Intrauterine drug exposure and nas newest10 17 14

Intrauterine Drug Exposure and the Management of Neonatal Abstinence Syndrome

Evelyn Fulmore, Pharm.D.

McLeod Regional Medical Center Florence, SC

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)

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

Prescription Drug Problem

Prescription and Illicit Drug Abuse

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

Scope of the Problem

Prevalence of Poly-Drug Use in Pregnancy

Drug Transfer Across the Placenta Transfer occurs

passive diffusion protein transport

Transfer dependent Molecular size (<500) pH Protein binding Lipid solubility

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

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

Model to Study Effects of Prenatal Drug Exposure on Developmental Outcomes

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188826/figure/f1-ascp-06-1-57/

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

Prenatal Drug Exposure: Potential Effects on Birth and Pregnancy Outcomes

Tobacco Marijuana Stimulants OpiatesPregnancy 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



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

Prenatal Drug Exposure: Potential Effects on CNS development, Cognitive Function, and Behavior*Tobacco Marijuana Stimulants OpiatesDisturbed maternal-infant interactionExcitabilityHypertoniaStress abstinence signsConduct DisorderReduced IQAggressionAntisocial behaviorImpulsivityADHDTobacco use and dependence

Mild withdrawal symptomsDelayed state regulationReading, spelling difficultyExecutive function impairmentEarly tobacco and marijuana use

CocaineNeonatal/InfancyEarly neurobehavioral deficits: orientation, state regulation, autonomic stability, attention, sensory, and motor asymmetry, jitterinessPoor clarity of infant cues during feeding interactionDelayed information processingGeneral cognitive delay

Abstinence syndromeLess rhythmic swallowingStrabismusPossible delay in general cognitive functionAnxietyAggressionFeelings of rejectionDisruptive/inattentive behavior

MethamphetaminePoor movement quality (3rd trimester exposure)Low arousalIncreased lethargyIncreased physiologic stressNo mental or motor delay

*Effects may be subtle and transientSonnia Minnes. Addict Sci Clin Pract. 2011 July; 6(1): 57–70.

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

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

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

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


Clinical Presentation - NASGastrointestinal

DysfunctionPoor feedingUncoordinated and

constant suckingVomitingDiarrheaDehydrationPoor weight gain

Autonomic SignsIncreased sweatingNasal stuffinessFeverMottlingTemp instability


Clinical Presentation - NASNeurologic excitability

TremorsIrritabilityIncreased wakefulnessHigh-pitched cryingIncreased muscle tone

Hyperactive deep tendon reflexes

Exaggerated Moro reflex

SeizuresFrequent yawning and

sneezing

Diagnosis of NASA maternal history of substance abuse during

pregnancy often forms the basis for diagnosis of NASAAP recommends the use of an objective abstinence

scoring method to measure the severity of withdrawalAPP favors the Finnegan method for NAS scoring


NAS Scoring ToolsNeonatal Abstinence Scoring System (NASS) or Finnegan Scoring System (1975)

Modified Finnegan Lipsitz Tool (1975)Neonatal Withdrawal Inventory (1998)Ostrea CriteriaRiley Infant Pain Scale

Sarkar, J Perinatol 2006

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

Modified Finnegan’s Neonatal Abstinence Scoring Tool.

Hudak M L et al. Pediatrics 2012;129:e540-e560

©2012 by American Academy of Pediatrics

NAS Scoring ProtocolInitiate scoring within 2 hours of admission Infants should not be awakened to obtain a scoreInfants at risk of opiate withdrawal are assessed for

signs of withdrawal ½ to 1 hour after each feedThe scoring chart is designed for term infants who are

fed q 4 hoursAllowances must be made for infants who are

preterm

Non-Pharmacologic Interventions NAS

SwaddlingRockingMinimal sensory or environmental stimulationMaintain temperature stabilityFeedBreastfeeding

Pharmacologic Therapy NASParegoric – no longer recommendedDilute Tincture of Opium (DTO) – no longer

recommended Dilute Morphine Sulfate Oral solutionMethadoneBuprenorphinePhenobarbitalClonidine


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

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

http://pediatrics.aappublications.org/content/129/3/e827.full

http://www.gograph.com/x-gg56057984.html

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

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

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

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

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’


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


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

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

http://www.gograph.com/illustration/word-cloud-for-amphetamine-gg63264469.html

Pharmacologic Therapy NASDilute Morphine Sulfate Oral solutionMethadoneBuprenorphinePhenobarbitalClonidine


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

Pharmacologic Intervention NASMorphine or methadone are first-line opiatesClonidine is a first line or adjunctive therapy used in

combo with an opiate for poly-substance exposurePhenobarbital is adjunctive therapy used in combo

with an opiate for poly-substance exposurePoly-substance dependency is likely seen with

opiates as well as barbiturates, sedative, and SSRIs/SNRIs

Dilute Oral Morphine Solution0.4 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

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


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

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 dosingInitial dose: 0.05 mg-0.1 mg/kg/dose every 6 hoursIncrement dose: 0.05 mg/kg/doseMaximum dose: to effect


Buprenorphine Oral Suspension60 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

Phenobarbital oral solution20 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

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)

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

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


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

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

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

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

References1. 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.

References9. 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.

Intrauterine Drug Exposure and the Management of Neonatal Abstinence Syndrome

Evelyn Fulmore, Pharm.D.

McLeod Regional Medical Center Florence, SC

Health & Medicine

Intrauterine drug exposure and nas newest10 17 14