Substance Use and Substance Use Disorders in Pregnancy: Clinical - - PDF document

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Substance Use and Substance Use Disorders in Pregnancy: Clinical Considerations

Jaime Bastian, PharmD Assistant Professor Idaho State University

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Learning Objectives

• Understand the scope of the problem with substance use and

abuse disorders during pregnancy

• Identify the most commonly encountered substances used by

pregnant women and their effects on the fetus/neonate

• Assess the impact of recreational use of marijuana on fetal growth

and development

• Describe the identification and management of withdrawal in

pregnant women and newborns

• Determine appropriate breastfeeding recommendations for women

with substance use disorders (SUD)

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Substance Use and Substance Use Disorders in Pregnancy

• Substance Use Disorder (SUD):
• Recurrent use of substances that cause clinically significant

impairment + failure to meet major responsibilities

• 2014: 27M reported using drugs in last 30 days (10.2%)
• Lead by marijuana use and prescription pain meds
• Pregnant women: 123K reported using drugs in last 30 days

(5.3%)

• Use did not differ by race in latest survey
• Highest rates in younger women and in the 1st trimester
• Validated screening tools
• 4P’s and CRAFFT

NSDUH:2014; Jones, AJOG 2014; Chasnoff et al, J Perinatol 2007

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Type and Recency of Substance Use in Pregnant Women: 2013/2014 NSDUH Data

5 10 15 20 Cigarettes Alcohol Marijuana Pain Meds Tranquilizers % Pregnant Women Within past 30 days 30+ days - 12 months

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49.8%

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Type and Recency of Substance Use in Pregnant Women: 2013/2014 NSDUH Data

0.5 1 1.5 2 Inhalants Stimulants Heroin Cocaine Hallucinogens Sedatives % Pregnant Women Within past 30 days 30+ days - 12 months

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How Does Idaho Compare Nationally?

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NSDUH:2014

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Clinical Care of the Substance Using Pregnant Mother - Maternal and Fetal Considerations

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Limitations of Available Evidence

1. Concurrent use of multiple substances is common 2. Accurate determination of fetal exposure is difficult 3. Many substance-using women are economically disadvantaged

• Poor maternal nutrition, hygiene, and prenatal visit attendance - ALL have

adverse perinatal effects!

4. Small population sizes & unblinded evaluations of drug- exposed newborns may bias associations

• Most evidence is “suspected” and not truly “causal”
• Lack of uniformity in defects and failure to use pregnant controls

5. Except alcohol, a birth defect syndrome has not been described for any illicit substances or prescription drugs of abuse

• Risk of stillbirth and/or miscarriage increases from use of any drug

6. Altered fetal behaviors: insidious, variable, hard to recognize

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Holbrook and Rayburn, 2014

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Tobacco Use and Dependency

• Nicotine concentrations are higher in fetal compartment
• ~30 compounds associated with adverse outcomes cross placenta
• Etiology of the adverse effects are not well understood
• Hypoxia, undernourishment, vasoconstriction
• PTB, placenta previa, placental abruptio, possible reduced risk for pre-

eclampsia*

• Identified as a preventable risk factor for LBW and IUGR for >50

years

• Decreased birthweight has some indication of dose-effect relationship
• By 24 mos, somatic growth differences disappear
• No “convincing” studies of neonatal nicotine withdrawal
• Abnormal newborn behavior more consistent with drug toxicity than with drug

withdrawal

• Impaired orientation and autonomic regulation plus abnormalities of muscle tone
• Higher neonatal irritability scores, increased need for handling to quiet newborn

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Behnke et al, Pediatrics 2013; Stroud et al, Pediatrics 2009; Rayburn, Clin Perinatol 2007

Clinical Care of Tobacco Dependency in Pregnancy

• Quitting <15wks = greatest benefit
• <28wks = eliminates much of the reduction in birth weight
• 50-60% women who quit smoking in pregnancy return to smoking within 1

year postpartum

• Smoking Cessation Interventions
• Counseling - including twice weekly phone calls during pregnancy and monthly calls

after delivery +/- contingency management (i.e. financial incentives)

• 5 A’s Motivational Interviewing - Ask, Advise, Assess, Assist, Arrange
• Nicotine replacement products - Conflicting evidence of increased rates of

abstinence in pregnant smokers yet often used in-patient

• Bupropion - Limited efficacy data, no risk of fetal anomalies/adverse pregnancy

effects

• Varenicline - No data on safety or efficacy during pregnancy
• Lack of information regarding vapes or e-cig use in pregnancy

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ACOG Committee opinion no. 471, 2010

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Alcohol Use and Dependency

• >50% women smoking in the 1st trimester also drink
• >50% women using illicit drugs during pregnancy also report smoking, drinking or

both

• Alcohol (EtOH) crosses placenta easily, with significant concentrations

in amniotic fluid and fetal blood

• Alters prostaglandin/protein synthesis; hormones; neurotransmitter levels in the

brain; brain morphology; neuronal development; hypoxia due to decreased placental blood flow and altered vascular tone

• Fetal Alcohol Spectrum Disorders
• One of most common, preventable causes of developmental and intellectual

disabilities in US

• Combination of physical, neurological, behavior and learning problems
• Includes: Partial FAS (PFAS), Alcohol-related Birth Defects (ARBD), Alcohol-related

Neurodevelopmental Disorder (ARND)*, and Neurodevelopmental Disorder Associated with Prenatal Alcohol Exposure (ND-PAE)*

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Cornelius and Day, Alcohol Research 2000; Behnke et al, Pediatrics 2013; Senturias and Asamoah, 2014

Clinical Care of Alcohol Dependency in Pregnancy

• Infants with FASDs characterized by poor suck and irritability
• Benefit from nutritional support and decreased environmental stimulation
• Poor self-soothing is most common presenting symptom
• No known “safe” amount or timing of alcohol in pregnancy
• Assess use on monthly basis
• Increase awareness of risks associated with alcohol use in pregnancy
• Introduce harm-reduction strategies for women that continue to drink
• Identification of risky drinking behavior with T-ACE screen
• Tolerance - Annoyance, Cut-Down, Eye-Opener
• Pharmacotherapy for Alcohol Withdrawal in Pregnancy
• Thiamine: 100 mg orally once daily for 3 days + folic acid 5 mg orally once

daily

• Diazepam: 20 mg orally every 1-2 hours until symptoms subside
• Lorazepam: 2-4 mg sublingually or orally every 1-2 hours as needed during

labor

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Wong S et al, 2011; Carson G et al, 2010

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Marijuana Use and Dependency

• One of most widely used psychoactive drugs in the world,

following tobacco and alcohol

• Accepted as relatively harmless recreational agent
• 85 cannabinoids have been identified
• Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) most abundant
• THC = only cannabinoid with psychoactive properties
• Endocannabinoids (naturally occurring) regulate movement,

memory, appetite, body temperature, pain and immunity

• 5 cannabinoid receptors identified
• CB1 (CNS) is involved in critical neurodevelopmental events
• Present in all layers of the placenta
• Stimulation may impair fetal growth by inhibiting cytotrophoblastic proliferation
• Small, lipophilic molecules (i.e. THC) readily cross BBB and

placenta

• THC levels 3-6x lower in cord blood vs maternal blood

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Jaques SC et al, J Perinatol 2014

Clinical Care of Marijuana Dependency in Pregnancy

• Evidence of fetal effects controversial
• Lack of human studies or ambiguous outcomes
• Largest study (France) found marijuana use increased risk for PTB and

SGA for ≥ once/month users compared to no use

• Analysis could not distinguish effect of tobacco smoking from cannabis smoking
• 5yr record linkage data demonstrated concurrent cannabis use with other

substance use, prompting investigation for SUD in these women

• 12% concurrently used opioids and 10% concurrently used stimulants
• 4% identified as having an alcohol-related diagnosis
• 50% reported smoking >10 cigarettes per day
• Neurobehavioral disturbances in newborns have been noted
• Exaggerated/prolonged startle reflex; increased hand-mouth behavior; high pitched

cries; sleep cycle disturbances; increased incidence of SIDS

• Little evidence that prenatal exposure affects behavior or cognition in infancy

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Saurel-Cubizolles MJ et al, BJOG 2014; Burns L et al, Addiction 2006; Huizink AC, 2013

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Past Month Marijuana, Cigarette or Alcohol Use

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Warner TD et al, Clin Perinatol 2014

After childbirth, use rebounds quickly!

Stimulant Use and Dependency: Caffeine

• Quantifying Caffeine -
• ften underestimated!
• Coffee
• Starbucks Venti Coffee:

415mg

• Panera Coffee: 189mg
• Tea
• Tazo Awake: 135mg
• Green Tea: 30-50mg
• Soda
• FDA official limit for soft drinks:

71mg

• Energy Drinks
• 5 Hour Energy: 208mg
• Monster/Rockstar: 160mg
• Caffeine metabolized by

CYP1A2

• AHR gene regulates CYP1A2

expression

• CYP1A2 activity is decreased

65% in pregnancy

• Half-life of caffeine in

pregnancy: 8.3h v 3.4h (adults)

• 2011 GWAS study
• Polymorphisms in AHR and

CYP1A2 genes associated with habitual caffeine intake

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Juliano and Griffiths, 2005; Cornelis MC et al, PLoS Genet 2011

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Clinical Care of Caffeine Dependency in Pregnancy

• Risks of miscarriage, stillbirth, PTB or SGA
• ACOG: moderate (<200mg/d) is not a risk for miscarriage or

PTB

• BMC Meta-Analysis: Each 100mg/d increment in maternal

intake (>150mg/d) associated with 13% increased risk for low birth weight

• Eur J Epi Meta-Analysis: Greater intake (>150mg/d) associated

with increased spontaneous abortion, stillbirth, low birth weight, SGA but not PTB

• Faster caffeine metabolism in the 2nd trimester

associated with reduced risk of subsequent severe pre- E

• Genetic polymorphisms in CYP1A2 may predispose women w/o
• ther risk factors beyond pregnancy induced metabolic changes 17

ACOG Committee Opinion 462; Chen LW et al, BMC Med 2014; Greenwood DC et al, Eur J Epi 2014; Eichelberger KY et al, Obstet Gyn 2014

Stimulant Use and Dependency: Cocaine

• Prenatal cocaine exposure
• Increases risk of placental abruptio
• Increases likelihood of PTB and generalized growth retardation
• Slower growth rates among exposed children through age 10
• Cocaine exposed infants have increased risk of:
• Tremors/jitters; irritability; excessive suck; hyperalertness; autonomic

instability; infections (hepatitis, syphillis, HIV exposure)

• Higher incidence of NEC
• Usually transient - acute cocaine/withdrawal effect??
• ANS/CNS effects additive if fetus exposed to opioids and/or nicotine
• Conflicting evidence concerning language and memory

effects during childhood, as well as behavior and attention problems

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Lambert and Bauer, J Perinatol 2012; Bauer CR et al, Arch Ped Adol Med 2005; Bada HS et al, 2002

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Clinical Care of Cocaine Dependency in Pregnancy

• No pharmacological intervention shown to be effective
• Possible role for opioid maintenance treatments for co-occurring cocaine and
• pioid dependency
• Interventions based on symptomatic relief only
• Some evidence of efficacy with contingency based (voucher)

incentives

• Combined with CBT, can reinforce abstinence and increase compliance with

prenatal care

• Home visits not shown to increase maternal or infant outcomes
• High loss to followup + other barriers prevent continued utility in treatment

programs

• Promising new pharmacotherapy
• Cocaine Hydrolases
• Possible Q2-4 week dosing regimen
• Accelerates cocaine metabolism to efficiently detox and inactivate cocaine without affecting

normal CNS function (preclinical data)

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Minnes S et al, 2011; Chen X et al, Proc Natl Acad Sci 2016; Butcher RE et al, J Pharmacol Exp Ther 2016

Stimulant Use and Dependency: Methamphetamines

• Increasing rates of hospitalization d/t amphetamine abuse

during pregnancy

• 50% increase in hospitalizations
• 82% hospitalizations concentrated in Western US
• 44% decrease in hospitalizations related to cocaine abuse
• More commonly associated with maternal vasoconstrictive disorders

compared with cocaine abuse

• Cocaine abuse more commonly associated with dx related to infant

mortality compared to amphetamines

• Increased risk of adverse pregnancy and neonatal
• utcomes
• Higher incidence neonatal mortality, low birthweight, PTB, Cx

delivery

• Higher rates of 1m Apgar <4 and 5m Apgar <7
• Higher rates of poor movement quality, decreased arousal,

increased stress

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Good MM et al, Obstet Gynecol 2010; Cox S et al, Obstet Gynecol 2008; Ladhani NN et al, AJOG 2011

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Opioid Use and Dependency

• Heroin vs pain narcotics
• Almost all studies include heroin or agonist maintenance treatments,

few examine use of pain narcotics

• Early vs Late use of any opioids in pregnancy (Medicaid

data)

• Long-term use = higher absolute risk NAS with additional risk factors

(absolute NAS risk/1000 births)

• Opioid misuse (220); polysubstance use (31); psychotropic meds (2); smoking (1.5)
• No risk factors (4.2)
• Late in pregnancy use = higher absolute risk NAS
• Late (7.8) v Early (4.2) use
• Prenatal opioid exposure
• Decreased birthweight, length and head circumference
• Increased risk PTB, stillbirth, SIDS, IUGR

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Patrick SW et al, JAMA 2012; Desai RJ et al, BMJ 2015

Clinical Care of Opioid Dependency in Pregnancy

• Methadone
• Gold Standard (1970s)
• Full mu agonist
• Doses range from 60-300mg/d, potential benefit if divided doses
• Higher incidence of NAS, especially seizures, compared to

buprenorphine and heroin

• Breastfeeding on methadone seems to assuage NAS symptoms
• Buprenorphine
• Available treatment option since 2002 with special licensure
• Less severe (mild) NAS with delayed onset (2-3 days post-delivery)
• Doses range from 2-32mg/d, often in divided doses
• Has potential to precipitate withdrawal (partial mu agonist/full kappa

antagonist, possible delta/sigmoid activity)

• Ceiling effect on adverse effects d/t partial mu agonism

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Neonatal Abstinence Syndrome (NAS)

• Prevalence + Incidence data
• Antepartum opioid use
• Increased from 1.19/1000 births (2000) to 5.63/1000 births (2009)
• NAS incidence
• Increased from 1.2 infants/1000 births (2000) to 3.39/1000 births

(2009)

• Using EMR and insurance claim data: NAS absolute risk 5.9/1000

births

• NAS signs/symptoms
• Abnormally high muscle tone/rigidity; inconsolable; irritability;

sneezing; stuffiness; excessive sucking; poor sucking ability; high-pitched cry (louder if exposed to cocaine also)

• Seizures + myoclonic jerks occur in 2-10% NAS infants

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Patrick SW et al, JAMA 2012; Desai RJ et al, BMJ 2015

NAS Treatment Interventions

• NAS treatments
• Supportive care may include
• Decreasing sensory stimulation
• Nutrition to promote adequate growth; Breastmilk associated with reduced severity
• f NAS
• Prone positioning may reduce severity of NAS, but associated with decreased

caloric intake

• Medications only needed if clinical distress or high withdrawal severity

scores

• Opioids generally recommended, including tincture of opium, morphine, or

methadone

• Opiates may reduce time to regain birth weight and duration of supportive care, but

increase duration of hospital stay

• Sublingual buprenorphine may be associated with shorter hospital stay than oral

morphine in term infants

• Sedatives are not preferred initial treatment
• Addition of clonidine to opium decreases duration of therapy by 27%
• Naloxone (Narcan) has insufficient data regarding efficacy and safety
• No studies evaluating rate at which withdrawal medication should be weaned

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Oei J and Lui K, 2007; Kuschel C, 2007; Hudak ML et al, Peds 2012

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Breastfeeding Considerations for Women with SUD

• Drug-exposed infants stand to benefit significantly from

breastfeeding

• Most illicit drugs are found in breastmilk with varying degrees of
• ral bioavailability
• PCP and cocaine have been found in high concentrations in breastmilk

leading to infant intoxication

• Methadone concentrations in breastmilk are low, encourage to

breastfeed regardless of maternal dose

• Lack of healthcare support + misinformation are significant, modifiable barriers
• Alcohol transfers easily, advise to wait 90-120m before breastfeeding
• r pump and dump during that period
• Use caution recommending breastfeeding in chronic marijuana users
• Smoking appears independent risk factor for non-initiation and

early cessation, encourage NRT (compatible with breastfeeding)

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Reece-Stremtan S et al, Breastfeed Med 2015

Summary on Perinatal Substance Use

• Substance use may effect the fetus directly or indirectly
• Passage through the placenta vs poor maternal health habits/environmental conditions
• Symptoms/disorders associated with prenatal exposure may not present

until adolescence or early adulthood

• Epidemiology studies confounded by multiple covariates, few prospective studies
• Pregnancy, itself, presents motivation for cessation
• Interventions must concentrate on cessation, and not abstinence, to have long-lasting

effects

• Screening tools should be used multiple times per pregnancy as rapport develops between patient

and provider

• Follow-up should continue into the postpartum period
• Idaho does NOT have state laws regarding mandatory reporting
• 17 States consider substance use during pregnancy as child abuse
• 3 States consider substance use as grounds for involuntary commitment to a mental

health or substance use treatment facility

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References

• Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from

the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). Retrieved from http://www.samhsa.gov/data/

• Jones et al. Clinical care for opioid-using pregnant and postpartum women: the role of obstetric providers. AJOG 2014

Apr;210(4):302-10

• Chasnoff IJ et al. Validation of the 4Ps Plus screen for substance use in pregnancy. J Perinatol 2007;27
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Jun;41(2):229-39

• Behnke M et al. Prenatal substance abuse: short- and long-term effects on exposed fetus. Pediatrics 2013

Mar;131(3)e1009-24

• Stroud LR et al. Maternal smoking during pregnancy and neonatal behavior: a large-scale community study. Pediatrics

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References

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• Cornelis MC et al. Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of

habitual caffeine consumption. PLoS Genet. 2011 Apr;7(4):e1002033

• ACOG Committee Opinion 462: Moderate caffeine consumption during pregnancy. Obstet Gynecol. 2010 Aug;116(2 Pt

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• Chen LW et al. Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review

and dose-response meta-analysis. BMC Med. 2014 Sep 19;12:174

• Greenwood DC et al. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-

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• Eicrhelberger KY et al. Second-Trimester Maternal Serum Paraxanthine, CYP1A2 Activity, and the Risk of Severe
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834

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