Impact of Marijuana on Pregnancy, the Fetus and NeonateMargaret Lynn Yonekura, M.D., FACOGDirector, Community HealthDignity Health California Hospital Medical CenterNovember 6, 2018
Learning ObjectivesAt the end of this lecture, participants will be able to:
Describe the types of cannabinoids and how they work
Discuss the prevalence and trends of cannabis use in the U.S.
Describe what is known about the short- and long-term health effects and social consequences of cannabis use
Discuss the prevalence and impact of cannabis use during pregnancy
CannabinoidsThree forms of cannabinoids: phyto (plant), endo (within) and synthetic (manufactured)
There are >100 unique phytocannabinoids in the Cannabis sativa plant along with terpenes (entourage/ensemble effects) and more than 500 other chemicals when combusted
The most abundant is the psychoactive THC; the second most abundant & most medically promising for conditions such as epilepsy is cannabidiol (CBD) which is not psychoactive, has no abuse potential and may even possess anti-addictive properties.
How Cannabis Works
Endocannabinoids(Brain Derived)
Phytocannabinoids(Plant Derived)
Synthetic Cannabinoids(Made in Lab)
Endocannabinoid Receptors: CB1 & CB2
The endocannabinoid system (ECS) is involved in regulating a variety of physiological processes including appetite, pain and pleasure sensation, immune system, mood and memory
Cannabinoid Receptors Are Also Located Throughout the Body
Terry et al., Eur J Nucl Med Mol Imaging, 2010 Ahmad et al., Mol Imaging Biol 2013
Endocannabinoids are produced on demand. They travel back to the transmitting neuron to dampen further activity.
EndocannabinoidsAnandamide is a partial agonist of CB1. 2-AG is a full agonist of both CB1 and CB2 receptors.
Plant-derived cannabinoidTHC is a partial agonist of CB1 receptors
What is marijuana/cannabis?
Dried flowering heads of the Cannabis sativa or indica plant cross breeds
Known as: marijuana (in US legislation), cannabis, pot, weed, ganja, dank, 420, grass, dope, bhang
Potency of principal psychoactive cannabinoid delta 9 tetrahydrocannabinol (THC) is generally higher than ever before (15-25%) and greatly differs by preparation technique with levels of cannabidiol (CBD) almost bred out of most strains
What is hashish?Hashish is cannabis resin, an extracted cannabis product composed of compressed or purified preparations of stalked resin glands, called trichomes.
More resin than herb consumed in Europe
Typically smoked in a pipe, bong, vaporizer, or joints where it is normally mixed with cannabis or tobacco, as pure hashish will burn poorly if burned alone.
THC content of hashish ranges from 1-65%
Trichomes on Cannabis, rich in cannabinoids
“Bubble melt” Cannabis indicahashish
Pressed hashish
Standard hashish from Morocco
Synthetic CannabinoidsFirst developed in 1980s by chemistry professor John Huffman to enhance understanding of the cannabinoid system (JWH-018)
First emerged in Europe in 2005 & then in U.S. in 2009
Known as: Spice, K2, fake weed, Yucatan fire, skunk, moon rocks, Black Mamba, crazy clown, Kronic, Kush, Joker
The synthetic cannabinoids are either sprayed on dried, shredded plant material so they can be smoked (herbal incense) or sold as liquids (liquid incense) to be vaporized and inhaled in e-cigarettes or other devices.
Plant matter itself can potentially be poisonous or hallucinogenic
Laced with flavors, rat poison, embalming fluids
Outbreak of Synthetic Cannabinoid-Associated Coagulopathy in IL
In March-April 2018, >150 pts presented to hospitals in IL with coagulopathy & bleeding diathesis.Brodifacoum, an anticoagulant, was the likely adulterant; effects last 2-12 months. 4 deaths due to ICH.
March 28-April 21, 2018, 34 pts presented to St. Francis Medical Center in Peoria, IL during 45 hospitalizations.Anticoagulant tests done on 15/34: brodifacoum (100%); difenacoum(33%), bromadiolone (13%) & warfarin (7%). One pt died from ICH. Median age 37; 71% male; 94% white. 47% daily users; 12% first-time users.
N Engl J Med 2018;379:1216-1223
Synthetic CannabinoidsHow used: 80% inhalation by smoking, 20% ingestion by eating or drinking as tea
Marketed legally as “not for human consumption”Sold in gas stations, truck stops, and online
7 main structural groups of synthetic cannabinoids
Many synthetic cannabinoids, e.g., JWH-018, are full and potent CB1 agonists and have a 4-fold higher affinity for CB1R and 10-fold higher affinity for CB2R, accounting for the higher prevalence of adverse reactions and toxicity
Synthetic Cannabinoids
Major Adverse Rxns:
• Heart attack
• Ischemic stroke
• Acute kidney injury
• Generalized tonic-clonic seizures
• Rhabdomyolysis
• Cannabinoid-induced hyperemesis synd.
• Death• Prolonged QTc
interval
Not detected on standard blood or urine tox screens
Cannabis: Most Commonly Used “Illicit” Drug in the U.S.
Over 22 million Americans 12 and older were past month marijuana users
Approximately 4.0 million Americans met criteria for cannabis use disorders in 2015
An estimated 2.6 million Americans used it for the first time; 1.2 million were between the ages of 12 and 17
2016 National Survey on Drug Use and Health, SAMHSA
Past Month Use Rates by Demographic,U.S., 2016
Demographic Past-Month Use Rate (%)
EthnicityWhite, non-HispanicAfrican-AmericanHispanic Asian, non-Hispanic
8.410.77.23.0
GenderMaleFemale
10.66.2
Education< HSHS graduateSome collegeCollege graduate
8.29.1
10.55.9
Family income< $10 k$20 k - $29.9 k$50 k - $74.9 k$75 k +
13.69.77.86.6
Age12-1718-2526-3435-4950+
7.120.113.07.13.9
Marijuana Use in Past Month & Perceived Risk of Great Harm from Use Among People Aged 12 or Older, Los Angeles County, 2012-2014
Marijuana use in past monthPerceived great risk of harm from smoking marijuana once a month
SPA1 & 5 = 9.77%2 = 8.03%3 = 6.18%4 = 10.50%6 = 10.62%7 = 7.00%8 = 9.01%
SPA1 & 5 = 21.44%2=25.49%3=34.66%4=30.18%6=32.00%7=35.10%8=27.35%
Dabbing
Dabs are concentrated, wax-like doses of cannabis made using a solvent like butane or carbon dioxide
Popular because they can contain up to 90% THC
Dabs are sometimes called butane honey oil, budder, shatter or wax. Dabs are usually smoked using a water pipe (bong)
Dabs are often placed onto a glass surface heated with blowtorch. The resulting smoke is inhaled.
Trends in Routes of Administration
In WA, an online survey of daily/near-daily users found that 27.5% used edibles, 22.8% used hash resin, and 20.4% “dabbed” in past week.
In CO’s recreational market, herbal cannabis accounts for 56% of sales and sales of solid concentrates (24%) and edibles(13%) are on the rise.
In WA, CO, and CA, a “standard dose” of THC is defined as 10 mg; in OR, it’s 5 mg.
Rising Marijuana Use in Colorado Post Legalization (2013)
Rocky Mountain HIDTA Report www.rmhidta.orgSupplement: The Legalization of Marijuana in CO: The Impact, Volume 4 (March 2017)
Average Δ9-THC Concentration of DEA Specimens by Year
Biol Psychiatry 2016; 79:613-619Potency of cannabis judged based on THC content of preparationPotency > 15% considered to represent “hard drug” in Holland
CBD Concentration Distribution in Cannabis Samples Confiscated by DEA and Average CBD
Biol Psychiatry 2016; 79:613-619
Cannabidiols lessen the psychoactive effects of THC. This means that a plant with a greater percentage of CBD has a lower potency.
Ratio of the Average Concentration of THC to CBD in DEA Specimens by Year, 1995-2014
Biol Psychiatry 2016;79:613-619
CBD has been almost bred out of cannabis strains
Distribution of THC in the body.
C. HEATHER ASHTON BJP 2001;178:101-106
©2001 by The Royal College of Psychiatrists
Clinical Pharmacokinetics of Cannabis
Inhaled Ingested
Absorption 10-20% 1-10%
Onset of action 6-12 min 30-120 min
Peak effect 20-30 min 2-3 hr
Duration of effect 1-3.5 hr 5-8 hr or more
Toxic dose (THC) 15 mg/kg
Lethal dose (THC) 30 mg/kg
Half-life 28 hr (56 hr chronic use)
Smoked 34 mg
Ingested 15 mg
Cannabis’ Acute Effects (Intoxication Phase)Euphoria
Calmness
Appetite stimulation
Altered perception of time
Heightened sensation
Impaired coordination and balance
Red eyes, dry mouth
Increased heart rate: 20-100%Some evidence of increased risk of heart attack, may be exacerbated in vulnerable individuals (e.g., baby boomers?)
Orthostatic hypotension initially; then increased BPRisk for ischemic stroke
Increased risk of accidents (~2 fold), higher when combined with alcohol JAMA 2014;370:23
Driving Related ImpairmentsCannabis-related impairments detected in a range of skills used in driving:
Tracking
Reaction time
Short-term memory
Hand-eye coordination
Time and distance perception
Decision making
Concentration
Selective and divided attention
Time estimation
Executive function
Size of impairment dose-related
Impairments for 4+ hours Wait 6 hr after inhaling and 8 hr after ingesting
Cannabis Use and Overdose Injuries or Deaths
Moderate evidence of a statistical association between unintentional cannabis ingestion and increased risk of overdose injuries including respiratory distress/failure and temporary coma, among pediatric populations in U.S. states where cannabis is legal. (edibles)
Insufficient evidence to support or refute a statistical association between cannabis use and death due to cannabis overdose.
CO law states that a single-serving edible cannabis product should contain no more than 10 mg of THC; however, currently available edible products, such as cookies or brownies, may contain as much as 100 mg of THC.
Case report of teenager who died after jumping from fourth floor balcony after ingesting a cookie containing 65 mg of THC.
http://www.nap.edu/24625
Unintentional Cannabis Intoxication in Toddlers, France, 2004-2014
In France, cannabis consumption is illegal.A retrospective, national, multicenter, observational study of all children <6 yr (N=235) admitted to tertiary-level pediatric ED for proven cannabis intoxication. 71% were < 18 mo old. Hashish resin was the main form ingested (72%).
Pediatrics 2017; 140:1-10
MML
Rocky Mountain HIDTA Report www.rmhidta.org Supplement: The Legalization of Marijuana in CO: The Impact, Volume 4 (March 2017)
Cannabis’ Acute Effects (Intoxication Phase)
CognitionImpaired short-term memory
Difficulty with complex tasks
Difficulty learning
Executive functionImpaired decision-making
Increased risky behavior – STDs, HIV?
Mood (especially after high doses or edibles)Anxiety – panic attacks
Psychosis - paranoia
Myth: You can’t become addicted to cannabis
~9% of cannabis users become dependent1 in 6 (17%) who start in adolescence
25-50% of daily users
Cannabis Use Disorder
A pattern of cannabis use leading to clinically significant impairment or distress that typically includes (DSM-5):
Difficulty controlling or cutting down
Craving
Using more than intended
Spending a lot of time on cannabis related activities
Giving up or reducing activities in favor of cannabis
Continuing to use despite physical/psychological problems
Using in high risk situations
Problems at work, school, and home related to use
Tolerance
Withdrawal syndrome upon cessation
Cannabis Use Disorder
Men Women
Similarities
At least one other mental health disorderLow rate of seeking treatment
Differences
Other substance use disorders Panic attacks
Antisocial personality disorder Anxiety disorders
Severity of disorder Disorder develops more quickly after first marijuana use
Effects of Long-Term or Heavy UseAddiction
Altered brain development*, teenage girls > boys
Poor educational outcome, with increased likelihood of dropping out of school*
Cognitive impairment, with lower IQ among those who were frequent users during adolescence*
Diminished life satisfaction and achievement
Symptoms of chronic bronchitis
Increased risk of chronic psychosis disorders (including schizophrenia) in persons with a predisposition to such disorders
* The effect is strongly associated with initial marijuana use early in adolescence
JAMA 2014;370:23
Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users
Regular exposure to cannabis associated with neuroanatomic alterations in regions high in cannabinoid receptors: hippocampus (reduced volumes and gray matter density, altered shape), followed by amygdala & striatum, prefrontal cortex, and cerebellum
Biological Psychiatry 2016; 79:e17-e31
Adjusted Prevalence of Marijuana Use Among 279,457 Pregnant Women in KPNC, 2009-2016
JAMA 2017; 318:2490
Universal screening for marijuana use done at ~8 wk GA
Association of Nausea & Vomiting in Pregnancy with Prenatal Marijuana Use
Using data from KPNC universal screening study at 8 wk GA, 2009-2016
NVP Category % Participants(N=220,510)
Marijuana UseaOR
p value
None 82.4% 1 NA
Mild 15.3% 2.37 <.001
Severe 2.3% 3.80 <.001
Adjusted for: age, race/ethnicity, median neighborhood household income, year, & self-reported marijuana use in the year before pregnancy
JAMA Internal Med 2018:178:
Why the Concern about Cannabis Use and Pregnancy?
THC 99% protein bound, lipid soluble, MW 314
THC crosses the placenta and BBB
THC highly lipophilic; rapidly distributed to fetal brain and fat
Concentration of THC in fetal blood ~1/3-1/10 of maternal conc.
Slow elimination prolonged fetal exposure
The fetal brain is densely populated with CB1 receptors that increase throughout gestation
Endocannabinoids play roles in a broad array of critical neurodevelopmental processes, from early neural stem cell survival and proliferation to the migration and differentiation of both glial and neuronal lineages as well as neuronal connectivity and synaptic function
Cannabis use could modify neurotransmitters (serotonin, dopamine, GABA), alter neuronal growth, maturation, and differentiation, and cause structural or functional abnormalities
BBB = blood-brain barrier
How Cannabinoids Affect Implantation
Impairment of fallopian tube motilityEctopic pregnancy
Non-hatched or non-viable embryo
Decreased uterine receptivity: embryotoxiceffects on uterine environment
Miscarriage (spontaneous abortion)Folic acid (vitamin B9) essential for embryo development and cannot be synthesized by body
THC significantly decreases fetal folic acid uptake SAb, NTDs, and LBW
BMC Pharmacology & Toxicology 2016;17:45Reproduction 2016;152: R191-R200
How Cannabinoids Affect Embryo DevelopmentTHC crosses placenta, enters fetal circulation, passes through blood-brain barrier and is concentrated in fetal fat.
The fetal brain is 60% fat; stores THC
Brain densely populated with CB1 receptors that mediate THC’s psychoactive properties
THC interferes with fetal folic acid uptake NTDs & LBW
THC interferes with critical pathways for cellular growth & angiogenesis
THC interferes with early neural stem cell survival & proliferation, migration & differentiation of both glial and neuronal lineages, as well as neuronal connectivity & synaptic function BMC Pharmacology & Toxicology 2016;17:45
Reproduction 2016;152: R191-R200
Fetal Cannabinoid Receptors and the “dis-joint-ed” brain
Microtubule turnover in the growing axon is required for directional axonal growth and synapse formation in the developing brain
The microtubule-binding protein SCG10/stathmin-2 is a specific molecular target for a CB1 receptor-mediated effect of THC in the fetal brain.
Considering the role of CB1 in modulating the specification and long distance migration of neurons in the perinatal brain, this study reveals an interesting mechanism potentially accounting for connectivity deficits during cortical development following exposure to THC during pregnancy
The EMBO Journal 2014; 33:665
Cannabis and Stillbirth
Cannabis use associated with stillbirth (pooled OR 1.74, 95% CI 1.03-2.93) but not perinatal death (pooled RR 1.09, 95% CI 0.62-1.91)
NICHHD Stillbirth Collaborative Research Network included 1,468 women with umbilical cord specimens
3.9% of SB and 1.7% of LB with cord homogenate positive for THC metabolites
Cannabis use associated with SB (OR 2.34, 95% CI 1.13-4.81); persisted after adjustment for tobacco use
Obstet Gynecol 2016; 128:713-23; Obstet Gynecol 2014; 123:113-25
Cannabis and Congenital AnomaliesTwo prospective studies of cannabis use and congenital anomalies
Linn et al (1983) 12,424 women, 10% used cannabis; no association with major congenital anomalies (OR 1.36; 95% CI 0.97-1.91)
Gibson et al (1983) 7301 women, 5% used cannabis; no association with congenital anomalies
Old studies when THC potency much lower
van Gelder et al (2009) found higher rate of anencephaly in fetuses of women who smoked marijuana immediately before & during first trimester; didn’t control for supplemental folic acid intake.
Epidemiology 2009;20: 60-66
Cannabis and Low Birth WeightRecent meta-analyses demonstrate an association between cannabis use and LBW
Conner et al only observed this association with heavy cannabis use
Cross-sectional study of 3,207 respondents from PRAMS with state-developed questions on cannabis use during perinatal period, CO, 2014-2015 demonstrated an association between cannabis use and LBW (OR 1.8, 95% CI 1.3-2.4, p=.0008); persisted when controlled for tobacco use
Generation R study evaluated fetal growth prospectively; demonstrated a relative “dose-response” effect of cannabis on fetal growth
Fetuses exposed to cannabis in early pregnancy grew 11.2 g (-15.3 to -7.1) per week less than those not exposed
Those with ongoing exposure grew 14.4 g (-22.9 to -5.9) per week less than those not exposed
Obstet Gynecol 2016; 128:713-23; BMJ Open 2016;6:e009986; J Pediatr 2018; 197:90-6J Am Acad Child Adolesc Psychiatry 2009; 48:1173-81
Cannabis and Preterm BirthConner et al found an association between moderate to heavy (at least once/wk) marijuana use and PTB
In an observational study of nulliparous women (N=3,184), those that regularly used cannabis pre-pregnancy had increased odds of sPTB with intact membranes (aOR 2.34, 95% CI 1.22-4.52)
Some studies find increased risk of PTB with cannabis use compared to nonusers that is no longer significant when control for tobacco use
Leemaqz et al found an increased risk of sPTB after adjustment for tobacco exposure (aOR 2.28, 95% CI 1.45-3.59)
Obstet Gyncol 2016; 128:713-23; PloS One 2012; 7:e39154; BJOG 2014; 121:971-7; Reprod Toxicol 2016; 62:77-86
Impact on Pregnancy, Fetal Development and Birth Outcomes (cont’d)
In a prospective cohort of 5588 nulliparous women from international Screening fOr Pregnancy Endpoints (SCOPE) study, continued maternal marijuana use at 20 wk GA was associated with sPTB [aOR 5.44 (95%CI 2.44-12.11)] when adjusted for maternal age, cigarette smoking, alcohol, and SES.
~90% Caucasians in this cohort
Of the women who continued to use marijuana at 20 wk and delivered preterm, nearly 64% delivered at <32 wk GA and 36.4% at <28wk.
Reproductive Toxicology 2016; 62:77
Maternal Cannabis Use and Other Associations
Two recent systematic reviews and meta-analyses
Gunn et al identified 6,854 articles, fully screened 881, and included 24
Association with anemia (pooled OR 1.36, 95% CI 1.10-1.69)
Association with LBW (pooled OR 1.77, 95% CI 1.04-3.01)
Higher odds of NICU admission (pooled OR 2.02, 95% cI1.27-3.21)
Conner et al identified 4,875 studies and included 31Moderate to heavy cannabis use (at least once/wk) associated with both LBW (RR 1.90, 95% CI 1.44-2.45) and PTB (RR 2.04, 95% CI 1.32-3.17)
BMJ Open 2016; 6:e009986Obstet Gynecol 2016; 128:713-23
Impact of Maternal Cannabis Use on Immediate Newborn Behaviors
Altered arousal patterns, regulation, and excitability, as measured by NICU Network Neurobehavioral Scale
Increased tremors & prolonged and exaggerated startle reflexes, as measured by Neonatal Behavioral Scale –observed in first week and persisted at 9 & 30 days of life (OPPS)
Poor habituation & responses to visual but not auditory stimuli, abnormal high-pitched cries, & abnormal sleep patterns with decreased quiet sleep & increased sleep motility in first wk of life
No data supports a clinical withdrawal syndrome from marijuana exposure J Pediatr 2006; 149:781-7; J Dev Behav Pediatr 1987; 8:318-326; Pediatr Res 1988; 24:101-5
Impact of Cannabis Use During Pregnancy on Child Development and Behavior
3 prospective longitudinal cohort studiesOttawa Prenatal Prospective Study (OPPS)
Initiated in 1978 & involved a group of Caucasian, predominantly middle-class families (N=698)
Fried, 2002
The Maternal Health Practices & Child Development (MHPCD) study
Started in Pittsburgh in 1982, based on a cohort of children of mostly African-American women from low SES (N=564)
Day, Sambaoorthi, Taylor, et al, 1991)
The Generation R study
Started in 2001, consisted of a multi-ethnic cohort of mothers (N=9778) & children (N=9749) with a predominantly higher SES from Rotterdam with delivery dates from April 2002 until January 2006
El Marroun, Tiemeier, Steegers, et al, 2009
All 3 studies began when women were pregnant and plan to follow their children into early adulthood
Between 1993 and 2008, potency of THC increased from 3.4% to 8.8%
OPPS Results4 yo: lower scores in verbal reasoning and memory tasks
6 yo: deficits in global measures of language comprehension, memory, visual and/or perceptual function & reading tasks requiring sustained attention, with a dose-response observed on impulsivity & hyperactive scales
9-12 yo: deficits in executive function tasks such as impulse control & visual problem-solving
13-16 yo: problems with attention, problem-solving, visual integration, & analytic skills requiring sustained attention
18-22 yo: fMRI revealed changes in neural activity with working memory tasks
MHPCD Results9 mo: impaired mental development
3,4, & 6 yo: deficits in executive function tasks similar to those observed in OPPS, with poorer memory & verbal measures
6 yo: impaired sustained attention on vigilance tasks and verbal reasoning and increased impulsivity & hyperactivity in those whose mothers smoked at least 1 jt/day in first trimester
9-12 yo: impaired executive functioning and visual problem-solving and increased impulsivity & hyperactivity and inattention at 10 yo for those whose mothers smoked marijuana during both first & third trimesters
MHPCD Results (cont.)
10 yo: lower reading & spelling scores in those whose mothers smoked at least 1 jt/day during first trimester & deficits in reading comprehension and underachievement with mothers who smoked marijuana during second trimester
14 yo: lower global achievement, reading, spelling, and math scores
Problem Behaviors and Mental Health Symptoms
OPPS6-9 yo: higher rates of problem behaviors
16-21 yo: higher rates of depressive symptoms; earlier onset and greater use of both marijuana & tobacco
MHPCD10 yo: higher rates of depressive symptoms and externalizing behaviors via parent & teacher report
14-21 yo: higher rates of marijuana and tobacco use, even after controlling for home environment and parental substance use
Young adults: increased risk of psychosis
Early Marijuana Initiation: The Link Between Prenatal Marijuana Exposure, Early Childhood Behavior & Negative Adult Roles
• Participants from MHPCD Project• 43% Caucasian; 57% African American; 48% males• 38% reported onset of marijuana use before age 15 (EAOM) and 67.5% of those
continued to report marijuana use at 22 yr assessment• 1st trimester marijuana exposure associated with behavioral problems at age 3 yr and
EAOM• EAOM associated with negative adult roles, including increased risk of being
arrested, lower educational attainment, having a child without being married, and unemployment at age 22
Neurotoxicology & Teratology 2016; 58:40-45
Generation R StudyMultiple ethnicities in Rotterdam; selection toward higher SES
Enrolled women with EDC between April 2002 and January 2006 (n=9778)
Completed questionnaire which included substance use during each trimester
220 women used cannabis during pregnancy; majority only in 1st trimester
43 continued to use cannabis throughout pregnancy
Maternal cannabis use30.9% = daily cannabis use (heavy use)
26% = weekly cannabis use (moderate use)
43.1% = once monthly cannabis use (light use)
Impact on Pregnancy, Fetal Development and Birth Outcomes
In Gen R study maternal cannabis use during pregnancy associated with reduced fetal growth reduction of -14.44 g/wk (95% CI -22.94 to -5.94, p=.001) and head circumference -0.21 mm/wk (95%CI -0.42 to 0.02, p=.07), compared with nonexposed fetuses
Maternal cannabis use during pregnancy resulted in more pronounced growth restriction than maternal tobacco use
Cannabis as a Neurodevelopmental Teratogen
There is compelling circumstantial evidence based on the principles of teratology and fetal malprogrammingsuggesting that pregnant women should refrain from marijuana use.The use of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS) which is present and active from the early embryonic stage modulating neurodevelopment & continuing this role into adulthood.
The 1st hit is landed by prenatal cannabis exposure (PCE) which leads to asymptomatic changes in the trajectory of fetal-postnatal neurodevelopment (ECSS alterations). The 2nd hit is landed in the form of: maternal stressors which also will impact the trajectory of fetal-postnatal neurodevelopment; postnatal exposure to other substances; or exposure to an incompetent or abusive caregiver which will impact the developmental profile. The 2nd hit is the power punch that cripples the developing nervous system & manifests in deficits in executive function/attention & behavioral, cognitive, language & motor development. In adulthood, these neurodevelopmental deficits may manifest as psychopathology, substance abuse and/or poor academic or social skills. Neurotoxicology & Teratology 2016; 58:5-14
Synthetic Cannabis Use During Pregnancy
Dose-dependent teratogenicity of synthetic cannabinoid CP-55,940 in mice Neurotoxicology and Teratology 2016; 58:15-22
Breastfeeding and CannabisCannabinoids are secreted in breastmilk
THC is in higher concentrations in breastmilk than in mother’s plasma
Mother 1: Breastmilk THC 340 ng; Plasma THC 105 ng, 3X difference
Mother 2: Breastmilk THC 60.3 ng; Plasma THC 7.2 ng, an 8X difference
THC accumulates in breast milk
Concentrations of metabolites 11-OH-THC, 9-carboxy-THC in fetal fecal sample were higher than in mother’s milk
This indicates that THC is absorbed and metabolized by infant
N Engl J Med 1982; 307:819-820
Transfer of Inhaled Cannabis into Human Breast MilkObjective: to evaluate transfer of THC and its metabolites into human breast milk after maternal inhalation of 0.1 g cannabis containing 23.18% THCStudy population: 8 mothers who regularly consumed cannabis, were 2-5 mo PP, and were exclusively breastfeeding their infantsProtocol: After discontinuing cannabis for at least 24 hr, collected baseline milk sample; then smoked cannabis and collected milk at 20 minutes, and 1, 2, and 4 hr.
Transfer of Inhaled Cannabis into Human Breast Milk
Average concentration in breast milk was 94 ng/mL which occurred 1 hr after consumption of cannabis
Estimated relative infant dose was calculated at 2.5% and the average absolute infant dose was estimated at 8 micrograms/kg/d
Therefore, exclusively breastfed infant ingests an estimated 2.5% of the maternal dose
Cannabis inhibits milk production by inhibiting prolactin production
Unanswered questionsWhat is plasma level in breastfeeding infant exposed to cannabis through human breast milk?
What effect would repeated and continuous doses have on breast milk concentration?
How much THC would transfer into breast milk after use of edibles?
What do exogenous cannabis products do to the endocannabinoid signaling system?
What is the lasting effect of exposing developing infants to cannabis?Obstet Gynecol 2018: 131:
Pediatrics 2018; 142: 1076
Median conc. of THC = 9.47 ng/mL; range: 1.01-323.0.
Half-life in breastmilk ~27 hr.
THC measurable in majority of breast milk samples up to ~6 days after maternal marijuana use
Concern for accumulation of various cannabinoids in nursing infant because of slow elimination from body fat stores & continuous daily exposure
Cannabinoid Concentrations in Breast Milk
Breastfeeding and CannabisTHC is rapidly distributed to brain and adipose tissue and stored in fat for weeks to months
T1/2 25-57 hrs and stays positive in urine for 2-3 wk
No data evaluating neurodevelopmental outcomes beyond age 1 yr in infants only exposed after birth
Potency of cannabis has been steadily increasing from ~3% in the 1980s to over 20% today
Current concern about cannabis use during lactation stems from possible infant sedation and maternal inability to safely care for her infant while under its influence
Neurotoxicol Teratol 1990; 12:161-8
Breastfeeding and Cannabis: Recommendations
Counsel mothers who admit to occasional use to avoid further use or reduce as much as possible while breastfeeding, advise them re its possible long-term neurobehavioral effects, and instruct them to avoid direct exposure of infant to cannabis or its smoke
Strongly advise mothers with positive urine screen for THC to discontinue exposure while breastfeeding and counsel them as to its possible long-term neurobehavioral effects
The lack of long-term f/u data on infants exposed to varying amounts of cannabis vis human milk, coupled with concerns over negative neurodevelopmental outcomes in children with in utero exposure, should prompt extremely careful considerations of risks vs benefits of breastfeeding in setting of moderate or chronic cannabis use. A recommendation of abstaining from any cannabis is warranted.
Laws re Women Using Substances During Pregnancy
Child Abuse Prevention and Treatment Act (CAPTA) requires states to have policies and procedures in place to
Notice Child Protective Services (CPS) agencies of substance-exposed newborns (SENs)
Establish a plan of safe care for newborns identified as being affected by illegal substance abuse or having withdrawal symptoms resulting from prenatal drug exposure
24 states and District of Columbia consider substance abuse during pregnancy to be child abuse under civil child-welfare statutes, and 3 consider it grounds for civil commitment
Need More Contemporary Data!Most studies done when potency of THC was much lower
Now the average potency of THC in CO is 20% and rising
Cannabis is stored in fat; we have an obesity epidemic
Impact of edibles?
Impact of synthetic cannabinoids on pregnancy unknown
Longer half-life, higher affinity for receptors
Could result in much higher levels in fetus
Impact of breastfeeding?