8/31/2018 MARIJUANA USE IN PREGNANCY: EXAMINING THE EVIDENCE CRESTA JONES, MD DISCLOSURES MARIJUANA

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1 MARIJUANA USE IN PREGNANCY: EXAMINING THE EVIDENCE CRESTA JONES, MD DISCLOSURES I am employed as a faculty physician by M Health, a sponsor of this conference. MARIJUANA Leaves, buds female cannabis sativa plant Medicinal and psychoactive properties mediated by cannabinoids Delta-9-tetrahydrocannabinol (THC) Mood and cognition alteration, increased dopamine release, psychoactive effects as neurotransmitter Krening

2 MARIJUANA THC - small, highly lipophilic Rapid distribution to brain and fat Half life 20 hours - 5 days (depending on use) Higher carbon monoxide levels than tobacco when smoked Krening 2018, Wu 1988 MARIJUANA A HISTORY BC Chinese emperors Possessing both yin and yang Healing properties similar to ginseng MARIJUANA A HISTORY BC Chinese emperors Possessing both yin and yang Healing properties similar to ginseng Component of holy anointing oil Exodus 30:

3 MARIJUANA A HISTORY Hemp brought to US by Jamestown settlers Grown by presidents Washington and Jefferson Exodus 30:22-23 MARIJUANA A HISTORY added to the US Pharmacopeia MARIJUANA A HISTORY added to the US Pharmacopeia 1911 outlawed by the state of Massachusetts 3

4 MARIJUANA A HISTORY 1937 Push to tax marijuana to limit use American Medical Association opposed taxing, encouraged research for possible use in medicine and psychology MARIJUANA A HISTORY United Nations convention to discuss cannabis use for medical and scientific purposes 1961 THC synthesized 1964 Univ. of Mississippi official grower of cannabis for federal government 1968 MARIJUANA A HISTORY THE 1970S Controlled Substances Act Cannabis Schedule 1 No accepted medical use, high potential for abuse heroin, lysergic acid diethylamide (LSD), 3,4-MDMA (ecstasy), methaqualone, and peyote Due to lack of sufficient data with pending studies Illegal under federal law 4

5 MARIJUANA A HISTORY Recommended removal from scheduling system Recommended decriminalization MARIJUANA A HISTORY Recommended removal from scheduling system Recommended decriminalization Rejected by President Nixon 5

6 MARIJUANA A HISTORY 1970s Multiple petitions to declassify Temporary IND for compassionate use 1980s Marinol created Mandatory minimum sentencing for all drug charges MARIJUANA A HISTORY 1990s Proposition California 2015 open to federally funded research DEA declines to reschedule to Class II Washington Post

7 Business Insider June 2018 WHAT DOES ALL THIS MEAN FOR OUR PATIENTS? Data on marijuana use in the United States Data on pregnancy and marijuana use in the United States Data on pregnancy outcomes Expert opinion and consensus on pregnancy What do our patients know? Social media, dispensaries MARIJUANA USE SAMHSA NSDUH

8 MARIJUANA USE 2.2 million Americans with current marijuana use 8.3% population 7% adolescents age12-17 yrs 19.8% young adults age years Essentially unchanged from 2014 data SAMHSA NSDUH 2015 INDICATIONS FOR MEDICAL MARIJUANA USE Chemotherapy-induced nausea and vomiting Appetite stimulation in patients with AIDS Intra-ocular pressure reduction glaucoma Reduce spasticity and chronic pain various conditions Epilepsy Multiple sclerosis spasticity and pain Mourh 2017 PREGNANCY AND MARIJUANA USE 8

9 PREGNANCY AND MARIJUANA USE Self reported - 2-5% of pregnancies Colorado % pregnancy, 5% early postnatal (similar to studies prior to recreational legalization) Up to 28% in young, urban, socioeconomically disadvantaged women Higher rates at delivery 34-60% of users continue during pregnancy Crume 2018,Passey 2014, El-Marroun 2011, van Gelder 2010 PREGNANCY AND MARIJUANA USE Challenges to identifying risks: Often associated with polysubstance use Adverse socioeconomic conditions Increased exposure to intimate partner violence Reporting and recall bias Changes in drug potency Alhusen 2013 WHAT DO THE DATA SAY? MATERNAL OUTCOMES, NEONATAL OUTCOMES, AND BREASTFEEDING 9

10 WHERE DO THE DATA COME FROM? Secondary analysis of magnesium for neuroprotection (Dotters-Katz 2017) Data from , < 35 weeks Secondary analysis of a stillbirth collaborative, (Metz 2017) 48 patient Retrospective cohort (Warshak 2016) Data from ; 361 marijuana users vs. all deliveries > 20 weeks Systemic reviews, meta-analyses (Metz 2015, Connor 2016, Mourh 2017) Human and animal data WHERE DO THE DATA COME FROM? Recent data lacking Often self report, urine drug screen No objective way to quantify level of use unless controlled study THC concentration is on the rise % % ElSohly 2016 MATERNAL OUTCOMES Colorado 2015, self reported use survey No increase in preterm delivery Systematic review 2015 No increase in preterm delivery Retrospective cohort, 2016 No increase in preterm delivery No increased preeclampsia No increase unplanned C/S Lower rate of gestational diabetes Warshak 2016, Metz 2015, Conner 10

11 BIRTH OUTCOMES Colorado survey, survey 2015 Increased low birth weight (50%) No increase in SGA, preterm birth, or NICU admission Retrospective cohort, 2016 Increased SGA (19%), No increase fetal anomalies, stillbirth Systematic review, 2015 Maybe 100 g decrease in birth weight Possible increase stillbirth (tobacco confounder) No increase fetal anomalies Warshak 2016, Metz 2015, Conner 2016 NEONATAL OUTCOMES Cannabinoid receptors endocannabinoid system Seen at 19 weeks, ongoing development after birth Attention, cognition, memory, emotion, movement, peripheral immune system Animal studies changes to dopaminergic pathways Postmortem fetal brains decreased dopamine receptors in amygdala, dose-dependent Studies challenged by confounders many findings appear reversible in childhood in well supported children Concerning pattern altered neurodevelopment early heavy use Metz 2015, Jutras-Aswas 2009, Campolongo P 2001, NEONATAL/CHILDHOOD OUTCOMES Secondary analysis 2017, NICHD study Magnesium for neuroprotection study , infants all < 35 weeks Marijuana exposed vs. non-exposed, 135 patients exposed No increase adverse neonatal or childhood outcomes Dotters-Katz

12 OVERALL OUTCOMES NICHD, secondary analysis of stillbirth study patients, 48 with marijuana exposure Composite adverse pregnancy outcome and neonatal morbidity/death No increase in composite adverse pregnancy outcome Composite neonatal morbidity /death increased (14.1% vs. 4.5%, p = 0.02) Infection morbidity(9.8% vs. 2.4%) Neurologic morbidity (1.4% vs. 0.3%) both significantly increased Metz, 2017 OVERALL OUTCOMES Systematic review and meta-analysis 31 observational studies, patients with marijuana use vs. 124,867 controls Unadjusted - increased risk of low birth weight (RR 1.43) and preterm birth (RR1.32) No increased risk of either when adjusted for tobacco use Not an independent risk factor for low birth weight or preterm birth Not an independent risk factor for composite adverse neonatal outcomes Could not account for amount of use Conner 2016 SO.WHAT DO I TELL MY PATIENT? Possible effects on fetal growth May increase stillbirth risk Possible increase in infections in newborns Most importantly, it affects receptors in the baby s brain that are still developing, and may be changed with marijuana exposure There is not enough data on long term effects for kids Bottom line.we just don t know enough yet! 12

13 BREASTFEEDING Effects on mother Transfer into milk Transfer to the offspring Effects on the offspring Human and animal data Crume 2018 BREASTFEEDING Patterns of marijuana use decrease in pregnancy, but increase after delivery Colorado (2015)- 5.0% prevalence early postnatal use in women who breastfed Difficult to assess : prenatal vs. breastfeeding exposure on behavior Difficult to assess : parenting with cannabis use vs. second hand inhalation vs. breastmilk transmission Decreased maternal sensitivity during play interactions with regular cannabis use, associated with lower toddler emotion regulation Crume 2018, Metz 2015, Eiden 2018 BREASTFEEDING A RESEARCH REVIEW Human/animal animal studies June 2017 Maternal decrease in prolactin (human and animals) Transfer to milk readily transferred, amounts depends on chronicity of use (human) ~0.8% mother s exposure Transfer to offspring stool/urine (humans), infant organs (animals); no data on passive inhalation Infant development mixed data, many confounders (human); increased anxiety, decreased nutrition, reduced sexual behavior (animals) Very poor overall evidence for harm or lack of harm Mourh

14 BREASTFEEDING 8 women, breast milk collection 2-5 mos postpartum, regular cannabis consumption, exclusive breastfeeding D/c 24 hours, smoked standardized amount/strain Collect milk 20 min, 1, 2, 4 hours Delta-9-tetrahydrocannabinol (THC) and metabolites Baker et al., 2018 BREASTFEEDING Delta-9-THC detected - all times points examined No metabolites detected Mean 2.5% of maternal dose ~8 mcg/kg/day Baker et al., 2018 BREASTFEEDING Breastmilk samples 54 women reporting marijuana use Reported last use, frequency and amount of use Standardized collection and reporting Bertrand

15 BREASTFEEDING Breastmilk samples 54 women reporting marijuana use Reported last use, frequency and amount of use Standardized collection and reporting 63% of samples with detectable THC Up to 6 days post use Increased frequency of use increased milk concentration Bertrand 2018 BREASTFEEDING Do the maternal and neonatal benefits of breastfeeding reduce or offset the potential sequelae from exposure to marijuana in breastmilk? Mourh 2017 WHAT DO THE EXPERTS SAY? EXPERT OPINIONS AND CLINICAL CONSENSUS 15

16 MARIJUANA USE IN PREGNANCY AND LACTATION Screen all women for marijuana use If use is identified: Review potential health consequences if ongoing Encourage to discontinue if pregnant or planning pregnancy Offer referral to treatment if indicated Discontinue medical marijuana if pregnant or contemplating pregnancy Insufficient data on lactation and breastfeeding use is discouraged ACOG 2017 MARIJUANA USE IN PREGNANCY AND LACTATION All women screening for substance use disorder at entry to prenatal care Urine testing should NOT be used for primary screening 2-3 days occasional users Several weeks in chronic users ACOG 2017, Metz

17 Information regarding long-term effects remain insufficient to recommend complete abstention from breastfeeding initiation or continuation Occasional or rare use avoid further use or reduce as much as possible while breastfeeding Positive urine screen recommend discontinue exposure while breastfeeding A recommendation of abstaining from any marijuana use in warranted ABM Clinical Protocol #21, 2015 When advising mothers on the medicinal use of marijuana during lactation, one must take into careful consideration and counsel on the potential risks of exposure of marijuana and benefits of breastfeeding to the infant. At this time, although the data are not strong enough to recommend not breastfeeding with any marijuana use, we urge caution. ABM Clinical Protocol #21,

18 Ryan, 2018 AAP MARIJUANA USE CLINICAL GUIDANCE Counsel on lack of definitive research, but potential adverse THC effects, on marijuana Advise not to use marijuana during pregnancy If using medical marijuana, counsel on lack of safety data, possible adverse THC effects, refer for alternative treatment Maternal marijuana use while breastfeeding is discouraged, and women are encouraged to abstain from using any marijuana products while breastfeeding Caution on risks of infant exposure to smoke from marijuana Ryan 2018 WHAT DO OUR PATIENTS KNOW? GENERAL PUBLIC, SOCIAL MEDIA AND MEDICAL EXPERTS 18

19 Types of Twitter messages marijuana use and infant and maternal health Reported health outcomes associated with prenatal and postnatal marijuana use Primary tweets and links Dakkak tweets 77.6% neutral tone suggesting uncertainty about effects Source links more likely to report negative health outcomes Outcomes: poor brain and CNS development, low birth weight, adverse behavioral outcomes, infant memory issues Lactation decreased quality/quantity of milk with increased marijuana use Dakkak 2018 Online media items Scientific studies, information about health and well-being, mode of ingestion and portrayal of risks and benefits Jarlenski

20 51% media items mentioned perinatal health risks marijuana 28% use for nausea and vomiting of pregnancy 59% risks > benefits Overall portrayal consistent with current scientific debate Jarlenski 2018 CANNABIS DISPENSARIES Colorado cross-sectional study Mystery caller approach - 8 weeks pregnant and experiencing morning sickness Primary outcome proportion of marijuana dispensaries that recommend cannabis products Dickson B 2018 CANNABIS DISPENSARIES 400 dispensaries contacted 37% medical 69% recommended cannabis products for morning sickness treatment 83% medical, 60% retail 65% based recommendation on personal opinion 36% cannabis safe in pregnancy Dickson B

21 CANNABIS DISPENSARIES 400 dispensaries contacted 37% medical 69% recommended cannabis products for morning sickness treatment 83% medical, 60% retail 65% based recommendation on personal opinion 36% cannabis safe in pregnancy 81.5% recommended discussion with health care provider But only 32% did so without prompting! Dickson B 2018 FOOD FOR THOUGHT - Discriminatory drug testing and reporting Inconsistent education Breastfeeding during marijuana use Punitive or legal interventions related to use Community standards of care based on opinion rather than science FOOD FOR THOUGHT Audio-recorded patient-health care provider first prenatal visits at 5 urban outpatient clinics 468 first OB visits, 90 patients (19%) disclosed marijuana use to 47 health care providers 48% of visits, the provider did NOT respond to marijuana use disclosures or offer counseling When counseling was offered it did NOT include specific information on risks or outcomes related to use We must do better!! Holland

22 FOOD FOR THOUGHT Drug prescription records in Medicaid programs in states with medical cannabis legalization million drug records Liang 2018 FOOD FOR THOUGHT Drug prescription records in Medicaid programs in states with medical cannabis legalization million drug records 29.6% reduction in Schedule III prescriptions 29.9% reduction in opioid dosage 28.8% reduction in related Medicaid spending Liang 2018 CONCLUSIONS Marijuana - not uncommon in pregnancy, with use and effects changing with changes in state legality and in concentrations of THC Universal screening for marijuana use during pregnancy/lactation is recommended If use is identified, counseling is recommended to review the lack of strong data on effects, current unknowns, and the recommendation to abstain from use during pregnancy and lactation Medical marijuana should be discontinued for alternative treatments during pregnancy and lactation Future studies are urgently needed to assess risks for mother, pregnancy, breastfeeding and neonatal/childhood outcomes 22

23 THANK YOU THANK YOU!! REFERENCES ACOG Committee Opinion #722. Marijuana use during pregnancy and lactation. Obstet Gynecol 2017;130(4):e El Marroun H, Tiemeier H, Jaddoe VW et al. Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population based cohort: the Generation R Study. Eur Addict Res 2011; 17: Van Gelder MM, Reefhuis J, Caton AR et al. Characteristics of pregnant illicit drug users and association between cannabis use and perinatal outcomes in a population-based study. Drug Alcohol Depend 2010;109: Passey ME, Sanson-Fisher RW, D Este CA et al. Tobacco, alcohol and cannabis use during pregnancy: clustering of risks. Drug Alcohol Depend 2014;134; Krening C, Hanson K. Marijuana perinatal and legal issues with use during pregnancy. J Perinat Neonat Nurs 32(1): Baker TB, Datta P, Rewers-Felkins, K et al. Transfer of inhaled cannabis into human breast milk. Obstet Gynecol 2018;131: Dakkak H, Brown R, Twynstra J et al. The perception of pre- and post-natal marijuana exposure on health outcomes: A content analysis of twitter messages. J Neonatal Perinatal Med 2018 May 23. Jarlenski M, Koma JW, Zank J et al. Media portrayal of prenatal and postnatal marijuana use in an era of scientific uncertainty. Drug Alcohol Depend Jun 1; 187: Warshak CR, Regan J, Moore B et al. Association between marijuana use and adverse obstetrical and REFERENCES Alhusen JL, Lecea MB, Bullock L, Sharps P. Intimate partner violence, substance use, and adverse neonatal outcomes among urban women. J Pediatr 2013;163: Metz TD, Stickrath EH. Marijuana use in pregnancy and lactation: a review of the evidence. Am J Obstet Gynecol. 2015;213(6): Conner SN, Bedell V, Lipsey K et al. Maternal marijuana use and adverse neonatal outcomes: a systematic review and meta-analysis. Obstet Gynecol. 2016;128(4): Crume TL, Juhl AL et al. Cannabis use during the perinatal period in a state with legalized recreational and medical marijuana: the association between maternal characteristics, breastfeeding patterns, and neonatal outcomes. J Pediatr Jun;197: Metz TD, Allshouse AA, Hogue CL et al. Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity. Am J Obstet Gynecol 2017;217:478.e1-8. Mourh J, Rowe H. Marijuana and breastfeeding: applicability of the current literature to clinical practice. Breastfeed Med 2017 Dec;12(10): Dotters-Katz SK, Smid MC et al. Risk of neonatal and childhood morbidity among preterm infants exposed to marijuana. J Matern Fetal Neonatal Med 2017 Dec;30(24): Liang D, Bao Yuhua, Wallace M, et al. Medical cannabis legalization and opioid prescriptions: evidence on US Medicaid enrollees during Addict 2018 doi: /add

24 REFERENCES Jutras-Aswas D, DinIeri JA, Harkany T et al. Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Eur Arch Psychiatry Clin Neurosci 2009;259: Campolongo P, Trezza V, Ratano P et al. Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents. Psychopharmacology 2001;214:5-15. ElSohly MA, Mehmedic Z, Foster S et al. Changes in cannabis potency over the last 2 decades ( ): analysis of current data in the United States. Biol Psychiatry 2016;79: Reece-Stremtan S, Marinelli KA. ABM Clinical Protocol #21: guidelines for breastfeeding and substance use or substance use disorder, revised Breastfeed Med 2015;10: Substance Abuse and Mental Health Services Administration. Results from the 2015 National Survey on Drug Use and Health: summary of national findings. Samhsa.gov, accessed August 2018 Holland CL, Rubio D, Rodriguez KL et al. Obstetric health care providers counseling responses to pregnant patient disclosures of marijuana use. Obstet Gynecol 2016 Apr;127(4): Dickson B, Mansfield C, Guiahi M et al. Recommendations from cannabis dispensaries about first-trimester cannabis use. Obstet Gynecol 2018;131: Eiden RD, Schuetze P, Shisler S, Huestis MA. Prenatal exposure to tobacco and cannabis; effects on autonomic and emotion regulation. Neurotox Teratol 2018; 68: REFERENCES Bertrand KA, Hanan NJ, Honerkamp-Smith G, Best BM, Chambers D. Marijuana use by breastfeeding mothers and cannabinoid concentrations in breast milk. Pediatrics 2018, Aug 27. doi: /peds [Epub ahead of print] Ryan SA, Ammerman SD, O Connor ME. Marijuana use during pregnancy and breastfeeding: implications for neonatal and childhood outcomes. Pediatrics 2018, Aug 27. doi: /peds