intrauterine drug exposure and the management of neonatal abstinence syndrome
TRANSCRIPT
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 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
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
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
Drug Transfer Across the Placenta Transfer occurs
passive diffusion protein transport
Transfer dependent Molecular size (<500) pH Protein binding Lipid solubility
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
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
Drugs/Substances assoc with NAS Alcohol Antidepressants - 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
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
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
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
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
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
Clinical Presentation - NASGastrointestinal
DysfunctionPoor feedingUncoordinated and
constant suckingVomitingDiarrheaDehydrationPoor weight gain
Autonomic SignsIncreased sweatingNasal stuffinessFeverMottlingTemp instability
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
Clinical Presentation - NASNeurologic excitability
TremorsIrritabilityIncreased wakefulnessHigh-pitched cryingIncreased muscle tone
Hyperactive deep tendon reflexes
Exaggerated Moro reflex
SeizuresFrequent yawning and
sneezing
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
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
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
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
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
APP Neonatal Drug Withdrawal. Pediatrics, 2012; 129 (2): e540-e560
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
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
Buprenorphine Effects on FetusCrosses the placentaLess frequent NASSymptoms of NAS may
be less severeFetal risk not greater
than methadoneCompatible with
breastfeeding
Jones HE, Finnegan LP, and Kaltebach K. Drugs 2012;72(6):747-757
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
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
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.
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
Time Course of NAS Symptoms over 16 days following birth
Annemarie Unger, et al. Addiction. 2011 July;106(7):1355-1362
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
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 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
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
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
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) 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
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
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.
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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,
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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.
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