NATIONAL PERINATAL ASSOCIATION CONFERENCE 2014 - Intrauterine Drug Exposure and the Management of Neonatal Abstinence Syndrome - Evelyn Fulmore, Pharm. D., McLeod Regional Medical Center

1. Intrauterine Drug Exposure and
the Management of Neonatal
Abstinence Syndrome
Evelyn Fulmore, Pharm.D.
McLeod Regional Medical Center Florence, SC

2. Disclosures
 No financial relationships or duality of
interest to disclose
 I will be discussing off-label use of agents
used to treat newborns with NAS (methadone,
morphine, clonidine)

3. Learning Objectives
 Overview of poly-drug use (illicit vs prescription) in
the US
 Discuss the impact of intrauterine drug exposure on
the fetus
 Compare various drugs associated with the
development NAS
 Define NAS and review pharmacologic therapies
used in the management of NAS
 Examine the evidence of poly-drug exposure on
short and long-term developmental outcomes

4. Prescription Drug Problem

5. Prescription and Illicit Drug Abuse

6. Scope of the Problem
 AAP refers to the increased reporting of withdrawal
syndrome in the newborn by ICD-9 code (779.5)
 Between 2000 and 2009, the national incidence of newborns
at risk of withdrawal due to intrauterine exposure to drugs
increased from 1.20 to 3.39 per 1,000 live hospital births per
year
 Between 2000-2009, the number of mothers using or
dependent on opiates increased from 1.19 to 5.3 per 1000
hospital births per year
 Use of medically prescribed drugs during pregnancy
contributes to an increasing incidence of fetal exposure

7. Prevalence of Poly-Drug Use in
Pregnancy

8. Drug Transfer Across the Placenta
 Transfer occurs
 passive diffusion
 protein transport
 Transfer dependent
 Molecular size (<500)
 pH
 Protein binding
 Lipid solubility

9. Neonatal Abstinence Syndrome (NAS)
 Exposure to illicit or
prescription drug
 Passes via placenta to
baby
 Dependency to drug
(mom and baby)
 Withdrawal
symptoms occur
shortly after birth Updated by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of
Pediatrics, University of Washington School of Medicine. Also reviewed by
David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc 1/29/2010

10. Drug of Abuse Effects on the Fetus
 Embryonic stage:
teratogenic
 Fetal development
stage:
 Abnormal growth
 Alteration in
neurotransmitters and
receptors
 Brain organization
 Altered delivery of
substrates/nutrients Updated by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of
Pediatrics, University of Washington School of Medicine. Also reviewed by
David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc 1/29/2010

11. Model to Study Effects of Prenatal Drug
Exposure on Developmental Outcomes

12. Intrauterine Effects of Drug Exposure
on the Fetus
 Active metabolites enter the CNS of the fetus
causing neuronal cell injury or death
 Studies have shown physiologic brain changes
 Impact on cognitive and behavioral development
 Side effects of certain drugs can cause
vasoconstriction and decrease blood supply
 Result in complications of pregnancy (placental
abnormalities, IUGR, preterm delivery)
 Drug abuse or chronic drug use can increase risk for
NAS

13. Prenatal Drug Exposure: Potential Effects on
Birth and Pregnancy Outcomes
Tobacco Marijuana Stimulants Opiates
Pregnancy complications No fetal growth effects Cocaine Stillbirth
Prematurity No physical abnormalities Prematurity Prematurity
Decreased birth weight Decreased birth weight Decreased birth weight
Decreased birth length Decreased birth length Decreased birth length
Decreased birth head
Decreased birth head
Decreased birth head
circumference
circumference
circumference
Sudden infant death
syndrome (SIDS)
Intraventricular
hemorrhage
Fetal and neonatal
abstinence syndrome
Increased infant mortality
rate
Methamphetamine Sudden infant death
syndrome (SIDS)
Small for Gestational Age
(SGA)
Decreased birth weight
Sonnia Minnes. Addict Sci Clin Pract. 2011 July; 6(1): 57–70

14. Prenatal Drug Exposure: Potential Effects on CNS
development, Cognitive Function, and Behavior*
Tobacco Marijuana Stimulants Opiates
Disturbed maternal-infant
Mild withdrawal symptoms
interaction
Delayed state regulation
Excitability
Reading, spelling difficulty
Hypertonia
Executive function
Stress abstinence signs
impairment
Conduct Disorder
Early tobacco and marijuana
Reduced IQ
use
Aggression
Antisocial behavior
Impulsivity
ADHD
Tobacco use and dependence
Cocaine
Neonatal/Infancy
Early neurobehavioral
deficits: orientation, state
regulation, autonomic
stability, attention, sensory,
and motor asymmetry,
jitteriness
Poor clarity of infant cues
during feeding interaction
Delayed information
processing
General cognitive delay
Abstinence syndrome
Less rhythmic swallowing
Strabismus
Possible delay in general
cognitive function
Anxiety
Aggression
Feelings of rejection
Disruptive/inattentive
behavior
Methamphetamine
Poor movement quality (3rd
trimester exposure)
Low arousal
Increased lethargy
Increased physiologic stress
No mental or motor delay
*Effects may be subtle and transient Sonnia Minnes. Addict Sci Clin Pract. 2011 July; 6(1): 57–70.

15. Definition of NAS
NAS is a complex of signs and symptoms in the
postnatal period associated with the sudden withdrawal
of maternally transferred opioid
A drug withdrawal syndrome in newborns caused by
the mother’s substance use during pregnancy
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560

16. Drugs/Substances assoc with NAS
 Alcohol
 Antidepressants/Antipsychotics - SSRIs/SNRIs
 Barbiturates
 Benzodiazepines
 Caffeine
 Marijuana
 Tobacco/Nicotine
 Opiates/Narcotics
 Stimulants – cocaine and methamphetamines

17. Symptom Presentation of NAS
 Type of drug
 Metabolism of the drug
 How much and how long
 Term versus Preterm

18. Time of Onset of NAS
 Heroin often begins within 24 hours of birth
 Methadone usually begins around 24-72 hours
 For both opiates, evidence of withdrawal may be
delayed until 5-7 days of age or later
 For infants exposed to buprenorphine, onset of
withdrawal peaked at 40 hours (severity of signs at
70 hours of age)
 If 1 week or longer has lapsed since last dose of
maternal opioid use and delivery of the infant, the
incidence of withdrawal is low

19. Clinical Presentation - NAS
Gastrointestinal
Dysfunction
Poor feeding
Uncoordinated and
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129
(2): e540-e560
constant sucking
Vomiting
Diarrhea
Dehydration
Poor weight gain
Autonomic Signs
Increased sweating
Nasal stuffiness
Fever
Mottling
Temp instability

20. Clinical Presentation - NAS
Neurologic excitability
Tremors
Irritability
Increased wakefulness
High-pitched crying
Increased muscle tone
Hyperactive deep
tendon reflexes
Exaggerated Moro
reflex
Seizures
Frequent yawning and
sneezing
APP Neonatal Drug Withdrawal. Pediatrics, 2012;
129 (2): e540-e560

21. Diagnosis of NAS
A maternal history of substance abuse during
pregnancy often forms the basis for diagnosis of NAS
AAP recommends the use of an objective abstinence
scoring method to measure the severity of withdrawal
APP favors the Finnegan method for NAS scoring
APP Neonatal Drug Withdrawal. Pediatrics, 2012;
129 (2): e540-e560

22. NAS Scoring Tools
Neonatal Abstinence Scoring System (NASS)
or Finnegan Scoring System (1975)
 Modified Finnegan
Lipsitz Tool (1975)
Neonatal Withdrawal Inventory (1998)
Ostrea Criteria
Riley Infant Pain Scale
Sarkar, J Perinatol 2006

23. Finnegan LP. Addict Dis, 1975; 2:141-58

24. Modified Finnegan’s Neonatal Abstinence Scoring Tool.
Hudak M L et al. Pediatrics 2012;129:e540-e560
©2012 by American Academy of Pediatrics

25. NAS Scoring Protocol
Initiate scoring within 2 hours of admission
Infants should not be awakened to obtain a score
Infants at risk of opiate withdrawal are assessed for
signs of withdrawal ½ to 1 hour after each feed
The scoring chart is designed for term infants who are
fed q 4 hours
Allowances must be made for infants who are
preterm

26. Non-Pharmacologic Interventions
NAS
Swaddling
Rocking
Minimal sensory or environmental stimulation
Maintain temperature stability
Feed
Breastfeeding

27. Pharmacologic Therapy
NAS
Paregoric – no longer recommended
Dilute Tincture of Opium (DTO) – no longer
recommended
Dilute Morphine Sulfate Oral solution
Methadone
Buprenorphine
Phenobarbital
Clonidine
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-
e560

28. Drugs/Substances assoc with NAS
 Alcohol
 Antidepressants/Antipsychotics - SSRIs/SNRIs
 Barbiturates
 Benzodiazepines
 Caffeine
 Marijuana
 Tobacco/Nicotine
 Opiates/Narcotics
 Stimulants – cocaine and methamphetamines

29. Alcohol
 Intrauterine exposure most commonly causes Fetal Alcohol
Spectrum Disorders
 Studies suggest alcohol increases risk for miscarriages and
premature births
 The
American Academy of Pediatrics Section on Breastfeeding
notes: “ingestion of alcoholic beverages should be minimized
and limited to an occasional intake but no more than 0.5 g
alcohol per kg body weight, which for a 60 kg mother is
approximately 2 oz liquor, 8 oz wine, or 2 beers. Nursing
should take place 2 hours or longer after the alcohol intake to
minimize its concentration in the ingested milk.”
 The evidence of negative association between moderate fetal
exposure to alcohol and later IQ is not conclusive

30. Nicotine
 1 of more than 4000 compounds the fetus is exposed to
 Approx 30 compounds assoc adverse outcomes
 Proposed mechanisms of fetal harm (hypoxia, nutrient
deprivation, direct vasocontrictor effects on the placenta and
umbilical vessels)
 Birth defects of the heart, brain, face
 Increase risk for SIDS, placenta abnormalities, preterm labor
 No convincing evidence that intrauterine exposure is
associated with NAS
 It is unclear if intrauterine exposure affects later cognitive
development

31. Opiates and Benzodiazepines (BZD)
 Severity and duration difficult to predict
 Occur 24–72 hours after birth
 Symptoms can include shaking or jerky movements,
high pitched crying, feeding difficulties, sneezing,
sensitivity to light or stimulus, vomiting and diarrhea
 Severity of symptoms not necessarily related to level
of antenatal exposure
 Increased risk of SIDS

32. Marijuana (Cannabis)
 Consequences similar to use of nicotine
 Smoking marijuana produces 5 times the amount of
carbon monoxide as does cirgarette smoking
 Tetrahydrocannabinol (THC)
 Crosses the placenta rapidly
 Effects on fetus associated with altered uterine blood
flow and altered maternal health behaviors
 Regular use associated with low birth weight and
prematurity

33. Serotonin Reuptake Inhibitors (SSRIs)
 Fluoxetine, paroxetine, sertraline, citalopram
 Increase risk of cardiac and congenital malformations
(paroxetine – 1st trimester)
 Persistent Pulmonary Hypertension (PPHN)
 Abstinence symptoms associated with withdrawal or
hyperserotonergic (serotonin toxicity) state
 Symptoms present several hours to several days to weeks
after birth
 Cry, irritability, jitteriness, restlessness, shivering, fever, tremors,
hypertonia, rigidity, tachypnea, respiratory distress, feeding
difficulty, sleep disturbance, hypoglycemia, seizures

34. Benzodiazepines (BZD)
 Benzodiazepines (e.g. Diazepam, Alprazolam,
Midazolam, Lorazepam)
 Increased risk of low birth weight and
prematurity
 Can cause serious withdrawal symptoms in
the newborn similar to opiate withdrawal
 Effects of withdrawal can last for several
months – ‘floppy baby syndrome’

35. Opiates
 Opiate drugs are highly lipophilic and have
relatively low molecular weights
 Cross the placenta by simple diffusion from mother to
fetus
 Tend to accumulate in the fetus
 Longer half-life in the fetus (enzymes of
glucuronidation and oxidation not fully developed,
immature renal function)
 Babies at increased risk of low birth weight and poor
growth. May have smaller head size and be born pre-term

36. Maternal Opioid Treatment: Human
Experimental Research ‘MOTHER’ Study
 Randomized, double-blind multicenter trial
 3 women (2 consecutive pregnancies = 6
neonates)
 Buprenorphine or methadone
 Outcome parameters: maternal and fetal
safety and efficacy, severity and duration of
NAS, the amount of NAS medication, and
birth outcomes

37. Stimulants:
Cocaine and Methamphetamine
 Symptoms appear 2-3 days after birth (assoc with
stimulant effect
 Irritability, hyperactivity, tremors, high-pitched cry,
excessive sucking, abnormal auditory brainstem responses
and ECG
 Cocaine or Methamphetamine exposure:
 Premature births and placental problems
 Increase chance for SGA, IUGR, low birth weight,
decreased head circumference
 Long term effects: behavioral, cognitive skills, and
physical dexterity
 Abstinence syndrome not clearly defined

38. Pharmacologic Therapy NAS
Dilute Morphine Sulfate Oral solution
Methadone
Buprenorphine
Phenobarbital
Clonidine
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-
e560

39. Pharmacologic Intervention
NAS
 Begin when 2-3 consecutive Finnegan scores are ≥8 or when
the sum of 3 consecutive Finnegan scores is ≥24
 Based upon toxicology and clinical presentation initiate drug
therapy
 Use Birth weight when calculating doses of NAS medications
Medications should be started within 2-4 hours after infant has
met criteria
 Vomiting and diarrhea associated with dehydration due to
narcotic withdrawal are indications for treatment even in the
absence of high abstinence scores

40. Pharmacologic Intervention
NAS
Morphine or methadone are first-line opiates
Clonidine is a first line or adjunctive therapy used in
combo with an opiate for poly-substance exposure
Phenobarbital is adjunctive therapy used in combo
with an opiate for poly-substance exposure
Poly-substance dependency is likely seen with
opiates as well as barbiturates, sedative, and
SSRIs/SNRIs

41. Dilute Oral Morphine Solution
0.4 mg/ml
 Prepared from commercial oral morphine
solution 2 mg/ml
 No additives or high alcohol content
 Equivalent to tincture of opium and paregoric
 Contraindicated in non-opiate withdrawal
 Has a short half-life
 Ideal for first-line treatment of NAS

42. Dosing of Oral Morphine for
Treatment of NAS
 Available as 10 mg/5 ml oral solution
 2 mg/ml concentration – alcohol FREE
 Beware of drug shortages which product your Rx stocks
 Recommended dosing from a dilute oral morphine
0.4 mg/ml concentration (must be compounded)
Morphine dosing
 Initial dose: 0.04 mg/kg/dose every 3-4 hours
 Increment dose: 0.04 mg/kg/dose
Maximum dose: 0.2 mg/kg/dose
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560

43. Methadone Oral solution
1 mg/ml
 Available as 1 mg/ml and 2 mg/ml oral
concentrate
 Contains alcohol – 8%
 Has a long half-life
 ? Ideal for first-line treatment of NAS
 Skill in dose titration and weaning
 Monitor for potential drug interactions

44. Dosing of Oral Methadone for
Treatment of NAS
 Available as 1 mg/ml and 2 mg/ml oral concentrate
solution (CAUTION)
Contains 8% alcohol
May dilute to 0.5 mg/ml concentration
Methadone dosing
Initial dose: 0.05 mg-0.1 mg/kg/dose every 6 hours
Increment dose: 0.05 mg/kg/dose
Maximum dose: to effect
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2):
e540-e560

45. Buprenorphine Oral Suspension
60 mcg/ml
 Not commercially available as an oral
suspension
 High alcohol content: 30%
 Rx compounded formulation: 60 mcg/ml
 Has long half-live
 Not recommended by AAP guidelines
 Buprenorphine dosing: 4.4-5.3 mcg/kg/dose
subligual every 8 hours

46. Phenobarbital oral solution
20 mg/5 ml
 Commercially available as 20 mg/5ml elixir
 Contains 15% alcohol
 Drug of choice for non-opiate withdrawal
 Consider adding on when CNS symptoms are not controlled with
opiate alone
 Has a long half-live
 Levels should be monitored if clinical indicated
 Goal level: 20-30 mcg/ml
 Caution: high doses may cause sedation and interfere with
feeding/sucking
 May not prevent seizures due to opiate withdrawal

47. Dosing of Oral Phenobarbital for the
Treatment of NAS
 Available as 4 mg/ml elixir (contains alcohol)
 Phenobarbital dosing:
 Loading dose: 10-15 mg/kg x 1
 Maintenance dose: 3-5 mg/kg/day divided BID
 Doses up to 8 mg/kg/day divided BID (if higher
NAS scores)

48. Clonidine oral suspension
20 micrograms/ml
 α-2 adrenergic agonist used for opiate detox
in adults
 Not commercially available in oral suspension
 Limited studies in newborn infants
 Use as an adjuvant therapy with a opiate
 Care in dosing (micrograms vs milligrams)
 Avoid abrupt discontinuation due to risk for
side effects

49. Dosing of Oral Clonidine for
Treatment of NAS
 Not available as a oral suspension
 Compounding Rx: 20 mcg/ml concentration –
stable 30 days in refrigerator
 Clonidine dosing
 Initial dose: 0.5-1 mcg/kg/dose every 3-6 hours
 Increment dose: Not studied
 Maximum dose: 1 mcg/kg/dose every 3 hours
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560

50. Clonidine in Treatment of NAS
 Limited studies (few case series)
 Total daily doses: 3-4 mcg/kg
 7 neonates exposed to maternal methadone
 6:7 neonates resolved/decrease “major” withdrawal
symptoms (MAP, HR, Temp) and decrease in opiate
dose
 No side effects
 Limitation: No abstinence scoring was performed
Leikin Jb et.al. Use of clonidine in the prevention and management of NAS.
Clinical toxicology, 2009 (47): 551-555

51. Breast feeding
 Breast feeding has been associated with less severe
NAS
 Breast feeding is allowed if the mother is
compliant/stable in a supervised drug treatment
program and is HIV and Hep C negative
 Methadone and buprenorphine are excreted in breast
milk at low levels
 Breast feeding is compatible with methadone or
buprenorphine use

52. Considerations for Discharge planning
 Establish early collaboration/intervention between
OB/GYN practitioner and Addiction specialist and
others
 Address concerns/barriers for outpatient treatment of
NAS in the community
 Breastfeeding
 Availability of medications
 Risk for diversion of medication
 Assessments of the infant (reliable)
 Loss to followup

53. Summary
 “Poly-substance” or “Poly-drug”abuse in pregnancy
is an ever increasing problem
 Neonatal withdrawal secondary to intrauterine
exposure is associated with a variety of drugs
(prescription or illicit)
 Non-pharmacologic and pharmacologic
interventions are indicated
 Long term neurodevelopmental effects need to be
determined
 Transition of care issues need to be addressed

54. References
1. Behnke M. et.al. APP Committee on Substance Abuse, and Committee on Fetus and Newborn.
Prenatal Substance Abuse: Short- and Long term Effects on the Exposed Fetus, 2013; e1009-e1024.
2. Bio LL, Siu A, Poon CY. Update on the pharmacologic management of neonatal abstinence
syndrome (review). Journal of Perinatology 2011;31(11):692-701.
3. Bruin JE et.al. Long-Term Consequences of Fetal and Neonatal Nicotine Exposure: A Critical
Review. Toxicological Sciences, 2010; 116(2):364-374.
4. Buck ML. Drugs in Pregnancy and Lactation: Literature and Resource Update. Pediatr Pharm 2010;
16(1). Jansson LM, Velez ML. Infant of Drug-dependent Mothers. Pediatrics in Review
2011;32(5):5-13.
5. Creanga AA, Sabel JC, Ko JY, et.al. Maternal Drug Use and Its Effects on Neonates: A Population-
Based Study in Washington State. Obstet Gynecol 2012; 119:924-33.
6. Hudak ML, Tan RC. Committee on Drugs. Committee on Fetus and Newborn. American Academy of
Pediatrics. Neonatal Drug Withdrawal. Pediatrics 2012; 129(2):e540-60, Feb 2012.
7. Jansson LM, Velez M. Neonatal Abstinence Syndrome. Current Opinion in Pediatrics 2012;
24(2):252-258.
8. Kaye AD, Gevirtz C, Bosscher HA, et.al. Ultrarapid opiate detoxification: a review. Can J Anesth
2003;50(7):663-671.

55. References
9. Kronstadt D. Complex Developmental Issues of Prenatal Drug Exposure. The Future of Children,
1991; 36-49.
10. Jefferies AL. Position Statement from the Canadian Pediatric Society. Selective Serotonin Reuptake
Inhibitors in Pregnancy and Infant Outcomes. 2013.
11. Lucas K, Knobel RB. Implementing Practice Guidelines and Education to Improve Care of Infants
with Neonatal Abstinence Syndrome. Advances in Neonatal Care 2012;12(1):40-45.
12. Smith HS. Opioid Metabolism. Mayo Clin Proc 2009; 4(7):613-624.
13. Wickstrom R. Effects of Nicotine During Pregnancy: Human and Experimental Evidence. Current
Neuropharmacology, 2007;5:213-222.

56. Intrauterine Drug Exposure and
the Management of Neonatal
Abstinence Syndrome
Evelyn Fulmore, Pharm.D.
McLeod Regional Medical Center Florence, SC