Pre-Summit Workshop: Latest Research on Intrauterine Drug Exposure and Neonatal Abstinence Syndrome

1. Latest Research on Intrauterine
Drug Exposure and Neonatal
Abstinence Syndrome
Presenters:
• Craig V. Towers, MD, FACOG, Division Director, Maternal-Fetal
Medicine, University of Tennessee
• Jonathan Davis, MD, Chief of Newborn Medicine, The Floating Hospital
for Children at Tufts Medical Center, and Professor of Pediatrics, Tufts
University School of Medicine
• 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
Moderator: Carla S. Saunders, NNP-BC, Advance Practice Coordinator,
Pediatrix Medical Group, and Neonatal Nurse Practitioner, East Tennessee
Children’s Hospital, and Member, Rx Summit National Advisory Board

2. Disclosures
• Craig V. Towers, MD, FACOG; Jonathan Davis, MD;
and Henrietta S. Bada-Elizey, MD, MPH, have
disclosed no relevant, real, or apparent personal or
professional financial relationships with proprietary
entities that produce healthcare goods and services.
• Carla Saunders – Speaker’s bureau: Abbott Nutrition

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:
– Kelly Clark – Employment: Publicis Touchpoint Solutions;
Consultant: Grunenthal US
– Robert DuPont – Employment: Bensinger, DuPont &
Associates-Prescription Drug Research Center
– Carla Saunders – Speaker’s bureau: Abbott Nutrition

4. Learning Objectives
1. Define IDE and NAS.
2. Outline the short-term and long-term impacts of
IDE and NAS, from the individual and public
health perspectives.
3. Explain research that finds genetic factors are
emerging as crucial components associated with
NAS outcomes.
4. Compare current and emerging standards of
care for treating dependence and addiction in
pregnant women.

5. Substance Abuse in Pregnancy
Craig V. Towers, MD, FACOG
Division Director of Maternal-Fetal Medicine
Professor Department Obstetrics & Gynecology
University Tennessee Medical Center, Knoxville

6. Disclosures
• Craig V. Towers, MD, FACOG, has disclosed no
relevant, real or apparent personal or
professional financial relationships with
proprietary entities that produce health care
goods and services.

7. Definitons
• Addict = a person who habitually or
obsessively uses a drug
• Dependence = the drug must be taken to
avoid withdrawal
• Tolerance = higher and higher doses are
needed to reach the same effect

8. Drugs of Abuse
• Tobacco
• Alcohol
• Tetrahydrocannabinol
• Opiates
• Stimulants
• Sedatives
• Hallucinogens

9. National Vital Statistics
United States Data – CDC / MMWR
Deaths 1999 Deaths 2007
MVA 44,000 MVA 45,000
Suicide 30,000 Drugs 38,000
Firearms 28,000 Suicide 34,000
Drugs 19,000 Firearms 31,000

10. East Tennessee Statistics
• In the last 10 years there have been more than
500 deaths in Knox County alone from drug
overdoses
• In the state of Tennessee – approximately 1
death every other day
• The death toll in Tennessee in the past 10
years from illicit drugs exceeds deaths from
fire & homicide in the State (as well as, the
Afghan War)

11. U.S. Statistics – CDC
MMWR July 2013
• 2010 – 15,323 drug overdose deaths in the
United States in women
• 9.8 deaths per 100,000 population
• 943,365 ED visits by women 2010
• Death from drug overdose in women exceeds
death from MVA since 2007

12. U.S. Statistics – CDC
MMWR July 2013
• 2010 enough opioid pain relievers were sold to
medicate every adult in the United States with 5 mg
of hydrocodone every 4 hours for a month
• Of the 15,323 deaths – 6,631 involved opioid
prescription pain medications (2010)
• 1999 – 5,591 drug overdose deaths in women with
1,287 involving opioid prescription pain medications
(5 fold increase)

13. U.S. Statistics – CDC
MMWR July 2013
• 2010 – deaths in women from opiate prescription
medications (6,631) = 4.2 per 100,000 which is 4
times that of cocaine and heroin combined (1,598) =
1 per 100,000
• 5,144 of 6,631 deaths (78%) were unintentional
overdoses (820 suicide / 658 undetermined)
• 752,214 ED visits by women for drugs in 2010 were of
childbearing age (of 943,365) or 80%

14. U.S. Statistics
NEJM Volkow et al, May 2014
• 2007 – prescription opioid abuse cost insurers
an estimated $72.5 billion
• 2012 – an estimated 2.5 million Americans
over the age of 12 abused/dependent on
prescription opiates (~ 1 in 95 people)

15. U.S. Statistics – CDC
MMWR July 2014
• 2012 – prescribers wrote 82.5 opioid pain medication
prescriptions per 100 persons in the United States
(37.6 benzodiazepine prescriptions per 100 persons)
• Alabama #1 at 142.9 prescriptions / 100 persons
• Tennessee #2 at 142.8 prescriptions / 100 persons
• West Virginia #3 at 137.6 prescriptions / 100 persons
• (South 93.7) (Midwest 88.4) (Northeast 70.8) (West
68.0)

16. Opiate Prescriptions in
Pregnancy - Medicaid
Obstetrics & Gynecology – Desai et al, May 2014
• 2000 through 2007 – 1.1 million pregnancies
• 21.6% filled an opiate prescription during the
pregnancy
• 18.5% rate in 2000 increased to 22.8% in 2007
• South again was #1 and the Midwest a close 2nd

17. NAS and Healthcare Cost
JAMA – Patrick et al, May 2012
• Discharge data from 2000 to 2009 – United States
• Maternal antenatal opiate use increased from 1.19 per
1000 births in 2000 to 5.63 per 1000 births in 2009
• NAS increased from 1.2 per 1000 newborns in 2000 to
3.39 per 1000 newborns in 2009
• Mean hospital charges for discharges with NAS
increased from $39,400 in 2000 to $53,400 in 2009

18. Trends
• MMWR – CDC October 2014
– Heroin on the rise again – except in the South
– Annual deaths for Northeast, Midwest, and West
2008 ~ 1/100,000 up to 2.5/100,000
– For the South ~ 0.5/100,000 up to 1/100,000
– Opiate prescription drug deaths essentially
unchanged over this period (South) ~ 7/100,000

19. Why the Opiate Increase
• Federal government felt that the medical
community was not adequately addressing
“chronic pain” issues
• Passed a law 2000 that all states develop
goals in treating chronic pain “Decade of
pain control and research” Public Law 106-
386 – Oct. 28, 2000

20. Why the Opiate Increase
• Over 3000 pain clinics have opened in the
United States since the passage of this
Law
• How do you measure true Pain?
• What are the checks and balances for
these clinics?

21. Opiates
(Opium)
Codeine 1/10 Methadone 4-5
Demerol 2/5 Levorphanol 5
Hydrocodone 3/5 Hydromorphone 5
Morphine 1 Oxymorphone 7
Oxycodone 1.5 Buprenorphine 40
Heroin 2-3 Fentanyl 100

22. Opiates
• Hydrocodone
– Vicodin, Lortab, Lorcet (Vikes or Hydros)
• Oxycodone
– Oxycontin 80 (slow release) – previously crushed for IV or
inhalation use – now gel coated that burns nostrils and clogs
needles (Oxy’s, O’s, hillbilly heroin)
– Roxicodone 15mg & 30 mg – no gel coating and not time-
released (Roxie’s, blues, stars)
– Percocet, Endocet, Roxicet vs. Percodan, Endodan, Roxiprin

23. Opiates
• Oxymorphone – Opana
– Time-released (stop signs, biscuits, octagons, Mrs. O)
• Fentanyl (china whites or perc-a-pop)
• Tramadol (weak opioid agonist)
– 100 mg Tramadol ~ 60 mg of codeine
• Methadone (half-life 18 to 36 hours – Mean 24)
– The long half-life made it a good option for opiate
maintenance programs

24. Opiates
• Buprenorphine (half-life 24-48 hours – mean 36)
– Created 1980’s in small doses for analgesia
– In the 2000’s higher doses were used for purposes
of treating opiate addiction
– ?? Less neonatal abstinence syndrome
• Buprenorphine (Subutex & Suboxone)
– Marketed for use in treating opiate addiction
– Obtained in similar (+/-) programs as methadone

25. Signs & Symptoms of
Drug Withdrawal
• Thirst
• Anxiety
• Rhinorrhea
• Lacrimation
• Tremors
• Yawning
• Diaphoresis
• N & V
• Hot & cold flashes
• Myalgias
• Diarrhea
• Hypertension
• Tachycardia
• Hyperpyrexia
• Abdominal pain / Cramps
• Convulsions / Coma

26. Opiates
• Affect all organs in the body
– Brain – decrease in pain / euphoria
– Heart – lowers heart rate
– Lungs – decreases respiratory rate
– GI Tract – constipation / diarrhea

27. Opiates in Obstetrics
• ?? Increased risk of fetal anomalies
• Broussard et al AJOG 2011 – slight increased risk of
ASD, VSD, NTD, & gastroschisis
• This has not been seen in the nearly all the other
studies evaluating opiates and the risk of fetal
anomalies
• (Category C drugs)

28. Prenatal Care Issues
• Little / intermittent / or no prenatal care
• Poor nutritional status / poor weight gain
• Often unemployed
• Often have poor family history or history of
physical, emotional, or sexual abuse
• Often have a low self-esteem
• Often the reliability of medical history is low

29. Prenatal Care Issues
• Often use more than one drug
• The purity of the street drug often varies
• The availability of the street drugs varies
• The type of abused drug has varied over time

30. Obstetrical Complications
• Preterm delivery (PPROM & PTL)
• Intrauterine growth restriction (IUGR)
• Intrauterine fetal demise (stillbirth)
• Increased risk of sexually transmitted
diseases (Chlamydia, gonorrhea, HSV,
syphilis, HBV, HIV, etc.) & (HCV)
• Higher Cesarean Section rate

31. Obstetrical Complications
• Placental abruption (primarily with the
stimulants – cocaine & amphetamines)
• Certain drugs will affect the FHR appearance
with fetal monitoring (opiates and sedatives
can produce nonreactive NST’s and
decreased variability)
• Neonatal withdrawal patterns vary

32. Obstetrical Complications
• IUGR has always been listed as a complication seen
in opiate addicted pregnant patients
• IUGR is either symmetric or asymmetric
• At UT we noticed that many opiate addicted
pregnant patients had IUGR seen by EFW on
ultrasound, but the issue was more head and femur
– not the fetal abdomen

33. Neonatal Opiate Addiction
• Visconti, Towers et al. 2015 AJP
• UTMCK study on 332 newborns admitted to
the NICU for NAS from January 2010 through
June 2012
• 89% were polysubstance abusers
• Found a decrease in HC and FL
measurements
• No specific opiate was the cause

34. Neonatal Opiate Addiction
UTMCK Study 2014
Subjects Controls Signif.
Number 332 332
HC <10th% 98(29.5%) 41(12.3%) p<.001
HC <3rd% 25(7.5%) 5(1.5%) p<.001
HC <10%>3% 73(22%) 36(10.8%) p<.001
SGA/IUGR 54(16.3%) 37(11.1%) p=0.07
HTN etc. 65(19.6%) 69(20.8%) p=0.8
Diabetes 26(7.8%) 36(10.8%) p=0.2

35. Neonatal Opiate Addiction
UTMCK Study 2014
Oxycodone 177
Buprenorphine 75
Hydrocodone 67
Methadone 42
Morphine 36
Oxymorphone 27
Hydromorphone 3
Heroin 3
Not classified 31

36. Risk of Intravenous
Oxymorphone (Opana)
• CDC – MMWR – 2012
• Intravenous abuse of Oxymorphone can lead
to thrombotic thrombocytopenia / hemolytic
uremic syndrome
• Several deaths reported
• 2 cases of maternal death in Tennessee

37. Prenatal Care
• Team approach of obstetrician, pediatrician,
social services, & drug dependency center
• Obtain the best possible pregnancy dating
• Frequent prenatal visits & indicated labs
• Serial ultrasounds for fetal growth etc.
• Antenatal testing in the third trimester
• Discuss delivery in an appropriate center – state
law issues, etc.

38. Drug Withdrawal During
The Pregnancy
• Often not recommended since fetal effects are
difficult to monitor (concern over a ?? higher
rate of Intrauterine Fetal Demise)
• Drug maintenance programs (methadone &
buprenorphine) assure drug purity, improve
contact with the medical community, & control
dosages

39. Drug Withdrawal During
Pregnancy
• 1973 Rementeria and Nunag AJOG – case report of a
stillbirth 2 days after a mother went through acute
withdrawal
• 1975 Zuspan et al., AJOG – reported an increase in
amniotic fluid epinephrine levels in a pregnancy of a
mother going through withdrawal
• Standard of Care since the 1970’s – do not withdrawal an
opiate addicted pregnant woman during the pregnancy –
place them in a methadone maintenance program for the
duration

40. Drug Withdrawal During
Pregnancy – Safety
• 1990 Maas et al. J Perinat Med – 58 mothers over 7
years with methadone detox program
– No fetal deaths / 17 (30%) success
• 1998 Dashe et al. Obstet Gynecol – 34 mothers over 7
years with in-patient withdrawal (tx. over 10-20 days)
– No fetal deaths / 60% full success / 30% relapsed /
10% never got off

41. Drug Withdrawal During
Pregnancy – Safety
• 2003 Luty et al. J Sub Abuse Treat – 101 mothers over
12 years with in-patient withdrawal (tx. over 21 days)
– No fetal deaths
• 2008 Jones et al. A J Addict – 175 patients over 7 years
(95 withdrawn and 80 on maintenance)
– No fetal deaths / 46% success / 54% relapsed
– More prenatal visits in the maintenance group

42. Drug Withdrawal During
Pregnancy – Safety
• 2013 Stewart et al. AJOG – 95 patients over 6 years
with in-patient withdrawal (tx. over 15-25 days)
– No fetal deaths / 56% success with 44% relapsed
• Overall 383 patients withdrawn – no fetal deaths after
24 weeks gestation
• Of 282 patients with data – 134 with overall success =
rate of 48% (range of 30% to 60%)

43. ACOG Recommendation
• ACOG Committee Opinion #524 May 2012
– Opiate withdrawal during pregnancy is not
recommended due to a high rate of relapse and
acute detox can lead to preterm labor, fetal distress,
or fetal demise
– Refer the pregnant patient to a methadone
maintenance program – a buprenorphine program
may also be considered

44. Expert meeting on Perinatal Illicit
Drug Abuse - CDC
• Meeting held in Atlanta – September 2012
• Obstetrics & Gynecology – April 2014
• 11 authors from NC, OH, FL, MA, MD, WA, GA
consisting of drug/pain treatment programs, FDA,
Obstetric, Pediatric, & Anesthesia departments
• Methadone and buprenorphine are pregnancy
category C medications
• Withdrawal during pregnancy should be discouraged
due to a high relapse rate

45. Current Research
BCBS Grant – Towers et al.
• Study of over 300 pregnant patients that
underwent detox during pregnancy
– No fetal deaths identified
– Evaluating the success rate
– 3 types of patients in the study
• Acute withdrawal
• In-patient treatment program
• Out-patient slow detox

46. Current Research - Grant
• With this study data and a review of the current
literature, there will be more than 600 cases of
opiate detox during pregnancy without a fetal
demise after 24 weeks
• Risk of stillbirth in the low risk population of
pregnant women in U.S. is 5-7 per 1000

47. Drug Withdrawal During
Pregnancy – Safe
• Option 1 – 100 opiate addicted pregnant women and
keep addicted to methadone or buprenorphine and at
delivery have ~ 80 to 100 NAS cases
OR
• Option 2 – 100 opiate addicted pregnant women you
withdraw – 50% relapse ~ 50 NAS cases
(a reduction of at least 30 NAS cases)

48. Drug Withdrawal During
Pregnancy – Safe
• Average cost of NAS treatment in Tennessee is
approximately $68,000 in 2014
• 30 less cases of NAS = $2,040,000 (Tennessee)
• And this is per 100 opiate addicted pregnant patients

49. Drug Addiction Management
Options in Pregnancy
1. Prenatal care with no change in drug usage
2. Acute detoxification
3. Methadone / Buprenorphine maintenance
4. Methadone / Buprenorphine slow detoxification
5. Drug withdrawal programs with continued support
(Incarceration issues ??)
(Relapse / side usage or “cheating”)

50. Neonatal Opiate Addiction
• AT UTMCK we currently recommend getting
pregnant patients that abuse opiates into
programs that will wean them down and
potentially off of opiates by the time of
delivery

51. Current Research – BCBS Grant
1. Safety of Withdrawal
2. Prospective study of neonates that go through NAS to
reexamine the question of bone growth
3. Outcome of pregnancies that deliver addicted to opiates
to those that have been withdrawn
4. Neonatal length of stay with specific NAS treatment
approach
5. Long term follow-up of neonates that suffered NAS
6. Hepatitis C issues in this population

52. Current Needs
1. More funding for research in this area
2. More access to buprenorphine / methadone
programs for pregnant women that practice
withdrawal
3. Better long-term psychosocial programs to follow
patients that succeed in becoming clean once they
deliver so they stay clean and not relapse
4. Fix pain clinic problem and decrease the number of
prescriptions written for opiates

53. HCV Epidemic
• Huge number of opiate abusers in
Tennessee are also HCV infected
• HCV testing is now a routine part of our
prenatal care laboratory assessment
• Many patients strongly argue that they do
not use intravenous drugs nor have they
ever used IV drugs in the past

54. HCV Epidemic
• Ongoing study of surveying HCV infected
pregnant women about potential methods
of transmission
• ?? of sharing straws used for snorting

55. “Bath Salts”
• Not a purchase from Bath & Body Works !!
• Psychoactive Bath Salts (PABS)
– Methylenedioxypyrovalerone (MDPV)
– Pyrovalerone – (1960’s) stimulant in Europe
– Combo effect of “Crystal Meth” and Hallucinogens
– ?? Just became controlled per substance-control laws
– Often called “legal cocaine”
– Purchased over the Internet as “Ivory Wave” / “Vanilla Sky”
/ “Purple Wave” / “Bliss”

56. Neonatal Abstinence Syndrome
Jonathan M. Davis, MD
Chief of Newborn
Medicine
Floating Hospital for
Children at Tufts
Medical Center
Professor of Pediatrics
Tufts University
School of Medicine
Boston, MA

57. DISCLOSURES
• I have no conflicts of interest to disclose
• I am funded by NIH (NIDA) to conduct large
scale studies on the prevention and treatment
of NAS
• I Chair the Neonatal Advisory Committee in
the Office of the Commissioner at the FDA. My
presentation reflects my own opinions and
not those of the FDA

58. Maine Governor Cites ‘Troubling
Epidemic’ of Addicted Babies
Feb 5, 2014 BY KATHARINE Q. SEELYE
Gov. Paul R. LePage, making a State of the State address,
was the second New England governor in a month to point
to the drug problem.
Mr. LePage said that 927 “drug-addicted babies” were born
in Maine in 2013, more than 7 percent of all births. This is a
“troubling epidemic” that was “tearing at the social fabric
of our communities.” “Each baby addicted to drugs creates
a lifelong challenge for our health care system, schools and
social services,”

59. Neonatal Abstinence Syndrome
• Opioid exposure in pregnancy – 5.6 infants/1000
births. MA – 17.5, ME – 34.5/1,000 births
• Incidence has tripled in the past 5-10 years
• Increased use prescription drugs, illegal drugs,
and opioid substitution while pregnant – opioid
related deaths >3x
• Smoking, polypharmacy important
• Signs of withdrawal in 60-80% of infants
• Prolonged treatment in hospital (3-4 weeks),
high healthcare costs ($53,000/infant)

61. Why is Treatment of NAS Difficult?
• Few new treatments in the past 20 years that
have significantly improved outcome
• Small market, rare diseases, high risk/liability
• Difficulty with designing and conducting large
enough studies
• Hard to establish safety and efficacy
• Need to wait to a long time to determine outcome
• Drug development driven primarily by existing
legislation (BPCA, PREA, FDASIA)

62. Agonist Treatments for Opiate-
Dependent Pregnant Women
• Methadone, buprenorphine, (BPH) slow
release morphine
• Cochrane review of 271 pregnant women
from 4 trials analyzed
• High drop out rate (30-40%), with
methadone better than other treatments
• No differences in side effects in mothers,
less frequent with BPH in infants
• No overall difference in the incidence of
NAS, but BPH may be better
• Maternal dose not associated with NAS

63. Treatment of NAS
• Significant variability in treatment (weight,
score) with no large, randomized trials
• Morphine and methadone most common
drugs
• Sublingual buprenorphine also being studied
• Treatment driven by Finnegan scoring system
• Clonidine, phenobarbital - second line drugs
• Some pediatricians are discharging babies on
methadone, phenobarb; weaning as an
outpatient

65. NAS Scoring
• Based on Finnegan scoring system
• In use for > 30 years
• Twenty or more factors to consider (are all
really needed?)
• Very subjective – when is scoring conducted
• Significant intra-observer variability
• Over and under treatment common
• Two consecutive scores ≥ 8; one score ≥ 12
for treatment and/or dose escalation

66. Dosing Regimen
• Starting dose and escalation occurs if the infant
continues to have NAS scores ≥ 8 for 2
consecutive scores, or 1 score ≥ 12
• Dosing related to BW and Finnegan score
• Wean 10% of the total dose every 24 - 48 hours
Level NAS Score Starting Dose - 0.4mg/mL
1 8-10 0.3 mg/kg/day ÷ q4h
2 11-13 0.5 mg/kg/day ÷ q4h
3 14-16 0.7 mg/kg/day ÷ q4h
4 17+ 0.9 mg/kg/day ÷ q4h

67. Treatment of NAS
• Oral morphine can have significant amounts
of preservatives – can use preservative free
• Oral methadone has 15% alcohol
• Phenobarbital has alcohol, propylene glycol
• These agents can have multiple side effects
(e.g. methadone – prolonged QTc)
• Short term outcomes (LOS) studied; concern
for long-term neurodevelopmental outcome
• Significant variability: incidence, severity,
response to rx – genetic factors important

68. Why has Drug Development in NAS
Been so Difficult?
• Few new treatments in the last 30 years that
have significantly improved survival/outcome
• Small market, rare diseases, high risk/liability
• Few appropriate animal models
• Difficulty with study design/outcome measures
• Need to wait to determine outcome (how long)
• Hard to establish safety – drug/drug
interactions
• Hard to establish efficacy

69. Long Term Follow-up of Infants with NAS
• Opioid exposed children more likely to have
ADHD, disruptive behavior, psych referrals
• Polydrug (including opiates) exposed children
have smaller brains, thinner cortex, reduced
cognitive ability and more behavioral problems
• Small studies - adjustments for drug exposure
during pregnancy, environmental factors
• No studies of long term effects of exposure to
buprenorphine or prescription opioids

70. Neonatal Abstinence Syndrome
• Genetic factors may be
important
• Single nucleotide
polymorphisms (SNPs):
Single base pair changes
that can alter protein’s
function
• SNPs influence opioid
dosing, metabolism, and
addiction in adults
• No prior studies of genetic
links to NAS

71. Candidate Genes for NAS
• SNPs present in 40-50% of the population have
been studied in adults
• Mu Opioid Receptor (OPRM1) = Site of Action
• 118A>G SNP
• Multi-Drug Resistance Gene (ABCB1) =
Transporter
• 1236C>T SNP; 3435C>T SNP; 2677G/T/A SNP
• Catechol-O-methyltransferase (COMT) =
Modulator
• 158A>G SNP

72. Results (Wachman et al JAMA 2013;309:1821)
DEMOGRAPHICS N=86
White 98%
Maternal Methadone 64%
Maternal Buprenorphine 36%
Maternal Smoking 78%
Maternal Benzodiazepines 12%
LOS All Infants Mean 22.3 days
LOS Treated Infants Mean 31.6 days
Treatment for NAS 65%
Treated with >2 medications 24%

73. OPRM1 118A>G Results
• AA vs AG/GG infants compared in models
that adjust for breastfeeding and study site
• Those with the AG/GG genotype - treated
less frequently and had shorter LOS
OUTCOME UNADJUSTED
RESULTS
ADJUSTED
RESULTS
P-VALUE
Infant
Treated
72% vs 48% OR = 0.76
(CI 0.63, 0.96)
0.006
Mean LOS 24.1 vs 17.6 days - 8.5 days 0.009

74. Maternal Genotype
• If mother has one G allele, ~50% chance infant
does well
• Maternal OPRM1 AG/GG associated with less
NAS treatment and shortened LOS
• No differences with COMT
OUTCOME ADJUSTED RESULTS P-VALUE
Infant Treated OR = 0.70 (CI 0.54, 0.90) 0.008
Length of Stay β = -8.9 days (CI -16.9, -0.8) 0.03
Wachman EM, JAMA, May 2013

75. COMT 158A>G Results
• AA infants vs AG/GG infants in models that
adjusted for breastfeeding and site
• AG/GG infants were treated less frequently
and had shorter LOS than AA infants
OUTCOME UNADJUSTED
RESULTS
ADJUSTED
RESULTS
P-VALUE
Infant
Treated
88% vs 60% OR = 0.79
(CI 0.61, 0.99)
0.02
Mean LOS 31.1 vs 20.4 days - 10.8 days 0.005

76. What is Epigenetics?
• Changes in DNA
(methylation, histone
modification) affecting
function without a
change in sequence
• Environmental triggers
• Can lead to gene
silencing
• Can be passed on
through generations

77. CpG Methylation

78. Epigenetics of Addiction
• Chronic opioid exposure -
methylation at CpG sites
within the OPRM1 gene
• OPRM1 promoter
methylation - decreased
mRNA content and reduced
levels of the mu opioid
receptor
• Methylation = Gene
silencing
• Changes can be passed on
to the next generation

79. Results (Wachman J Peds 2014;165:472)
• Within OPRM1, the % methylation at the -10 CpG
was 6.5% (95% CI 3.4, 9.7) in infants treated with
> 2 medications vs 2.5% (95% CI 1.6, 3.5) in
those receiving ≤1 (adjusted p=0.006)
• Within COMT, increased methylation at the -51
(r=0.25, adjusted p=0.04) and -46 (r=0.23,
adjusted p=0.02) CpG sites correlated with
increased LOS
• Those with hypermethylation had worse NAS
outcomes, consistent with gene silencing

80. Conclusions
• NAS is a complex disorder with many factors
contributing to the incidence & severity
• Significant uncertainty - who to treat, when to
treat, how to treat, how to wean, and the
optimal agent(s) to use
• Concerns of safety and efficacy of NAS
treatments – primum non nocere
• Genetic factors appear to be important
• Larger studies in mothers and infants, more
genetic studies, research consortia, legislation

81. Take Away Messages
• We need to better understand why NAS is
increasing so quickly – a national registry is
essential
• Current treatments of NAS are costly and require
lengthy hospitalization - we need to establish best
practices
• Infants who recover from NAS can lead normal
healthy lives, but long-term outcomes need better
study
• We can’t do this on our own - a multidisciplinary
approach involving health care workers, addiction
specialists, social scientists, and law enforcement is
urgently needed

82. Coordinated Recovery for
Babies (CRIB) Act
• To improve research and understanding of
prevention, treatment, and barriers to care for
women of child-bearing age and pregnant women
with substance use disorders, including
dependence on prescription drugs
• To improve research and understanding of
prevention, treatment, barriers to care, and long-
term impacts for infants diagnosed with NAS
• To ensure that family-centered care is preserved
when addressing maternal addiction and NAS

83. That’s All
Folks!

84. Neurodevelopmental Outcomes of
Neonatal Abstinence Syndrome
Henrietta S. Bada-Ellzey, MD, MPH
Professor and Vice Chair, Academic Affairs
Department of Pediatrics
College of Medicine
University of Kentucky
Dr. Bada-Ellzey has no conflicts of interest
She has documented that she has nothing to disclose.

85. Disclosures
Henrietta S. Bada-Ellzey, MD, MPH, has disclosed no
relevant, real, or apparent personal or professional
financial relationships with proprietary entities that
produce healthcare goods and services.

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

87. NAS Hospitalizations (Kentucky)
Year
Fifteen-fold increase: 1.3 per 1000 to 19.1 per 1000 live births

88. Neonatal Abstinence Syndrome
• NAS will not disappear
• Will only increase and or evolve from different opioid
formulation or Rx 2013-2015
Heroin
1960’s
Methadone
1970 – 1980s
Methadone,
Hydro-
morphone
Cocaine
19980-1990s
Other opioids
(oxycodone,
hydro-morphone,
tramadol)
1990s to 2000s
Bupre-
norphine+/-
Naloxone,
Methadone,
other opioids
Mid 2000s to
present

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

90. OUTCOME IN THE FIRST YEAR
Early Childhood Outcomes of Opiate-exposed Children

91. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Strauss ME, Ostrea EM, Stryker, JC (n=113; 53/113 “addicted”)
(n=34 Opiate exposed, all smoked; 42 Nicotine)Outcome categories
1 year*
Opiate-exposed
n=25
Not opiate-
exposed n=26 p value
Mental Developmental
Index (MDI)
113.4 (10.2) 114.8 (11.3) n.s.
Psychomotor
Developmental Index (PDI)
102.8 (11.0) 110.4 (9.7) <0.01
% 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.

92. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Wilson GS, Desmond MM, Wait RB (n=125; no Rx – 29; methadone Rx-39; controls-57)
Outcome at 1
year
Opiate-exposed;
No Rx
(n=29)
Methadone Rx
(n=35)
Drug free
(n=55)
Mental
Developmental Index
(MDI)
97.2 (17.6) 99.3 (15.5) 105.5 (15.6)
Psychomotor
Developmental Index
(PDI)
92.2 (19.2)* 89.9 (12.6)* 99.0 (14.5)
Poor Fine Motor 75%* 82%* 50%
Short attention span 29%* 24%** 7%
J Pediatr 1981; 98(5): 716-722
*p<0.05 Compared to controls
**p<0.01 compared to controls

93. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Bunikowski R et al. (One year follow-up)
(n=34 Opiate exposed, all smoked; 42 nicotine for exposure)
Measures*
Opiate-exposed
n=27
Not opiate-
exposed n=42 p value
Griffiths Developmental
Quotient: Average
100.5 (9.3) 107.9 (17.2) <0.05
Locomotor 100.8 (13.6) 111.4 (16.9) <0.05
Personal/social 104.1 (10.9) 107.3 (9.2) n.s.
Hearing & speech 97.0 (8.6) 98.8 (9.1) n.s.
Hand & eye 100.7 (10.9) 105.6 (9.7) n.s.
Intellectual performance 100.5 (9.3) 107.9 (17.2) <0.05
Eur J Pediatr 1998 157:724-730
* 7 with questionnaire, no visit

94. 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 and 12months
• Control for gestation in the analysis
Van Baar A, J Child Psychol Psychiat 1990; 31(6): 911-920

95. Mental Developmental Index at 1 Year
0
20
40
60
80
100
120
140
Strauss (1976) Wilson (1981) Van Baar (1990)
No exposure Opiate-Exposed
One Year: No significant difference between exposed and non-exposed

96. Psychomotor Development at 1 Year
0
20
40
60
80
100
120
140
Strauss (1976) Wilson (1981) VanBaar (1990)
Controls Opiate-Exposed
*
*
*p<0.05

97. OUTCOMES: AGE 2-3 YEARS
Long Term Follow-up of Opiate Exposed Children

98. 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 18, 24, and 30 months
• Control for gestation in the analysis
Van Baar A, J Child Psychol Psychiat 1990; 31(6): 911-920

99. 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

100. 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

101. 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

102. Adverse Neurodevelopmental Outcomes
Of Infants Exposed to Opiate In-utero
Hunt et al. 2008 (133 cases/103 controls)
Measures at 3 years Opiate- exposed Controls
IQ 99.9 (15.1) 107.5 (13.4)
Motor (McCarthy)* 49.5 (8.7) 53.9 (8.3)
Expressive Language* 35.5 (7.9) 42.8 (12.6)
Receptive Language* 42.4 (11.6) 49.2 (11.4)
Early Human Development 2008; 84:29-35
* Results expressed as T scores

103. SUMMARY OF OUTCOMES: AGE 2-3 YEARS
Long Term Follow-up of Opiate Exposed Children
Significantly Lower Cognitive Abilities
Low MDI or Low IQ
Poor Language Development

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

105. 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 development
• 11% moderate psychomotor impairment
• 5 depravation syndrome; 2 spastic tetraplegia, 1 rubella
syndrome
Acta Paediatr Scand 72:407-410, 1983

106. 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

107. 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

108. Adverse Neurodevelopmental Outcomes Of
Infants Exposed to Opiate In-utero
100.4 102.79 102.3 102.9
92.7 91.9
96.03 93.33
0
20
40
60
80
100
120
IQ (Stanford-Binet) WAIS Verbal score WAIS Performance WAIS Full scale
Controls Exposed
The International Journal of the Addictions 1986; 21(8): 849-863
**p<0.01; ***p<0.001
*** ***** **

109. 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

110. 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 =6 years 52% 82%
Soepatmi, Acta Paediatr Suppl 1984, 404:36-39

111. 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
Expression 50 (6) 46 (6) <0.05
Dev Med Child Neurol 1994 36:1063-1075

112. 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

113. 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

114. 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

115. • Enrollment period: May 1993-May 1995
• Screening for enrollment
– Birth weight >500 grams
– Gestational Age <43 weeks
– Singletons
• Informed consent and maternal interview
• Meconium collection
Patient Recruitment

116.  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
Results

117. 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
Externalizing Behavior Problem:
Results From Longitudinal Modeling1
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

118. – Externalizing behavior problem scores : normed to mean
(SD) of 50 (10)
– A 3-point upward shift will increase the number of
children with scores in the referral or deviant range by
50% (an increase of 16% to 26%).
Opiates and Long Term Behavior Outcomes
Bada HS et al. Pediatrics 2007
Variables Regn. Coefficient2 p value
Prenatal opiate (year 5) 3.09 0.041

119. • Children with prenatal opiate exposure did not start out with
high problem scores at early ages.
• From caretaker report: behavior problem scores: worse with
time
– Internalizing Behavior Problems
– Total problems
– Attention problems
• From teacher report
– Attention Problem Scores worse with time
Effects of Prenatal Opiate at 13 years From
Caretaker and Teacher Report
Bada HS et al. Neurotoxicology Teratology 2011

120. SUMMARY OF OUTCOMES
AFTER AGE 3 YEARS
Long Term Follow-up of Opiate Exposed Children
Lower IQ scores than non-exposed children (8-15 points difference)
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%.
Poor Language development
Behavior and school problems: 1 out of 4 children.

121. Summary: Prenatal Opiate Drug Exposure and
Outcomes at Late childhood
• 8 to 15-point difference (lower) in IQ scores after prenatal opiate
exposure compared to non-exposed children
• Lower Language scores in Exposed Children
• Maternal opioid replacement treatment was not associated with
improved cognitive development in exposed children
• Higher rates of behavior problems that become worse with time
• Need more research on the appropriate treatment of infants with
NAS, Rx that will not continue or aggravate the effects of in utero
exposure
• These prenatal and post natal drug exposure effects and other
factors could have implications for antisocial behavior, child mental
health, and school functioning.
• More research to mitigate behavior problems in exposed children

122. Complexity in Outcomes: Cumulative Risks Will
Influence Outcomes

124. Drug Use &
Other Risks
Protective
Factors
CAN WE CHANGE CHILD OUTCOMES?

125. 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

126. 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
Risk and Protective Factors

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

128. • Externalizing Behavior Problems
– Delinquent behavior
– Aggressive behavior
• Internalizing Behavior Problems
– Withdrawn
– Somatic complaints
– Anxious/depressed
• Total Behavior Problems
– Externalizing, internalizing, social problems, thought
problems, attention problems, sex problems
Problem Behaviors

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

130. Drug Use &
Other Risks
Protective
Factors
YES: WE CHANGE CHILD OUTCOMES?

131. SUMMARY AND CONCLUSION
Long Term Outcomes of Prenatal Opiate
Exposure

132. • 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
• Adverse outcomes are noted even with maternal opioid treatment during
pregnancy; therefore focus much needed to treatment of neonatal
abstinence syndrome and on 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 to minimize the adverse effects of prenatal
drug exposure.
• We need to address maternal treatment, child treatment and
development
Clinical and Policy Implications

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

135. THE END
Thank you

136. Latest Research on Intrauterine
Drug Exposure and Neonatal
Abstinence Syndrome
Presenters:
• Craig V. Towers, MD, FACOG, Division Director, Maternal-Fetal
Medicine, University of Tennessee
• Jonathan Davis, MD, Chief of Newborn Medicine, The Floating Hospital
for Children at Tufts Medical Center, and Professor of Pediatrics, Tufts
University School of Medicine
• 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
Moderator: Carla S. Saunders, NNP-BC, Advance Practice Coordinator,
Pediatrix Medical Group, and Neonatal Nurse Practitioner, East Tennessee
Children’s Hospital, and Member, Rx Summit National Advisory Board