Intrauterine Drug Exposure and the Management of Neonatal Abstinence Syndrome: The participant will be able to: Identify the impact of poly-drug exposure and NAS in the neonate; describe the current pharmacologic therapies used to manage NAS in the neonate and identify short and long term outcomes in the neonate with intrauterine drug exposure.

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
 Discuss the impact of intrauterine drug exposure on
the fetus
 Compare various drugs associated with the
development NAS
 Describe 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 Abuse

5. Prescription Drug Problem - Opiates

6. Illicit Drug Use in Pregnancy

7.  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
 Use of medically prescribed drugs during pregnancy
contributes to an increasing incidence of fetal
exposure
Scope of the Problem

8. 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

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

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

11. APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
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

12. 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

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

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

15. 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

16. 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

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

18. 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

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

20. APP Neonatal Drug Withdrawal. Pediatrics, 2012;
129 (2): e540-e560
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

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

22. 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

23. 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
 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

24. 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

25. 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

26. 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 mcg-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

27. Jansson LM et.al. Methadone Maintenance and Breastfeeding Pediatrics,
2008; 121(1):106-114

Crosses the placenta

Does not cause fetal
abnormalities

Not associated with
premature and LBW

Infant can be weaned (if
needed)

Capatible with
breastfeeding
Methadone Effects on Fetus

28. Buprenorphine Effects on Fetus
Crosses the placenta
Less frequent NAS
Symptoms of NAS may
be less severe
Fetal risk not greater
than methadone
Compatible with
breastfeeding
Jones HE, Finnegan LP, and Kaltebach K. Drugs
2012;72(6):747-757

29. 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
circumference
Decreased birth head
circumference
Decreased birth head
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

30. Prenatal Drug Exposure: Potential Effects on CNS
development, Cognitive Function, and Behavior*
Tobacco Marijuana Stimulants Opiates
Disturbed maternal-infant
interaction
Excitability
Hypertonia
Stress abstinence signs
Conduct Disorder
Reduced IQ
Aggression
Antisocial behavior
Impulsivity
ADHD
Tobacco use and dependence
Mild withdrawal symptoms
Delayed state regulation
Reading, spelling difficulty
Executive function
impairment
Early tobacco and marijuana
use
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.

31. 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

32. 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

33. Time Course of NAS Symptoms over 16
days following birth
Annemarie Unger, et al. Addiction. 2011 July;106(7):1355-1362

34. 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

35. 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’

36. 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

37. Stimulants:
Cocaine and Methamphetamine
 Abstinence syndrome not clearly defined
 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

38. 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
 It is unclear if intrauterine exposure affects later
cognitive development

39. 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

40. Serotonin Reuptake Inhibitors (SSRIs)
 Abstinence symptoms associated with withdrawal or
hyperserotonergic (serotonin toxicity) state
 Symptoms present several hours to several days after
birth
 Cry, irritability, jitteriness, restlessness,
shivering, fever, tremors, hypertonia, rigidity,
tachypnea, respiratory distress, feeding difficulty,
sleep disturbance, hypoglycemia, seizures

41. Summary
 “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

42. 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.

43. 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.

44. Thank You!