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

I have nothing to disclose Learning Objectives At the end of this lecture, participants will be able to: Describe the types of and how they work Discuss the prevalence and trends of 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 Cannabinoids Three forms of cannabinoids: phyto (plant), endo (within) and synthetic (manufactured) There are >100 unique phytocannabinoids in the 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 (CBD) which is not psychoactive, has no abuse potential and may even possess anti-addictive properties. How Cannabis Works

Endocannabinoids Phytocannabinoids (Brain Derived) (Plant Derived) (Made in Lab)

Endocannabinoid Receptors: CB1 & CB2

The (ECS) is involved in regulating a variety of physiological processes including appetite, pain and pleasure sensation, immune system, mood and memory Receptors Are Located Throughout the Brain 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.

Endocannabinoids Anandamideis 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 How Cannabis Works 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, , dank, 420, grass, dope, Potency of principal psychoactive cannabinoid delta 9 (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 Trichomes on Cannabis, What is hashish? rich in cannabinoids Hashish is cannabis , 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, , vaporizer, or joints where it is normally mixed with cannabis or , as pure Standard hashish from hashish will burn poorly if burned alone. THC content of hashish ranges Pressed hashish from 1-65%

“Bubble melt” hashish 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, , 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 Sent out April 5, 2018 at 4:50 pm 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 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 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” 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 Marijuana Use Among People Aged 12 or Older, by Age Group, 2017 Demographic Past-Month Use Rate (%) Ethnicity White, non-Hispanic 8.4 Past Month Use African-American 10.7 Hispanic 7.2 Rates by Asian, non-Hispanic 3.0 Gender Demographic, Male 10.6 Female 6.2 U.S., 2016 Education < HS 8.2 HS graduate 9.1 Some college 10.5 College graduate 5.9 Family income < $10 k 13.6 $20 k - $29.9 k 9.7 $50 k - $74.9 k 7.8 $75 k + 6.6 Age 12-17 7.1 18-25 20.1 26-34 13.0 35-49 7.1 50+ 3.9

Marijuana Use in Past Month & Perceived Risk of Great Harm from Use Among People Aged 12 or Older, Los Angeles County, 2012-2014

Perceived great risk of harm from Marijuana use in past month smoking marijuana once a month

SPA SPA 1 & 5 = 9.77% 1 & 5 = 2 = 8.03% 21.44% 3 = 6.18% 2=25.49% 4 = 10.50% 3=34.66% 6 = 10.62% 4=30.18% 7 = 7.00% 6=32.00% 8 = 9.01% 7=35.10% 8=27.35%

Dabbing

Dabs are concentrated, Dabs are often placed wax-like doses of onto a glass surface cannabis made using a heated with blowtorch. like butane or The resulting smoke is carbon dioxide inhaled. 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)

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. November 2017 Rising Marijuana Use in Colorado Post Legalization (2013)

Rocky Mountain HIDTA Report www.rmhidta.org Supplement: The Legalization of Marijuana in CO: The Impact, Volume 4 (March 2017)

Average Δ9-THC Concentration of DEA Specimens by Year

Potency of cannabis judged based on THC content of preparation Biol Psychiatry 2016; 79:613-619 Potency > 15% considered to represent “hard drug” in Holland CBD Concentration Distribution in Cannabis Samples Confiscated by DEA and Average CBD

Cannabidiolslessen the psychoactive effects of THC. This means that a plant with a greater percentage of CBD has a lower potency. Biol Psychiatry 2016; 79:613-619 Ratio of the Average Concentration of THC to CBD in DEA Specimens by Year, 1995-2014

CBD has been almost bred out of cannabis strains Biol Psychiatry 2016;79:613-619 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

Ingested 15 mg

Smoked 34 mg

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) Cannabis’ Acute Effects (Intoxication Phase) 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 BP Risk for ischemic stroke Increased risk of accidents (~2 fold), higher when combined with JAMA 2014;370:23 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

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, 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)

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 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

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 disorder Low 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 Cannabis Withdrawal Syndrome

Substance Abuse & Rehabilitation 2017;8:9-37 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 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

Universal screening for marijuana use done at ~8 wk GA

JAMA 2017; 318:2490 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 Marijuana Use p value (N=220,510) aOR 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 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 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 Fetal Cannabinoid Receptors and the “dis--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 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 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 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, 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; 197:90-6 J Am Acad Child Adolesc Psychiatry 2009; 48:1173-81 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 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% cI 1.27-3.21) 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 1.44-2.45) and PTB (RR 2.04, 95% CI 1.32-3.17)

BMJ Open 2016; 6:e009986 Obstet 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 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% 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 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 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 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 OPPS 6-9 yo: higher rates of problem behaviors 16-21 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 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 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 1st 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) 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 Effects on Neurocognitive Functioning

Porath-Waller, AJ, Canadian Centre on , 2015 Cannabis as a Neurodevelopmental Teratogen

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 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: modulating maternal stressors which also will impact the trajectory of fetal-postnatal neurodevelopment; 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 continuing this role into nervous system & manifests in deficits in executive function/attention & behavioral, cognitive, adulthood. 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 https://www.acog.org/Patients/FAQs/Marijuana-and-Pregnancy Synthetic Cannabis Use During Pregnancy

Dose-dependent teratogenicity of synthetic cannabinoid CP-55,940 in mice Neurotoxicology and Teratology 2016; 58:15-22 Pediatrics 2018; 142(3):e20181889 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; 307:819-820 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. Transfer of Inhaled Cannabis into Human Breast Milk Average concentration in breast Unanswered questions milk was 94 ng/mL which occurred What is plasma level in 1 hr after consumption of cannabis breastfeeding infant exposed to cannabis through human breast Estimated relative infant dose was milk? calculated at 2.5% and the average What effect would repeated and absolute infant dose was estimated continuous doses have on breast at 8 micrograms/kg/d milk concentration? How much THC would transfer Therefore, exclusively breastfed into breast milk after use of infant ingests an estimated 2.5% of edibles? the maternal dose What do exogenous cannabis products do to the Cannabis inhibits milk production endocannabinoid signaling by inhibiting prolactin production system? What is the lasting effect of exposing developing infants to Obstet Gynecol 2018: 131: cannabis? Cannabinoid Concentrations in Breast Milk 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

Pediatrics 2018; 142: 1076 Breastfeeding and Cannabis THC 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? https://www.cdph.ca.gov/Programs/DO/letstalkcannabis/Pages/LetsTalkCannabis.aspx