center– GHS)
MAiN Program
Service Map
Inroads
Birth Hospital
1. Same criteria above but not referred prenatally
2. Positive drug screen at birth
for non-prescribed or illicit drug
Inpatient Pathway
Documents new referrals
Enrolls treatment groups in MAIN
Makes all Supporting Referrals
Documents inpatient
mother/baby outcomes
Home Caremap
4-week home medication wean
Weekly provider visits
DHEC Newborn Home visits
Developmental screening at 3m
Case Management until 3m
Help Me Grow to age 8
OR

38. Next Steps: Community
Hospital(s) Feasibility Study
• Share and replicate MAiN Program Model
• Recruit pilot sites in Upstate SC
• Compare patient and program outcomes
• Publication of results
• Expansion

39. Critical Questions
What is the effect of chronic opioid exposure on the developing brain?
– Intrauterine abstinence syndrome is life-threatening to the fetus; opioid
maintenance during pregnancy is recommended to prevent preterm labor, fetal
seizures and death.
– Methadone exposure may cause
• prolonged QTc on postnatal day 1-2 (Parikh 2011)
• disrupted brain maturation (Vestal-Laborde 2014)
• abnormal visual development (McGlone 2013)
• neurodevelopmental delays at 18 months and 3 years (Hunt 2008)
– Buprenorphine effects have not been well-studied. Limited evidence suggests
neurodevelopmental effects similar to those of methadone, though risk of
withdrawal is reported to be lower.

40. Critical Questions
What is the effect of acute opioid withdrawal on the developing
brain?
– Excessive excitatory amino acid activation results in excitotoxic damage to
developing neurons. These changes promote…increased anxiety, altered
pain sensitivity, stress disorders, hyperactivity/attention deficit disorder,
leading to impaired social skills and patterns of self-destructive behavior.
Anand KJS, Scalzo FM. Can adverse neonatal
experiences alter brain development and
subsequent behavior? Biol Neonate, 2000

41. Critical Questions
Are negative developmental and health outcomes the result of
opioid exposure, withdrawal, parenting problems associated with
substance use disorders, or all of the above?
– Childhood trauma and adverse experiences can lead to a variety of negative
health outcomes, included increased risk for suicide, mood disorders, and
substance use disorders in adolescence and adulthood (Dube 2001).
– Mothers with substance use disorders have higher rates of comorbid
conditions, including smoking, mental health issues, criminal behavior, and
a history of abuse/neglect with their children.

42. Why Treat NAS
The goal of treatment should be to provide comfort to the
mother and infant in relieving symptoms, improve feeding
and weight gain, prevent seizures, reduce unnecessary
hospitalization, improve mother-infant interaction and
reduce the incidence of infant mortality and abnormal
neurodevelopment.
Neonatal Drug Withdrawal:
AAP Committee on Drugs and
Committee for Fetus and
Newborn. Pediatrics, 2012
preventing
establish
maximize
minimize
Anand KJS. Pharmacological
approaches to the
management of pain in the
neonatal intensive care unit. J
Perinatol, 2007

43. Conclusions
• Critical questions about the effects of opioids and withdrawal on
the childhood development remain unanswered.
• Models exploring the prevention of NAS born to opioid-dependent
mothers have not been described in the literature to date.
However, neonates with iatrogenic opioid dependence are
routinely weaned from opioids in order to prevent withdrawal.
• Our newborns experienced early and effective symptom control
and low rates of NICU transfer, safety events, and readmission,
despite a relatively short length of stay.
• This model of care may be feasible for Level 1 nurseries, have
widespread applicability, and may further confer social, medical,
and economic benefits associated with family-centered care,
parental engagement, and shorter hospital stays.

44. Selected Additional Reading
• Neonatal Abstinence Syndrome: How States Can Help Advance the Knowledge Base for
Primary Prevention and Best Practices of Care. Association of State and Territorial Health
Officials, 2014
• Management of Neonatal Opioid Withdrawal. Vermont Department of Health, 2014
• Managing Chronic Pain in Adults with or in Recovery From Substance Use Disorders.
Substance Abuse and Mental Health Services Administration Treatment Improvement
Protocol 54, 2012
• Lee J, et al. Neonatal abstinence syndrome: Influence of a combined inpatient/outpatient
methadone treatment regimen on the average length of stay of a Medicaid NICU
population. Popul Health Manag, 2015

45. Long Term Outcomes of Neonatal
Abstinence Syndrome
Henrietta S. Bada, MD, MPH
Professor and Vice Chair, Academic Affairs
Department of Pediatrics
College of Medicine
University of Kentucky
Henrietta Bada, MD has disclosed no relevant, real or apparent personal or
professional financial relationships with proprietary entities that produce
health care goods and services.”

46. Learning Objectives
• Explain the long-term effects reported in children
with prenatal exposure to opiates.
• Outline factors that may influence and mitigate the
long-term outcomes related to NAS.

47. Outline
• Epidemiologic significance of NAS
• Potential factors that may affect short term and
long term outcomes
• Studies of outcomes post discharge in the first few
years of life
• Reported outcomes on opiate exposed children at
later ages to early adolescence
• Factors that may change outcome trajectories

48. Neonatal Abstinence Syndrome
• NAS will not disappear
• Will only increase and or evolve from different opioid
formulation or Rx
1960s
Heroin
2013-2016
1970 – 1980s
Heroin
Methadone
1980-1990s
Methadone,
Hydromorphone
Cocaine
1990s - 2000s
Cocaine
Other opioids
(oxycodone, hydro-
codone, tramadol)
Mid 2000s to
present
Buprenorphine
Methadone,
other opioids

49. Lexington Herald-Leader
Source: Drug Enforcement Administration

50. Kentucky NAS (2000-2014)
50

51. The Tennessee Experience
Patrick et al. 2015 Pediatrics 135:842
6/1000 births
10.7/1000
births

52. Neonatal Intensive Care Units
• 674,845 admissions (2004 to 2013); 299 NICUs
• NAS Increased from 7/1000 to 27 cases/1000
admissions
• Increase in receiving pharmacotherapy from 74% in
2004-2005 to 87% in 2012-2013
• Morphine use increase from 49% in 2004 to 72% in
2013
Tolia et al. NEJM 2015;372:2118-26

53. Tolia et al. NEJM 2015;372:2118-26

54. Opiate Exposure Effects
Neonatal Abstinence Syndrome

55. The Developing Brain

56. R R RL L1:
L
R R RL L

57. • Behavior Teratology Framework: No obvious malformations
but vulnerability of the CNS to injury extends beyond fetal,
neonatal, and infancy stage
• Functional abnormalities that may not be detected at
birth but later in childhood, adolescence, or
adulthood.
• Barker hypothesis: Any perturbation during fetal development
may have enduring effects on later behavior.
Prenatal Exposure & Brain
Development

58. Perinatal Factors That May Affect Long
Term Outcomes
• Maternal polydrug use (legal, other Rx, illegal)
• Duration of in utero drug exposure
• Dose-effect relationship
• Withdrawal symptoms versus drug effects
• Severity of withdrawal manifestations
• Continuing drug exposure from postnatal treatment
– Type of drug, duration of postnatal treatment

59. • Maternal age
• Co-morbidities (psychological/psychiatric disorders)
– Depression, anxiety disorders, PTSD, etc.
• Risky lifestyle
• Hospitalizations due to violence
• Pregnancy complications
• Sexually transmitted diseases (increasing
prevalence of Hepatitis C)
Maternal and Family Factors

60. Number of NICU Admissions
(Infants of Hepatitis C Positive Mothers)
0
10
20
30
40
50
60
70
80
90
100
Hepatitis C
Hepatitis C
Hep C+ trend

61. • CPS reporting and involvement
• Discharge placement:
– Biological parent
– Kinship care
– Non-kinship care
– Group home
Discharge Considerations

62. Bada H et al. J Dev Behav Pediatr 2005

63. Age of Child (Fatalities/Near Fatalities
(KY 2011 -2015)
36
15
13
8
4
9
0
5
10
15
20
25
30
35
40
< 1 y 1 2 3 4 5-7
Percent
AGE (years)

64. 47
53
39
0
20
40
60
80
100
Physical abuse Neglect Impaired
caregiver
Percent
67
73
52
0
20
40
60
80
100
Substance
abuse
Domestic
violence
Mental illness
Percent
Categories of maltreatment Risk factors in fatalities/near
fatalities
Child Fatalities/Near Fatalities
(KY 2011-2015)

65. OUTCOME IN THE FIRST THREE YEARS
Early Childhood Outcomes of Opiate-exposed Children

66. Developmental Outcomes Of Infants
Exposed to Opiate In-utero
Strauss ME, Ostrea EM, Stryker, JC (n=113; 53/113 “addicted”)
Outcome categories
1 year*
Opiate-
exposed
n=25
Not opiate-
exposed
n=26
p value
% growth retardation
Weight/Height/Head Circ
14/52/21 4/27/22 <0.01
J Pediatr 1976; 89 (5): 842-846
* Attrition issues: unable to track,
incarceration, refuse to return, etc.

67. Neurodevelopmental Outcomes Of Infants
Exposed to Opiate In-utero
Psychomotor Developmental Index
Studies
Number
Exp/Non
Opiate-
exposed
Non opiate-
exposed p value
Strauss (1976) 25/26 102.8 (11.0) 110.4 (9.7) P<0.01
Wilson (1981) 29/55 92.2 (19.2) 99.0 (14.5) P<0.05
Maternal
methadone
35/55 89.9 (17.6) 99.0 (14.5) P<0.05
Bunikowski (1998) 27/42 100.8 (13.6) 111.4 (16.9) P<0.05

68. Adverse Neurodevelopmental Outcomes Of
Infants Exposed to Opiate In-utero
• Van Baar, A (1990)
• 35 Exposed infants (1983-1985); 26/35 term with follow-up
• Methadone, heroin +/-cocaine and other drugs (30% used
methadone only in the 3rd trimester)
• 37 comparison infants
• Bayley Scales 6, 12, 18, 24, and 30 months
• Control for gestational age in the analysis
• PDI and MDI were no different between exposed and
comparison infants in the first year
Van Baar A, J Child Psychol Psychiat 1990; 31(6): 911-920

69. 2 – 3 Year Outcomes Of Infants Exposed to
Opiate In-utero (MDI and PDI)
98
101 100 101
86 87
105
98
86 87
102
96
0
20
40
60
80
100
120
MDI 24 months MDI 30 months PDI 24 months PDI 30 months
Comparison Total Exposed Term Exposed
* *** **
van Baar A, J Child Psychol Psychiat 1990; 31(6): 911-920

70. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
• Hunt et al, 2008 (133 cases/103 controls)
• Cases: mothers compliant with methadone program
• Controls: negative for drug use history and drug
screen
• Follow-up at 18 months and 36 months
Early Human Development 2008; 84:29-35

71. Outcomes of Exposed Versus Controls
105
110.13
107.5
53.9
42.8
49.2
88.2
107.5
99.9
49.5
35.5
42.4
0
20
40
60
80
100
120
MDI PDI Stanford-Binet McCarthy
Motor
Expressive Receptive
Controls
Opiate Exposed
***
**
*
*
*
Hunt et al. Early Human Dev 2008 ; 84:29-35
*** p<0.001; **p<0.01; *P<0.05

72. SUMMARY OF OUTCOMES: FIRST 3 YEARS
Long Term Follow-up of Opiate Exposed Children
 Significant delay in psychomotor development in
the first year of life: transient
No difference at 18 to 24 months
 Significantly Lower Cognitive Abilities 2-3 years,
not evident at 1 year
Low MDI or Low IQ
Poor Language Development

73. OUTCOMES AFTER AGE 3 YEARS
Long Term Follow-up of Opiate Exposed Children

74. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Olofsson et al. 1983
• N=89 (methadone, morphine, heroin)
• 72/89 with follow-up 1-10 years
• 25% normal physical, mental, and behavior
• 56%: hyperactive, aggressive, with lack of concentration and
social inhibition
• 10% severe psychomotor impairment
• 11% moderate psychomotor impairment
• 5 depravation syndrome; 2 spastic tetraplegia, 1 rubella
syndrome
Acta Paediatr Scand 72:407-410, 1983

75. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Olofsson et al. 1983
• N=89
• 72/89 with follow-up 1-10 years
• 43% removed from the home
• Average environment change: 6/child; maximum 30
• Average change in caregiver: 5/child; maximum 11
“These findings indicate that there is an urgent need for politicians, social welfare
and health personnel to reexamine their roles in helping these children, who will
otherwise develop into a new generation of social losers.”
Acta Paediatr Scand 72:407-410, 1983

76. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Bauman P & Levine S (1986)
70 exposed (methadone); 70 non-exposed; 3 to 6 years of age
Measures
3 – 6 years
Non-exposed
n=70
Opiate exposed
n=70
p value
IQ (Stanford-Binet) 100.4 (18.36) 92.7 (15.4) 0.002
WAIS Verbal score 102.79 (20.96) 91.90 (17.28) <0.001
WAIS Performance 102.3 (14.95) 96.03 (12.44) 0.003
WAIS Full scale 102.90 (18.3) 93.33 (13.90) <0.001
The International Journal of the Addictions 1986; 21(8): 849-863

77. Personality Structure and Functioning
California Psychological Inventory
0
10
20
30
40
50
60
Sense of well-
being
Responsibility Self-control Psychological
mindedness
Empathy Social maturity
index
Controls Methadone
*
*
*
*
*
*
*all significant p<0.001
The International Journal of the Addictions 1986; 21(8): 849-863

78. Outcomes After Prenatal Opiate
Exposure (4 – 5 years)
Van Baar and de Graaff, 1994 (n=70)
Measures
4 - 5 ½ years
Non-exposed
n=35
Mean (SD)
Opiate exposed
n=35
Mean (SD)
p value
IQ (RAKIT)) 102 (17)
13% below 1SD
90 (22)
41% below 1SD
<0.05
Language
Comprehension
52 (6) 46 (6) <0.01
Language
Expression
50 (6) 46 (6) <0.05
Dev Med Child Neurol 1994 36:1063-1075

79. Behavior and School Outcomes After
Exposure to Opiate In-utero
Soepatmi 1994 (67/157 with follow-up)
Measures
3.5-7 years
Opiate- exposed
With mothers
n=31
Opiate-Exposed
Foster care
n=34
IQ less than 7 years 104.2 (15.8) 90.9 (13.2)
IQ 7-12 years 91.4 (14.3) 90.6 (14.0)
High total behavior
problems score and IQ <85
5.3% 21.9%
School problems at 6 years 52% 82%
Soepatmi, Acta Paediatr Suppl 1984, 404:36-39

80. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Ornoy et al. 2001 (160 total)
Follow-up at 5-12 years
33 with DD-fathers
31 with home DD-mothers
34 DD-mothers adopted
32 with low SES
30 controls average SES
Ornoy et al. Dev Med Child Neurol 2001 43:668-675

81. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Ornoy et al. 2001 (160 total)
Measures
5-12 years
Opiate-
exposed
With mothers
n=31
Opiate-
Exposed
Not-with
mothers
n=34
Drug
Dependent
Fathers
n=33
Non-exposed
Low SES
n=32
Non-
exposed
controls
Average SES
n=30
WISC-R Verbal
IQ
102 (8.8)*# 108 (17.6) 105.7 (18.7)* 100.5 (18.5)*# 110.4 (22.1)
WISC-R
Performance
101 (24)*# 106.2 (24.9)* 106.4 (25.7)* 102.8 (16.7)*# 115.3 (22.4)
Externalizing
Problems
20.07(13.5)*# 13.5 (9.13)* 16.4 (9.05)* 12.77 (9.48)* 3.6 (4.01)
Internalizing
Problems
9.16 (4.94)*# 5.88 (4.99)* 7.87 (5.67) 9.13 (8.46) 3.7 (5.17)
Ornoy et al. Dev Med Child Neurol 2001 43:668-675
*p<0.05, lower/worse than controls; #p<0.05, lower/worse than adopted children

82. Buprenorphine and Child Outcomes
• Sundelin et al 2013 (n=25)
• 5-6 years Children with prenatal buprenorphine
exposure
• Lower Performance IQ (90.6 vs 100)
• Attention problems
• Visual motor integration

83. Visual integration and NAS
(Melinder A, Addiction, 2013, 108:2175)
Characteristics/
procedures at 4 years
Comparison (n=23) Exposed (n=26) P value
Age (months) 51.6 (1) 52.4 (1.5) 0.05
NAS (methadone/bupre) 61% / 87% n.s
Smoking 100% 0.000
Birth weight, g 3563 (346) 3104 (658) 0.004
Birth length, cm 50.6 (1.4) 47.7 (3.3) 0.000
Gestational age 39.87 (0.7) 38.95 (2.95) 0.15
Attention problems 50.68 (1.92) 53.9 (5.27) 0.01
Bender Gestalt 17.43 (7.28) 9.96 (4.60) <0.001

84. Maternal Lifestyle Study (MLS)
MLS is conducted under the
auspices of the following
Institutes (Program Scientists):
• NIDA (Nicolette Borek)
• NIMH (Julia Zehr)
• NICHD NICU Research
Network (Rosemary Higgins)
Phases 1 and 2: The NICHD Neonatal Research Network
NIDA, ACYF, CSAT
Phases 3, 4, 5: NICHD Neonatal Research Network, NIDA, NIMH

85. Results
 Enrollment
19,079 - mother/infant dyads screened for recruitment
16,988 - eligible for enrollment
11,811 - consented to study participation
3,184 - no meconium or inadequate for confirmation
7,442 - confirmed non-exposed,
(may have tobacco and or marijuana)
1,185 - exposed (977 – cocaine; 113 opiate only; 92 -
opiate and cocaine)
1,388 – enrolled in long-term follow-up

86. Externalizing Behavior Problem:
Results From Longitudinal Modeling1
Variables Regn. Coefficient2 p value
Maternal age -0.220 <0.001
Prenatal tobacco 0.072 0.044
Prenatal alcohol 0.870 0.015
Prenatal marijuana -0.014 0.987
Prenatal opiate (year 5) 3.09 0.041
Prenatal cocaine (high use) 3.089 0.003
Caretaker SES -0.045 0.048
Ongoing tobacco use 1.980 <0.001
Ongoing alcohol use 1.252 0.006
1 Only effects for prenatal drug exposures and statistically significant (p < 0.1) covariates are presented
2 Adjusted for time trends, site and other covariates listed previously

87. Effects of Prenatal Opiate at 13 Years From
Caretakers and Teachers
• Children with prenatal opiate exposure did not start out with
high problem scores at early ages.
• Caretakers reported behavior problems became worse with
time
– Internalizing Behavior Problems
– Total problems
– Attention problems
• Teachers reported Attention Problems worse with time
Bada HS et al. Neurotoxicology Teratology 2011

88. SUMMARY OF OUTCOMES
AFTER AGE 3 YEARS
Lower IQ scores than non-exposed children (8-15 points
difference)
Poor Language development
Behavior and school problems: 1 out of 4 - 5 children.
Maternal opioid replacement treatment has not been
associated with improved cognitive development in
exposed children

89. Above
average
??Special
education
?? early
intervention
services
Considering that normal IQ is mean (SD) = 100 (15); a 10-point lower mean IQ in exposed
children translates to a probability of an increase in the number of children in the below
average range from 16% to 36%.

90. Global IQ distribution for subsamples of sex offenders and NSV criminals.
Guay et al. / International Journal of Law and Psychiatry 28 (2005) 405–417

91. MITIGATING ADVERSE OUTCOMES

92. Considerations in Prenatal Opiate Drug Exposure
and Childhood Outcomes
• NATURE versus NURTURE
–Prenatal effects versus postnatal
environment
• To mitigate adverse outcomes in exposed
children
–Address TOXIC Stress : child and caretaker
(mother)

93. Toxic stress: refers to what’s going on physiologically in our
bodies when our stress response system is activated for
long periods of time without being brought back to
baseline.
93
Adverse Childhood Experiences: Mother, Family, Home
Why Toxic Stress?

94. 94

95. Risks and Protective Factors
Risk Protective Factors
Individual Male Resilience
Small head Temperament
Low verbal or full IQ
Overweight (medical
problems)
Family Depression, psychological
functioning
Secure attachment
Domestic violence Home
Illegal and legal drug Use Caretaker involvement
Caretaker supervision
Family support/resources
Community Violence Neighborhood
Gangs, Crimes Friends, extracurricular
activities

96. Risk and Protective Factors
Determine outcomes considering the balance
between cumulative risk and protective index
◦ High risk index – low protective index
◦ High risk index – high protective index
◦ Low risk index – low protective index
◦ Low risk index – high protective index
Bada HS, Pediatrics 2012; 130(6):e1479

97. Categories of Prenatal Drug Exposure
• High Cocaine/Other Drug Exposure (High PCE/OD)
• Some Cocaine/Other Drug Exposure (Some PCE/OD)
• Opiates, Other Drugs/No Cocaine (PCE-/OD+)
• No Cocaine/No other drugs (PCE-/OD-)

98. Total Behavior Problems: Balance of Risk
and Protective Factors

99. Intervention for Mother-
Infant Dyad
99
MOTHER
CHILD
Prenatal drug
exposure,
Medical conditions
Mother with addiction
or dependency:
Polydrug use
Medical issues
Co-morbidities
Family/support
Legal issues
Employment
Maternal-infant interaction attachment
caretaker involvement
Parenting
skills
Mental Health
Caretaker
Involvement
COMMUNITY

100. SUMMARY AND CONCLUSION

101. Clinical and Policy Implications
• Prenatal opiate exposure often occurs in the context
of polydrug exposure
• High incidence of withdrawal (NAS) in illegal opiate
use or even maternal medical replacement therapy
(methadone or buprenorphine)
• Increase in likelihood of adverse effects noted at
later childhood or adolescence
• Lower IQ, lower language scores, higher rate of
behavior problems among exposed children

102. Clinical and Policy Implications
• Adverse outcomes are noted even with maternal
opioid treatment during pregnancy
• Focus on treatment and beyond neonatal
abstinence syndrome; enhance child development.
• Prenatal exposure effects can be aggravated by
environmental risks but can also be mitigated by
protective factors (at individual, family, and
community levels).
• Need to explore interventions not only to minimize
the adverse effects of prenatal drug exposure but
also enhance protective factors.

103. it takes a village to disentangle the world
of the drug-exposed child
the entangled
web

104. Some children thrive happily, others languish sadly.
Are they not all ours?
Sheldon B. Korones, MD, 1993
Thank you

105. QUESTIONS?

106. Questions?

107. Treatment and Long-Term Outcomes of
Neonatal Abstinence Syndrome (NAS)
Presenters:
• Jennifer A. Hudson, MD, Medical Director for Newborn
Services, Greenville Health System
• Henrietta S. Bada, MD, MPH, Professor and Vice Chair for
Academic Affairs, Department of Pediatrics, College of
Medicine and Department of Health Behavior, College of
Public Health, University of Kentucky
Treatment Track
Moderator: Carla S. Saunders, NNP-BC, Advance Practice Coordinator, Pediatrix
Medical Group, and Neonatal Nurse Practitioner, East Tennessee Children’s
Hospital, and Member, Rx and Heroin Summit National Advisory Board