Impact of Marijuana on Pregnancy, the Fetus and Neonate

Transcription

1 Impact of Marijuana on Pregnancy, the Fetus and Neonate Margaret Lynn Yonekura, M.D., FACOG Director, Community Health Dignity Health California Hospital Medical Center November 6, 2018

2 Disclosures I have nothing to disclose

3 Learning Objectives At 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

4 Cannabinoids Three 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.

5 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

6 Cannabinoid Receptors Are Located Throughout the Brain

7 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

8 Endocannabinoids are produced on demand. They travel back to the transmitting neuron to dampen further activity. Endocannabinoids Anandamide is a partial agonist of CB1. 2-AG is a full agonist of both CB1 and CB2 receptors. Plant-derived cannabinoid THC is a partial agonist of CB1 receptors

9 How Cannabis Works

10 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

11 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% Standard hashish from Morocco Trichomes on Cannabis, rich in cannabinoids Pressed hashish Bubble melt Cannabis indica hashish

12 Synthetic Cannabinoids First 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

13 Sent out April 5, 2018 at 4:50 pm

14 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:

15 Synthetic Cannabinoids How 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

16 Synthetic Cannabinoids Major Adverse Rxns: Heart attack Ischemic stroke Acute kidney injury Generalized tonicclonic seizures Rhabdomyolysis Cannabinoidinduced hyperemesis synd. Death Prolonged QTc interval Not detected on standard blood or urine tox screens

17 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 National Survey on Drug Use and Health, SAMHSA

18 Past Month Marijuana Use Among People Aged 12 or Older, by Age Group, 2017

19 Demographic Past-Month Use Rate (%) Ethnicity White, non-hispanic African-American Hispanic Asian, non-hispanic Gender Male Female Education < HS HS graduate Some college College graduate Family income < $10 k $20 k - $29.9 k $50 k - $74.9 k $75 k + Age Past Month Use Rates by Demographic, U.S., 2016

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22 Marijuana Use in Past Month & Perceived Risk of Great Harm from Use Among People Aged 12 or Older, Los Angeles County, Marijuana use in past month Perceived great risk of harm from smoking marijuana once a month SPA 1 & 5 = 9.77% 2 = 8.03% 3 = 6.18% 4 = 10.50% 6 = 10.62% 7 = 7.00% 8 = 9.01% SPA 1 & 5 = 21.44% 2=25.49% 3=34.66% 4=30.18% 6=32.00% 7=35.10% 8=27.35%

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24 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.

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26 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.

27 November 2017

28 Rising Marijuana Use in Colorado Post Legalization (2013) Rocky Mountain HIDTA Report Supplement: The Legalization of Marijuana in CO: The Impact, Volume 4 (March 2017)

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31 Average Δ 9 -THC Concentration of DEA Specimens by Year Potency of cannabis judged based on THC content of preparation Potency > 15% considered to represent hard drug in Holland Biol Psychiatry 2016; 79:

32 CBD Concentration Distribution in Cannabis Samples Confiscated by DEA and Average CBD Cannabidiols lessen the psychoactive effects of THC. This means that a plant with a greater percentage of CBD has a lower potency. Biol Psychiatry 2016; 79:

33 Ratio of the Average Concentration of THC to CBD in DEA Specimens by Year, CBD has been almost bred out of cannabis strains Biol Psychiatry 2016;79:

34 Distribution of THC in the body. C. HEATHER ASHTON BJP 2001;178: by The Royal College of Psychiatrists

35 Clinical Pharmacokinetics of Cannabis Ingested 15 mg Smoked 34 mg Inhaled Ingested Absorption 10-20% 1-10% Onset of action 6-12 min min Peak effect min 2-3 hr Duration of effect 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)

36 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: % Some evidence of increased risk of heart attack, may be exacerbated in vulnerable individuals (e.g., baby boomers?) Orthostatic hypotension initially; then increased BP Risk for ischemic stroke Increased risk of accidents (~2 fold), higher when combined with alcohol JAMA 2014;370:23

37 Driving Related Impairments Cannabis-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

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39 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.

40 Unintentional Cannabis Intoxication in Toddlers, France, 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

41 Rocky Mountain HIDTA Report Supplement: The Legalization of Marijuana in CO: The Impact, Volume 4 (March 2017) MML

42 Cannabis Acute Effects (Intoxication Phase) Cognition Impaired short-term memory Difficulty with complex tasks Difficulty learning Executive function Impaired decision-making Increased risky behavior STDs, HIV? Mood (especially after high doses or edibles) Anxiety panic attacks Psychosis - paranoia

43 Myth: You can t become addicted to cannabis ~9% of cannabis users become dependent 1 in 6 (17%) who start in adolescence 25-50% of daily users

44 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

45 Cannabis Use Disorder Men Similarities Women At least one other mental health disorder Low rate of seeking treatment Other substance use disorders Antisocial personality disorder Severity of disorder Differences Panic attacks Anxiety disorders Disorder develops more quickly after first marijuana use

46 Cannabis Withdrawal Syndrome Substance Abuse & Rehabilitation 2017;8:9-37

47 Effects of Long-Term or Heavy Use Addiction 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

48 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

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53 Adjusted Prevalence of Marijuana Use Among 279,457 Pregnant Women in KPNC, Universal screening for marijuana use done at ~8 wk GA JAMA 2017; 318:2490

54 Association of Nausea & Vomiting in Pregnancy with Prenatal Marijuana Use Using data from KPNC universal screening study at 8 wk GA, NVP Category % Participants (N=220,510) Marijuana Use aor 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:

55 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

56 How Cannabinoids Affect Implantation Impairment of fallopian tube motility Ectopic pregnancy Non-hatched or non-viable embryo Decreased uterine receptivity: embryotoxic effects 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;17:45 Reproduction 2016;152: R191-R200

57 How Cannabinoids Affect Embryo Development THC 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

58 Fetal Cannabinoid Receptors and the dis-joint-ed brain The EMBO Journal 2014; 33:665 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 CB 1 receptormediated effect of THC in the fetal brain. Considering the role of CB 1 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

59 Cannabis and Stillbirth Cannabis use associated with stillbirth (pooled OR 1.74, 95% CI ) but not perinatal death (pooled RR 1.09, 95% CI ) 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 ); persisted after adjustment for tobacco use Obstet Gynecol 2016; 128:713-23; Obstet Gynecol 2014; 123:113-25

60 Cannabis and Congenital Anomalies Two 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 ) 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

61 Cannabis and Low Birth Weight Recent 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, demonstrated an association between cannabis use and LBW (OR 1.8, 95% CI , 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; 197:90-6 J Am Acad Child Adolesc Psychiatry 2009; 48:

62 Cannabis and Preterm Birth Conner 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 prepregnancy had increased odds of sptb with intact membranes (aor 2.34, 95% CI ) 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 ) Obstet Gyncol 2016; 128:713-23; PloS One 2012; 7:e39154; BJOG 2014; 121:971-7; Reprod Toxicol 2016; 62:77-86

63 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 )] 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

64 Maternal Cannabis Use and Other Associations Two recent systematic reviews and metaanalyses Gunn et al identified 6,854 articles, fully screened 881, and included 24 Association with anemia (pooled OR 1.36, 95% CI ) Association with LBW (pooled OR 1.77, 95% CI ) Higher odds of NICU admission (pooled OR 2.02, 95% ci ) Conner et al identified 4,875 studies and included 31 Moderate to heavy cannabis use (at least once/wk) associated with both LBW (RR 1.90, 95% CI ) and PTB (RR 2.04, 95% CI ) BMJ Open 2016; 6:e Obstet Gynecol 2016; 128:713-23

65 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: ; Pediatr Res 1988; 24:101-5

66 Impact of Cannabis Use During Pregnancy on Child Development and Behavior 3 prospective longitudinal cohort studies Ottawa 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%

67 OPPS Results 4 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 yo: problems with attention, problem-solving, visual integration, & analytic skills requiring sustained attention yo: fmri revealed changes in neural activity with working memory tasks

68 MHPCD Results 9 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

69 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

70 Problem Behaviors and Mental Health Symptoms OPPS 6-9 yo: higher rates of problem behaviors yo: higher rates of depressive symptoms; earlier onset and greater use of both marijuana & tobacco MHPCD 10 yo: higher rates of depressive symptoms and externalizing behaviors via parent & teacher report yo: higher rates of marijuana and tobacco use, even after controlling for home environment and parental substance use Young adults: increased risk of psychosis

71 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 1 st 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

72 Generation R Study Multiple 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 1 st trimester 43 continued to use cannabis throughout pregnancy Maternal cannabis use 30.9% = daily cannabis use (heavy use) 26% = weekly cannabis use (moderate use) 43.1% = once monthly cannabis use (light use)

73 Impact on Pregnancy, Fetal Development and Birth Outcomes In Gen R study maternal cannabis use during pregnancy associated with reduced fetal growth reduction of g/wk (95% CI to -5.94, p=.001) and head circumference mm/wk (95%CI to 0.02, p=.07), compared with nonexposed fetuses Maternal cannabis use during pregnancy resulted in more pronounced growth restriction than maternal tobacco use

74 Effects on Neurocognitive Functioning Porath-Waller, AJ, Canadian Centre on Substance Abuse, 2015

75 Cannabis as a Neurodevelopmental Teratogen The 1 st hit is landed by prenatal cannabis exposure (PCE) which leads to asymptomatic changes in the trajectory of fetal-postnatal neurodevelopment (ECSS alterations). The 2 nd 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 2 nd 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 There is compelling circumstantial evidence based on the principles of teratology and fetal malprogramming suggesting 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. psychopathology, substance abuse and/or poor academic or social skills. Neurotoxicology & Teratology 2016; 58:5-14

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78 Synthetic Cannabis Use During Pregnancy Dose-dependent teratogenicity of synthetic cannabinoid CP-55,940 in mice Neurotoxicology and Teratology 2016; 58:15-22

79 Pediatrics 2018; 142(3):e

80 Breastfeeding and Cannabis Cannabinoids 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:

81 Transfer of Inhaled Cannabis into Human Breast Milk Objective: to evaluate transfer of THC and its metabolites into human breast milk after maternal inhalation of 0.1 g cannabis containing 23.18% THC Study population: 8 mothers who regularly consumed cannabis, were 2-5 mo PP, and were exclusively breastfeeding their infants Protocol: 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.

82 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 Obstet Gynecol 2018: 131: Unanswered questions What 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?

83 Cannabinoid Concentrations in Breast Milk Median conc. of THC = 9.47 ng/ml; range: 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 Pediatrics 2018; 142: 1076

84 Breastfeeding and Cannabis THC is rapidly distributed to brain and adipose tissue and stored in fat for weeks to months T1/ 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

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86 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.

87 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

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89 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?

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