CLINICAL REPORT

Guidance for the Clinician in Rendering Pediatric Care

Marijuana Use During Pregnancy Sheryl A. Ryan, MD, FAAP,​a Seth D. Ammerman, MD, FAAP, FSAHM, DABAM,​b Mary E. O’Connor, MD, MPH, FAAP,​c,​d COMMITTEEand ONBreastfeeding: SUBSTANCE USE AND PREVENTION, SECTION ON ImplicationsBREASTFEEDING for Neonatal and Childhood Outcomes Marijuana is one of the most widely used substances during pregnancy in abstract the United States. Emerging data on the ability of cannabinoids to cross the placenta and affect the development of the fetus raise concerns about both pregnancy outcomes and long-term consequences for the infant or child. Social media is used to tout the use of marijuana for severe nausea associated with pregnancy. Concerns have also been raised about marijuana aDepartment of Pediatrics, Penn State Health Milton S. Hershey Medical use by breastfeeding mothers. With this clinical report, we provide data on Center, Hershey, Pennsylvania; bDivision of Adolescent Medicine, Department of Pediatrics, Stanford University and Teen Health the current rates of marijuana use among pregnant and lactating women, Van, Stanford Children’s Health, Palo Alto, California; cDepartment of Pediatrics, School of Medicine, University of Colorado, Aurora, discuss what is known about the effects of marijuana on fetal development Colorado; and dDartmouth-Hitchcock Medical Center, Lebanon, New and later neurodevelopmental and behavioral outcomes, and address Hampshire implications for education and policy. Dr Ammerman helped draft and revise the manuscript and critically reviewed the manuscript; Dr Ryan took the lead on drafting the manuscript and helped revise and critically reviewed the manuscript; Dr O’Connor helped draft and revise the manuscript and critically reviewed the manuscript with a focus on the breastfeeding portion; and all authors approved the final manuscript as submitted.

PREGNANCY AND MARIJUANA USE This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have Epidemiology filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. Data from 2016 reported in the National Survey on Drug Use and Health Clinical reports from the American Academy of Pediatrics benefit from (NSDUH) revealed that 4.9% of pregnant women 15 through 44 years of expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of age reported use of marijuana* in the past month,1 compared with 11% Pediatrics may not reflect the views of the liaisons or the organizations of nonpregnant women in the same age group. This was an increase or government agencies that they represent. from the prior year, 3.4% and 10.3%, respectively. Among 18- through The guidance in this report does not indicate an exclusive course of 25-year-old pregnant women, 8.5% reported past month marijuana use in treatment or serve as a standard of medical care. Variations, taking 2016, compared with 3.3% of pregnant 26- through 44-year-old women. into account individual circumstances, may be appropriate.

* For the purposes of this report, the word “marijuana” is used intentionally to denote all To cite: Ryan SA, Ammerman SD, O’Connor ME, AAP COM­ substances derived from the cannabis plant, in lieu of the word cannabis, even when specifically MITTEE ON SUBSTANCE USE AND PREVENTION, AAP SECTION designated as such by cited research to avoid confusion; the exception is when the term ON BREASTFEEDING. Marijuana Use During Pregnancy and cannabis is part of a quotation. “Cannabis” is less typically used in most clinical settings and Breastfeeding: Implications for Neonatal and Childhood currently refers more to commercial products. Using the term marijuana also is consistent with Outcomes. Pediatrics. 2018;142(3):e20181889 many previous publications on this topic.

Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018:e20181889 FROM THE AMERICAN ACADEMY OF PEDIATRICS 8 Although 2016 data are not available (available at cdc.​gov/​prams). PRAMS marijuana during their pregnancy. for pregnant 15- through 17-year-old has conducted surveys on a sample In contrast12 to these studies, Forray women, 2012–2013 data revealed of women in Vermont with live et al found that, of 101 women 14.6% reporting use of illicit† drugs births since 2001 and has included who reported using marijuana at in the past month. Among these questions about marijuana use8 the beginning of pregnancy and who illicit substances, marijuana is the during pregnancy since 2009. In received substance abuse counseling, substance most commonly used by 2013, 9.4% of women in Vermont 78% were abstinent at a mean of 151 pregnant women. Widely variable reported marijuana use during their days later and remained abstinent rates are reported among published pregnancy, with no significant change until delivery. studies in both the United States in rates since 2009. PRAMS data from 13 Mark et al demonstrated in a and the United Kingdom. Authors of Hawaii revealed that women who δ retrospective cohort study of urban, a US multicenter lifestyle study in reported experiencing significant predominantly African American 2001 reported a prevalence of -9- nausea during their pregnancy women that, of patients receiving tetrahydrocannabinol (THC), the reported higher rates of marijuana prenatal care and delivering at psychoactive substance in marijuana, use (3.7%) compared with pregnant 9 their institution, 21.8% initially in infant meconium samples to be women without nausea (2.3%). The 2 – had positive screen results for 7.2%. Authors of a 2006 United 2012 NSDUH found that pregnant marijuana use (by either self- Kingdom based pilot study found women reported a decrease in their report or urine toxicology), but that 13.25% of a cohort of Scottish marijuana use from 9.0% to 4.8% only 1.9% had positive urine screen newborn infants had meconium in the first and second trimesters, results for marijuana at the time of samples that had positive results respectively, to 2.4% by the third delivery. They attributed their high for tetrahydrocannabinol and/or trimester. Reported rates of tobacco rate of cessation of marijuana use tetrahydrocannabinol-9-carboxylic use during pregnancy decreased 3 during pregnancy to be related to acid. In studies of urban, young, and from 19.9% to 13.4% and to 12.8% in opportunities for education about socioeconomically disadvantaged the first, second, and third trimesters, adverse effects of drug use, including pregnant women, reported rates respectively. Authors of other studies – tobacco and marijuana, during of marijuana use ranged between have found that 48% to 60% of 13 4 6 prenatal visits. 15% and 28%. ‍ Using NSDUH7 data marijuana users report continuing from 2002 to 2014, Brown et al “ ” use during their entire pregnancy, Marijuana use during pregnancy reported that the prevalence of believing4, 10,​it to11​ be safer than has been found to be associated past month marijuana use among tobacco. ‍ ‍ In the Longitudinal with higher rates of licit and pregnant women 18 through 44 Development and Infancy Study illicit substance use and certain years of age increased from 2.37% from11 the United Kingdom, Moore socioeconomic and demographic to 3.84%, with the highest use rates et al found that most pregnant characteristics. For example, in the reported in 18- through 25-year-old women who used cocaine, ecstasy, Vermont PRAMS study, researchers women (7.47% in 2014). Several methylenedioxymethamphetamine, found that pregnant women who state-specific surveys have also and other stimulants stopped using reported marijuana use were more been used to document increasing these substances by the second likely to be younger (<25 years of rates of marijuana use among trimester, but 48% of previous age), to be from households with pregnant women. The Pregnancy marijuana users continued to use lower income, to smoke cigarettes, Risk Assessment Monitoring marijuana as well as alcohol (64%) and to report having experienced System (PRAMS), a surveillance and tobacco (46%) throughout a significant emotional stressor project of the Centers for Disease their entire pregnancy. In addition, (traumatic, financial, or partner

Control and Prevention and state the Longitudinal Development and related) before8 or during13 the health departments, collects state- Infancy Study revealed that the pregnancy. Mark et al found that specific, population-based data on frequency and amounts of both use of marijuana was more common maternal attitudes and experiences marijuana and tobacco use were in women who reported being before, during, and after pregnancy sustained throughout the entire unemployed, without a high school pregnancy, similar to prepregnancy diploma, users of either alcohol or † The NSDUH defined illicit drug use to levels, whereas the extent of reported cigarettes, depressed, or a victim of include marijuana/hashish, cocaine (including alcohol use was reduced. PRAMS data abuse. In the Generation R study in14 crack), heroin, hallucinogens, inhalants, or from Vermont also revealed that for the Netherlands, El Marroun et al prescription-type psychotherapeutics used nonmedically. 2013 births, 44.6% of women who found in a sample of more than reported being marijuana smokers 7000 pregnant women that 85% before pregnancy continued to use of marijuana smokers were also Downloaded from www.aappublications.org/news by guest on November 2, 2018 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS cigarette6 smokers. Schempf and their pregnancy, because there are Studies that have been used to assess Strobino found that marijuana use few data available on the benefits the ability of metabolites of drugs was not independently related to of marijuana use9 during pregnancy. of abuse, including marijuana, to prenatal care. In their population of Roberson et al found that women cross the placenta are not recent poor, urban women, lack of adequate reporting marijuana use during and have revealed that recreational prenatal care, defined as 1 or no pregnancy were more likely to and licit substances directly cross prenatal visits, was significantly more report experiencing severe nausea the placenta, either through passive likely among cocaine and6 opiate users and vomiting (3.7%) compared with diffusion or, less commonly, through23 but not marijuana users. Reasons those not experiencing these severe active transport or pinocytosis. reported for this correlation with symptoms (2.7%). In a second study Among the numerous cannabinoids cocaine and opiate use included of women using marijuana during present in marijuana, the substance fear of being reported to police or their pregnancy, 51% reported using most responsible for the psychoactive child protective services and lower it for relief of nausea and vomiting, effects, THC, has been24 shown to readily perceived benefit of prenatal care. and 92% of those women reported cross the placenta. The THC molecule

Emphasized in these studies is its effectiveness; no controls19 were is highly lipophilic and is distributed the importance of considering the included in this study. Although the rapidly to the brain and fat of the potential confounding of additional use of marijuana is being touted on fetus after ingestion or inhalation by demographic and behavioral variables social media as an effective and safe the pregnant woman. After maternal when evaluating the independent role treatment of nausea and vomiting ingestion, concentrations of THC of marijuana on pregnancy15,16​ and fetal of pregnancy, there are currently in fetal blood are approximately and infant outcomes. ‍ no indications for its use during one-third to one-tenth24,25​ of maternal pregnancy; the American College concentrations. ‍ These It is important to note that of Obstetricians and Gynecologists concentrations can vary depending reported marijuana use rates can (ACOG) clearly stated this in5 its on the permeability and 26biological vary depending on the method of Committee Opinion in 2015. Of capacity of the placenta. In addition, screening used. Current guidance note, none of the states with legal when marijuana is smoked, serum recommends routine screening of all medicinal marijuana laws list carbon monoxide concentrations pregnant women for substance use pregnancy as a contraindication in the pregnant woman are 5 times by way of validated questionnaires5,17​ or for recommending or18 dispensing higher than those when tobacco conversations with patients. ‍ medicinalPharmacokinetics marijuana of. Cannabinoids is smoked, resulting potentially in Authors of most studies to date During Pregnancy impaired maternal respiratory gas have relied predominantly on self- exchange and subsequent27 adverse report, which may have resulted in effect on the fetus. Given these significant underestimation compared Marijuana can affect the normal known effects of marijuana on the with questionnaires or objective transport functions and physiologic placenta and placental transport, it is measures using urine screening or status of the20 placenta throughout biologically plausible that marijuana meconium samples. However, even pregnancy. One study has use during pregnancy could affect these objective measures will provide revealed that short-term exposure bothAdverse maternal Effects and of Marijuanafetal outcomes. on variable results, depending on the to cannabidiol, a nonpsychoactive Pregnancy and on the Neonate, Infant, Child, and Adolescent chronicity and intensity of use and the substance found in marijuana, recency of use related to the time that can enhance the placental barrier Outcomes During the Neonatal Period a urine sample is obtained. With the permeability to pharmacologic increasing number of states legalizing agents and recreational substances, marijuana use and with marijuana potentially placing the fetus21 at risk Two recent systematic reviews and being touted on the Internet as a safe from these agents22 or drugs. El meta-analyses have been published treatment of nausea during pregnancy, Marroun et al found that marijuana to determine the independent effect current rates of use of marijuana use during pregnancy, as compared of marijuana use during pregnancy during pregnancy are a concern. with either no marijuana use or on both maternal and early neonatal

Health care providers may see tobacco use, results in increased outcomes.28 The first study by Gunn increases in the number of pregnant resistance index and pulsatility index et al was used to review 24 studies women using marijuana during at18 of the uterine artery, with resulting to determine the effect of marijuana least a portion of their pregnancy. potential effects on uterine blood use on maternal anemia; neonatal flow, such as increased placental growth parameters, such as birth It is unclear why pregnant women resistance and reduced placental weight, head circumference, and are choosing to use marijuana during circulation. length; admission to the NICU; Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018 3 gestational age; and preterm demographic factors to control for pregnancy. These include the Ottawa birth. They found that women these confounders and determine Prenatal Prospective Study (OPPS), a who used any marijuana during the independent role of marijuana longitudinal cohort study of low-risk, pregnancy had a higher likelihood use. Exposure to marijuana was white, predominantly30,31​ middle-class of developing anemia, and infants defined as any amount, frequency, families ‍ ; the Maternal Health exposed prenatally to marijuana had or duration during the pregnancy, Practices and Child Development – a decrease in birth weight (mean assessed through self-report or Study (MHPCD), a cohort study of difference in weight of 110 g for objective means when available; high-risk, low socioeconomic status exposed versus unexposed neonates) comparison groups were women who women, representing both white32 and a higher likelihood of needing did not use any marijuana during and African American women ; the admission to an NICU. They found their pregnancy. When analyses Generation R study, a population- – 14 no relationship between marijuana controlled for concomitant tobacco based study from the Netherlands ; use and any of their other selected use, women who smoked marijuana and the United Kingdom based Avon outcomes. The authors pointed out, only were not at risk for preterm Longitudinal Study33 of Pregnancy however, that a major limitation delivery, but those who smoked and Childhood. Researchers of of their study was their inability to both tobacco and marijuana did the OPPS and the MHPCD found no determine the independent effect experience higher rates of preterm independent relationship between of marijuana, given that most of the delivery compared with those not prenatal marijuana use and preterm studies assessed did not exclude using either marijuana or tobacco. births, miscarriages, pregnancy individuals with polysubstance use, They also found no independent complications, or Apgar scores or including tobacco or alcohol, or relationship between marijuana use physical anomalies in the neonates, measure use of those substances. and small-for-gestational-age status, but researchers of the OPPS did find The authors also cited additional placental abruption, need for NICU a decrease in the length of gestation limitations, such as how the use of admission, or spontaneous abortion. by 0.8 weeks associated34,35​ with heavy marijuana was identified mainly by They did find that women using marijuana use. ‍ Researchers of self-report, and few of the outcomes marijuana during pregnancy were the MPHCD study found that weight assessed were standardized across more likely to deliver an infant with at birth was increased for neonates studies. lower mean birth weight or lower prenatally exposed to marijuana 35in 29 Apgar scores and to experience the third trimester of pregnancy. Conner et al has attempted to stillbirth, but these results were In the Generation R study, fetal address the limitations28 cited in the unadjusted, because the authors growth was measured by using review by Gunn et al by adjusting were limited in their analytic ability ultrasonography, and the researchers the effects of marijuana exposure to provide adjusted relative risk rates found an independent effect of during pregnancy for tobacco use for these outcomes. They concluded marijuana use, over and above the and other confounders, such as other that maternal marijuana use during effect observed with concomitant drug use, wherever possible, in a pregnancy was not an independent tobacco use, on decreased fetal second meta-analysis. Their study risk factor for several outcomes, growth that was observed beginning given the confounding effect with included the systematic review of “ in the second trimester and resulted 31 studies (from 1982 to 2015) in factors such as tobacco use. They in lower birth weight, specifically which they specifically evaluated stated that the increasing frequency when marijuana use was begun of marijuana use during pregnancy the effect of maternal marijuana use ” early in pregnancy and continued14 on neonatal outcomes that included may play a role in risk for adverse throughout the entire pregnancy. ’ “ low birth weight (<2500 g), preterm neonatal outcomes but cautioned The Generation R study was also delivery (<37 weeks gestation), birth that women who use marijuana used to assess the role of paternal more frequently are also more likely weight, gestational age at delivery, ” marijuana use, and no independent admission to the NICU, small-for- to use higher amounts of tobacco association with fetal growth was gestational-age status, stillbirth, and other drugs,​ which could not found. In the Avon Longitudinal33 spontaneous abortion, low Apgar be accounted for completely in their Study, Fergusson et al found scores, placental29 abruption, and review. an association between prenatal perinatal death. A major strength marijuana use and smaller birth of this review was the inclusion Both systematic reviews included lengths, smaller head circumferences, of cohort studies used to measure longitudinal cohort studies used and lower birth weights among those use of other substances, such as to provide data that are mixed in reporting marijuana use in pregnancy, tobacco and other recreational terms of adverse outcomes in infants compared with women in the control drugs, and socioeconomic and exposed to prenatal marijuana during group who did not report use. Downloaded from www.aappublications.org/news by guest on November 2, 2018 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS Authors of another recent large, pregnancy, although the authors did described in the previous section) population-based cohort study found not control for whether these women have been used to observe cohorts that self-reported marijuana use, took supplemental folic acid during of prenatally exposed individuals without concomitant use of nicotine early pregnancy. Immediate newborn from infancy through adolescence and/or tobacco, was not associated behaviors that have been observed and early adulthood, and these with pregnancy complications, in those infants who were exposed provide most of the limited available preterm birth, or changes in to marijuana in utero include altered evidence on the long-term adverse neonatal outcomes such as Apgar36 arousal patterns, regulation, and neurodevelopmental effects scores and growth parameters. excitability, as measured by the resulting from30, prenatal32​ exposure However, concomitant use of both NICU 39Network Neurobehavioral to marijuana. ‍ Authors of both marijuana and tobacco, compared Scale. Increased tremors and studies have assessed long-term with tobacco use alone, resulted in prolonged and exaggerated startle outcomes in the areas of executive an increased risk of multiple adverse reflexes, as measured by the Neonatal function, cognition, academic perinatal outcomes, higher rates of Behavioral Assessment Scale, were achievement, and behavior. maternal asthma and preeclampsia, observed in the first week and 40 preterm births, and infants with persisted at 9 and 30 days of life. Researchers of OPPS have observed decreased (<25th percentile) head Poor habituation and responses41 to its cohort since 1978 (original total circumferences and decreased (<25th visual but not auditory stimuli,​ 42 of 84 pregnant women who use percentile) birth weights. Less than 1% abnormal high-pitched cries,​ marijuana) and have demonstrated of the total sample of 12069 women and abnormal sleep patterns with that, independent of tobacco and reported use of marijuana, which raises decreased quiet43 sleep and increased other drugs, marijuana exposure has concerns about the representativeness sleep motility have also been noted significant and pervasive effects that of the sample or validity of self- in the first week44 of life. A study by are noticeable in children beginning reported use of substances. Dreher et al of Jamaican infants at 4 years of age and continuing into exposed to marijuana prenatally young adulthood. Initial observable A small number of studies have been did not reveal any abnormalities. effects at 4 years of age included used to assess the role of marijuana Although researchers have suggested lower scores in verbal45 reasoning in outcomes not addressed in the that these behaviors share some and memory tasks. At 6 years of 2 systematic reviews above, such similarities with symptoms observed age, children exposed to marijuana, as outcomes in preterm infants, in the neonatal abstinence syndrome compared with nonexposed children neonatal behavioral outcomes, as well as with opioid withdrawal, in the control group, showed and 37fetal anomalies. Dotters-Katz there are no data being used now deficits in global measures of et al published a secondary data to support a clinical withdrawal language comprehension, memory, ’ analysis on a group of preterm syndrome with marijuana exposure. visual and/or perceptual function, infants born before 35 weeks and reading tasks that require In summary, the evidence for gestation comparing the neonatal sustained attention, with a dose independent, adverse effects of outcomes of those with prenatal response observed, in that those n marijuana on human neonatal marijuana exposure by maternal exposed to higher amounts of outcomes and prenatal development report or drug screening ( = 138) marijuana prenatally demonstrated n is limited, and inconsistency in – versus infants with no marijuana higher dysfunction on impulsive findings may be the result of the 46 48 exposure ( = 1732). They found and hyperactive scales. ‍ ‍ At 9 potential confounding caused by the that prenatal marijuana exposure through 12 years of age, marijuana high correlation between marijuana had no detrimental effect on death exposure was not independently use and use of other substances such before hospital discharge, grade 3 associated with global intelligence as cigarettes and alcohol, as well or 4 intraventricular hemorrhage, or verbal subscales on intelligence as sociodemographic risk factors. periventricular leukomalacia, testing but was associated with However, the evidence from the necrotizing enterocolitis, deficits in executive function tasks, available research studies indicate – bronchopulmonary dysplasia, such as impulse control and visual – reason for concern, particularly in fetal 49 52 cerebral palsy, and/or a Bayley problem-solving. ‍ ‍ At 13 through growth and early neonatal behaviors. Scales of Infant Development II <70 Later Effects During Childhood, 16 years of age, problems were 37 38 Adolescence, and Early Adulthood at 2 years of age. van Gelder et al seen in attention, problem-solving,– found a higher rate of anencephaly visual integration, and analytic51, skills53​ 55 in fetuses of women who smoked requiring sustained attention. ‍‍ marijuana immediately before Two longitudinal studies (the OPPS A functional MRI study of this cohort and during the first trimester of and the MHPCD, which have been at ages 18 through 22 years revealed Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018 5 – changes in neural activity with Test Revised, with mothers who For more distal outcomes, such working memory tasks that were reported smoking marijuana62 during as later childhood and adolescent not observed in unexposed matched56 the second trimester. Lower global cognition and behavior, studies were children in the control group. achievement, reading, spelling, limited in the environmental and sociodemographic variables that the Fried et al have postulated that the and math scores were63 also seen behavioral problems and decreased at 14 years of age. Measures of authors could control, which could be performance on global measures problem behaviors and mental health expected to influence development70, 71​ observed throughout childhood and symptoms were also reported in across childhood and adolescence. ‍ into early adulthood reflect deficits both cohort studies. The authors Despite these limitations and the in executive 31,functioning,54,​ 57,​ 58​ not overall of the OPPS found higher rates of relative paucity of research in this intelligence. ‍ ‍ area, the findings regarding growth reported problem behaviors64 at 6 72 through 9 years of age and higher variables and neurodevelopmental Researchers of the MHPCD have rates of depressive symptoms at 16 and behavioral outcomes can be used observed a cohort of exposed 65 through 21 years of age. Authors to suggest that marijuana use during infants since 1982 to determine the of the MHPCD also found higher pregnancy may not be harmless. In independent effects of marijuana on addition, the existing cohort studies cognition, behavior, temperament, rates of depressive symptoms and externalizing behaviors via parent were conducted when the available mental health disorders, and marijuana had a much lower potency substance use from infancy through and teacher report in the exposed cohort at 10 years of age and an than what is available today, which adolescence and early adulthood. raises concern that the adverse increased66,67​ risk of psychosis in young At 9 months of age, impaired59 mental consequences of prenatal exposure adults. ‍ Higher rates of substance development was seen. At 3, 4, and in currently pregnant women may use were also reported by these 2 6 years of age, deficits in executive be much greater than what has cohort studies. Authors of the OPPS “ 18” function tasks similar to those been reported to date. (See the found earlier onset and greater use observed in the OPPS, with poorer Other Considerations section for of both marijuana and tobacco in the memory60,61​ and verbal measures were discussion on potency.) Rigorous exposed cohorts, observed at ages found ‍ ; at 6 years of age, impaired 65 research is needed to determine the 16 through 21 years,​ and authors sustained attention on vigilance tasks independent effects of marijuana, of the MHPCD found higher rates of and verbal reasoning and increased as well as tobacco and other drugs, marijuana and tobacco use across the impulsivity and hyperactivity on neonatal and later childhood and ages of 14 through 21 years, even after was observed with those exposed adultMechanisms outcomes. Used to Explain controlling for home environment during the first trimester whose 66,68​ Underlying Effects on the Developing mothers61 smoked at least 1 joint per and parental69 substance use. ‍ Fetus day. Adverse consequences in Sonon et al have also demonstrated later childhood included impaired higher rates of marijuana use in young executive functioning and visual adulthood after prenatal exposure to Cannabinoids mediate their problem-solving at 9 through 12 years marijuana. effects through the cannabinoid of age and increased hyperactivity, In summary, it is essential to note receptors, type 1 and 2. The impulsivity, and inattention at 10 that the studies discussed above have endocannabinoid system (ECS) years of age for those whose mothers limitations that may threaten the comprises these receptors, had smoked marijuana during62 both validity of the findings. For example, along with the neurochemical the first and third trimesters. Unlike the studies in which authors look cannabinoids anandamide and the OPPS, whose authors did not find at proximal results, such as fetal or 2-arachidonoylglycerol. This has deficits in intellectual abilities and early neonatal outcomes, rely in most been studied in both animal as well on measurements of standardized part on self-report of marijuana use, as human models, specifically for academic tests at ages 6 through 9 and there is little standardization its effect on the immune system 23 or 13 through 16 years, authors of across studies in the amount of and the central nervous system. the MHPCD did find lower reading marijuana used and frequency of Although the consequences of and spelling scores in 10-year-old use. Many of these studies included prenatal marijuana exposure in children whose mothers reported pregnant women who used other pregnant women, both behavioral smoking at least 1 joint per day during substances in addition to marijuana, and developmental, have been the first trimester of pregnancy and such as tobacco, alcohol, or other documented in epidemiological deficits in reading comprehension drugs, and analytic methods were studies, the molecular mechanisms and underachievement, as measured used to control for the confounding that are postulated to be associated by the Wide Range Achievement effects of these other substances. with these effects of prenatal Downloaded from www.aappublications.org/news by guest on November 2, 2018 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS drug exposure are only now being fetal brain development. The result changes to the genetic code that elucidated. The ECS is detectable is a disruption of the precisely occur after the genetic makeup ’ from the early stages of embryonic orchestrated signaling and of the individual is determined, development (as early as 5 weeks sequencing functions of the ECS, either prenatally or postnatally. gestation) and has been found to affected by the CB1 receptors, and These genetic alterations include play an essential role in the early mediated through the excessive microRNAs, DNA methylation, and stages of neuronal73 development degradation of the intracellular 74 posttranslational modifications77 and cell survival. Researchers substances such as SCG10 and JNK1. of nucleosomal histones. They of new data elucidate how this Researchers have also found that are stable alterations that occur system is involved in the control of unlike the adult brain, in which CB1 during critical developmental neuronal developmental processes receptors are widely distributed periods and result in enduring77 such as cell proliferation, migration, throughout most areas of the brain, phenotypical abnormalities. For and differentiation; thus, it is in the fetus, CB1 receptors are found example, researchers have found that not surprising that cannabinoid primarily in the mesocorticolimbic marijuana exposure in early fetal life exposure during early developmental structures such as the amygdaloid decreases the expression of genes stages can result in the long-term complex, the hippocampus, and the (through histone lysine methylation) neurobehavioral consequences ventral striatum, all areas that are for dopamine receptors (DRD2) in described previously. important for emotional75 regulation, those areas of the brain important cognition, and memory. Researchers for reward recognition (ventral Although authors of early studies have also found that male fetuses may striatum, nucleus accumbens), relied on animal models, authors of have a greater vulnerability to early which may explain higher rates of recent studies conducted on electively developmental effects65, of76​ prenatal drug addiction in adults 78exposed aborted fetuses have provided marijuana exposure. ‍ It is still prenatally to marijuana. THC specific human data, which have been unclear to what extent this disruption also causes substantial changes in used to support findings observed 20 or alteration of developmental gene expression levels of several with animal models. Tortoriello et al synaptic organization is responsible other significant systems in the brain that are linked to the ECS, have used sophisticated quantitative for early neonatal birth effects, γ and qualitative molecular analyses longer-term neurodevelopmental such as the opioid, glutamate, and and pharmacologic methods to effects, or increased vulnerability -aminobutyric acid systems, which79 study human fetuses electively of later teenagers and adults for Linkagesmay persist of wellthe ECS into to adulthood. Other aborted during the second trimester, addiction or psychiatric illness. Neurotransmitter Systems in both pregnant women who With the limited data, it is suggested smoked marijuana and pregnant that the neuronal systems involved women in a control19 group who did in early development need to be The ECS has been found to have a μ δ κ not use marijuana. They found studied further for us to understand strong interaction with the opioid that in fetuses exposed prenatally more fully the molecular mechanism systems, through the , , and to marijuana, levels of molecular underlying the effects of maternal 80 opioid79 receptors,​ Jutras-Aswad substances essential for neuronal marijuana on the human fetal et al have found that early cell axonal elongation (SCG10) are brain and specifically for those marijuana exposure influenced the significantly reduced, which affects systems involved in neurocognition, expression and activity of opioid the disassembly of microtubules impulsivity, and addiction “ ” 76 receptors that have been found to be essential for axonal elongation vulnerability. important in reward and subsequent and the pathfinding essential addictive behaviors. The ECS has also for the development of normal Epigenetic mechanisms are also been found to be associated with the neuronal circuitry during early brain being proposed as one of the γ serotonergic, adrenergic, glutamate,78 development. THC acts as a partial explanations for the consequences and -aminobutyric acid systems. agonist and binds to the cannabinoid of prenatal marijuana exposure Issues for the Clinician receptors (CB1) during fetal on fetal neurodevelopment and to development by reducing endogenous explain why adolescents and adults endocannabinoid synthesis who have been exposed to marijuana The American Academy of (especially 2-arachidonoylglycerol) “ ” prenatally demonstrate an increased Pediatrics (AAP), the ACOG, and and subsequent CB1 expression. This vulnerability to later addiction77 and the American Society of Addiction results in a functional hijacking psychiatric disorders. Epigenetics Medicine recommend that all or supraphysiological modulation refers to the mechanism by which women considering pregnancy, of the normal ECS during early gene expression is altered without pregnant women throughout their Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018 7 pregnancy, and those attending still an illicit substance under federal recreationally, the benefits of predelivery pediatric visits be law, this law applies to marijuana breastfeeding must be weighed screened routinely for alcohol and exposure in all states regardless of against the effects of the drug on ’ ’ other drug use, including marijuana, the legal status of marijuana use by the infant to make a decision that by using a validated17,81​ screening adults in each state. Individual states is in the infant s and mother s best questionnaire. ‍ Screening and may have other requirements for the interests. Many medications that brief intervention techniques are reporting of newborn infants exposed mothers use while breastfeeding are recommended to counsel abstinence to drugs and84 other exposures to also taken during pregnancy. It can for individuals using substances children. be difficult to determine whether and to refer for treatment those effects of the drug on the infant are Given these legal requirements, individuals meeting criteria for attributable to exposure during 81 it is advisable for all health care ’ any substance use disorder. pregnancy or from breastfeeding. providers who see pregnant women Despite these recommendations, in Additionally, a mother s ability to 82 to be aware of the specific reporting 1 study, Holland et al found that care for her infant may be impaired requirements of their state and of the 19% of women reporting because of her use of marijuana. the potential adverse legal and current marijuana use (53%) or Infants can also be exposed to social consequences of identifying past marijuana use at their initial marijuana through inhalation of substance use in their patients. When prenatal visit, only 52% received any marijuana smoked in the presence of a legal or medical obligation exists 86,87​ kind of counseling. In addition, the the infant. ‍ for a health care provider to test a Epidemiology counseling that was provided was patient, he or she should counsel focused mainly on legal and child patients about these potential protective consequences of detection consequences before ordering drug at delivery, rather than specific There are few data about the tests and make a reasonable effort medical or health effects of marijuana 5 frequency of use of marijuana by to obtain informed consent. Of use. In July 2015, the ACOG published women while breastfeeding. A report note, in states with requirements a position statement that was from Colorado, where marijuana “ for the reporting of newborn infants specifically used to advise against is legal for some, surveyed women exposed to drugs, these supersede the prescribing or suggesting the attending the Special Supplemental federal law on confidential protection use of marijuana for medicinal Nutrition Program for Women, ” of patient records when receiving ’ purposes during preconception, Infants, and Children program 5 addiction treatment (42 Code of pregnancy and lactation. Most 81 in the state s largest local health Federal Regulations Part 2). states that have legalized medicinal department. It revealed that 7.4% of marijuana have not specifically BREASTFEEDING AND MARIJUANA USE mothers younger than 30 years of limited its dispensing to pregnant age and 4% of mothers older than 30 women. Oregon is the only state that years of age were current marijuana has legislated specific point-of-sale Breastfeeding is recognized as the users. Of all marijuana users (past, ideal feeding method for infants ever, current), 35.8% said that warnings to dispensaries for women83 who are pregnant or breastfeeding. because of the numerous short- they had used at some point during It is beyond the scope of this term and long-term benefits of pregnancy, 41% had used since the report to discuss specific validated breastfeeding for the mother and the infant was born, and88 18% had used questionnaires that are available infant. These benefits include but are Pharmacokineticswhile breastfeeding of. Marijuana in or various means for objective not limited to decreased infections, Human Milk screening. such as gastroenteritis, ear infections, and severe respiratory diseases; Health care providers are mandated decreased obesity and diabetes The excretion of medications into to report to child protective services mellitus; decreased rate of sudden human milk depends on chemical any cases of suspected child abuse infant death syndrome; improved factors about the drug, including or neglect. The 2010 Child Abuse intellectual development; decreased ionization, the molecular weight, and Prevention and Treatment Act postpartum blood loss; increased the solubility in lipids and water, requires all states to have policies child spacing; and decreased risk and the pH of the drug. The major and procedures for reporting of type 285 diabetes mellitus for the psychoactive cannabinoid of newborns and other children who mother. marijuana, THC, is 99% protein are exposed to illicit substances bound, is lipid soluble, and89 has a under the definition of child abuse When pregnant mothers take molecular weight of 314. The and/or neglect. Because marijuana is medications prescribed or low molecular weight and high Downloaded from www.aappublications.org/news by guest on November 2, 2018 8 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 Primary Sources for the Concentrations of THC Transmission Into Human Milk Mother Maternal Marijuana Dose Amount of THC in Maternal Amount of THC in Human Milk lipid solubility combine to cause Plasma marijuana transfer into human A91 Smoked in pipe 1 time per — 105 ng/mL milk. It also causes storage of THC day in lipid-filled tissues such as the B91 Smoked in pipe 7 times 7.2 ng/mL 60.3 ng/mL brain. Little is known about the per day other cannabinoids in marijuana C90 No information — 86 ng/mL and their transfer into human —, not applicable. milk. There are few data about the transfer of THC into human milk. With Table 1, we list the results from the only 2 primary references about of infants exposed to marijuana breastfeeding from prenatal concentrations of THC in human milk. through breastfeeding, self-selection exposure. These limited data by Perez-Reyes of mothers who participated in 90 91 Another area of concern is the use of and Wall and Marchei et al reveal the 1-year follow-up, and lack of expressed maternal milk for feeding that THC transfers into human milk. control for use of other substances, 92 preterm infants when the mother has There is no information about how particularly alcohol. reported marijuana use or receives the amount transferred is related 93 positive test results for marijuana. to the concentration of THC in the Astley and Little studied diet, Expressed maternal milk has been marijuana, the frequency of use, alcohol, and tobacco use during shown to significantly improve or the concentration in maternal lactation in a group of middle-class outcomes in preterm infants by plasma.The Effect of Marijuana on Breastfed mothers. Developmental evaluation decreasing the rate of necrotizing Infants at 1 year was completed on 68 infants enterocolitis (both surgical and whose mothers used marijuana while nonsurgical), contributing to earlier breastfeeding who were matched attainment of full enteral feeds, There are 2 small studies by Tennes with mothers with similar alcohol 92 93 decreasing the rate of sepsis, and et al and Astley and Little from and tobacco use who did not use improving neurodevelopmental the 1980s in which the authors marijuana while breastfeeding. Of outcomes, especially for the preterm attempt to evaluate the effect of the breastfeeding mothers, 79% infants with a birth weight of less maternal marijuana use while reported marijuana use while 85 than 1500 g. breastfeeding on the infant. Both pregnant, compared with 15% of Published Recommendations From studies included mothers who mothers of infants who were fed Other Organizations ’ also used alcohol, other92 drugs, and formula. In multivariate regression tobacco. Tennes et al studied analysis, the infant s exposure to “ 258 mothers using marijuana and marijuana during breastfeeding in The 2012 AAP policy statement, ± ” compared them to mothers who did Breastfeeding and the Use of the first month was associated with “ not use marijuana. They examined 14 5 points decrease in motor Human Milk,​ included the following the infants at 24 to 72 hours of age guidance: maternal substance abuse scores after controlling for tobacco, ” “ and a subgroup at 1 year of age. alcohol, and cocaine use during is not a categorical contraindication They found the following results: pregnancy and lactation. There was to breastfeeding. Street drugs such (1) marijuana users were more likely no effect of marijuana use in the third as PCP (phencyclidine), cocaine, and to use illicit drugs and alcohol with month of life while breastfeeding. cannabis can be detected in human a significant linear dose-response milk, and their use by breastfeeding R Marijuana use in the first trimester ’ Prelationship between the use of of pregnancy confounded these mothers is of concern, particularly marijuana and alcohol ( = 0.45; regarding the infant s long-term results, and it was not clear whether ” < .01); (2) infants exposed to exposure prenatally or during neurobehavioral development85 marijuana were slightly shorter; breastfeeding had more association.92 and thus are contraindicated. ‍ (3) most mothers decreased use of The studies by Tennes93 et al and Although this has been interpreted marijuana during pregnancy; and Astley and Little had small sample by some professional organizations (4) no differences were noted in the sizes, were completed more than 30 to indicate that in the parent ’ “ ” 1-year growth and scores on the years ago, were associated with use using marijuana, the choice to Bayley Scales of Infant Development; of marijuana during the mother s breastfeed is contraindicated,​ however, only 27 of the infants tested pregnancy, and had no long-term this was not the intent of that at 1 year were exposed to marijuana follow-up. These limitations make statement. It is suggested instead while being breastfed. These results it difficult to separate independent that the mother be encouraged to are limited by the small number effects of marijuana use during breastfeed while, at the same time, Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018 9 it is strongly encouraged that she than what was available a decade given the potential confounding abstain completely from using ago. The potency of THC in samples of the effect of marijuana during marijuana as well as other drugs, studied in 1983 averaged 3.2%, and pregnancy by other licit and illicit alcohol, and tobacco. This position the average in 2008 was 13.2%; the substances and sociodemographic has been supported by several other authors of that same study identified and environmental risks factors. professional organizations and isolated samples with THC contents95 However, highlighted in the resources. For example, LactMed as high as 27.3% and 37.2%. These available epidemiological and (a free searchable database from higher potencies as well as new animal data are concerns regarding the National Library of Medicine) practices of marijuana use, such as both short-term growth and long- recommends that mothers be dabbing or vaping, can significantly term neurodevelopmental and encouraged to abstain from or increase the concentration of THC behavioral consequences of prenatal reduce their marijuana use while being consumed. Studies have exposure to marijuana. Our current breastfeeding and to minimize revealed that the development understanding of the ECS and its of marijuana strains with higher role in the development of neural infant exposure to marijuana smoke. “ ” The LactMed peer review panel, THC concentrations has reduced circuitry early in fetal life also which reviews published data the concentration of cannabidiol, provides theoretical justification to ensure scientific validity and possibly decreasing the medicinal for the potential of marijuana currency, recommends86 continuing benefits for a select number of substances, particularly18 THC, to affect breastfeeding. This is similar to conditions. There are many other neurodevelopment. “ the recommendations of the ACOG, substances contained in the which state, There are insufficient marijuana plant in addition to THC Breastfeeding has numerous valuable data to evaluate the effects of and cannabidiol about which little health benefits for the mother and marijuana use on infants during is known. Additionally, marijuana the infant, particularly the preterm lactation and breastfeeding, and in is often grown with the use of infant. Limited data reveal that THC ” does transfer into human milk, and the absence of such 5data, marijuana pesticides, herbicides, rodenticides, “ there is no evidence for the safety use is discouraged. ‍ The Academy and fertilizers,96,97​ many of which are of Breastfeeding Medicine states A toxic. ‍ Exposure to marijuana may or harm of marijuana use during recommendation of abstaining from also expose the fetus and infant to lactation. Therefore, women also any marijuana use is warranted. At these toxins. need to be counseled about what is this time, although the data are not CONCLUSIONS AND known about the adverse effects of strong enough to recommend not RECOMMENDATIONS THC on brain development during ” early infancy, when brain growth and breastfeeding with any94 marijuana use, we urge caution. ‍ After development are rapid. ≥ Colorado legalized the use of Pediatricians are in a unique position The importance of the published marijuana by adults 21 years old, to counsel women of childbearing findings and the emerging research the Colorado Department of Public age about the potential negative regarding the potential negative Health and Environment developed consequences of marijuana use effects of marijuana on brain educational material about marijuana during pregnancy and breastfeeding. development are a cause for concern use during pregnancy and while Discussing what is known despite the limited research and breastfeeding. These materials about adverse consequences of are the basis for the following include patient education handouts marijuana use during pregnancy recommendations: that may be helpful to pediatricians and breastfeeding at prenatal visits and families and are available at the with either the pediatrician or the 1. Women who are considering following link: www.​colorado.gov/​ ​ obstetric provider is an important becoming pregnant or who pacific/​sites/​default/​files/​MJ_​RMEP_​ component of promoting the best are of reproductive age need Pregnancy-​Breastfeeding-Clinical-​ ​ health outcomes for both the to be informed about the lack Guidelines.pdf.​ Other states that have pregnant woman and the infant. of definitive research and legalized marijuana may have similar Legalization of marijuana may give counseled about the current educational information for health the false impression that marijuana concerns regarding potential care providers and families. is safe. Given ethical concerns, there adverse effects of THC use OTHER CONSIDERATIONS are no randomized controlled trials on the woman and on fetal, on the effect of marijuana use by infant, and child development. pregnant and lactating women, and Marijuana can be included as The potency of marijuana now the available longitudinal studies part of a discussion about the routinely available is much higher must be viewed with caution use of tobacco, alcohol, and other Downloaded from www.aappublications.org/news by guest on November 2, 2018 10 FROM THE AMERICAN ACADEMY OF PEDIATRICS Stephen W. Patrick, MD, MPH, MS, FAAP Jennifer Plumb, MD, MPH, FAAP drugs and medications during unknown, women should be Joanna Quigley, MD, FAAP pregnancy. informed of the potential risk Leslie R. Walker-Harding, MD, FAAP of exposure during lactation 2. As part of routine anticipatory FORMER COMMITTEE MEMBERS and encouraged to abstain from guidance and in addition to Seth D. Ammerman, MD, FAAP, FSAHM, DABAM using any marijuana products contraception counseling, Lucien Gonzalez, MD, MS, FAAP while breastfeeding. it is important to advise all LIAISON adolescents and young women 7. Pregnant or breastfeeding that if they become pregnant, women should be cautioned Gregory Tau, MD, PhD – American Academy of Child and Adolescent Psychiatry marijuana should not be used about infant exposure to during pregnancy. smoke from marijuana in the STAFF environment, given emerging 3. Pregnant women who are using Renee Jarrett, MPH data on the effects of passive marijuana or other cannabinoid- marijuana smoke. containing products to treat a SECTION ON BREASTFEEDING EXECUTIVE COMMITTEE, 2017 2018 medical condition or to treat 8. Women who have become – nausea and vomiting during abstinent from previous Joan Younger Meek, MD, MS, RD, FAAP, IBCLC, Chairperson pregnancy should be counseled marijuana use should be Maya Bunik, MD, MSPH, FAAP encouraged to remain about the lack of safety data and Mary E. O’Connor, MD, MPH, FAAP the possible adverse effects of abstinent while pregnant and Lisa Stellwagen, MD, FAAP THC in these products on the breastfeeding. Jennifer Thomas, MD, MPH, FAAP Julie Ware, MD, FAAP developing fetus and referred 9. Further research regarding to their health care provider for the use of and effects of SUBCOMMITTEE CHAIRPERSONS alternative treatments that have marijuana during pregnancy and Lawrence Noble, MD, FAAP Policy Chairperson better pregnancy-specific safety – breastfeeding is needed. Krystal Revai, MD, MPH, FAAP – Chief Chapter data. Breastfeeding Coordinator 10. Pediatricians are urged to 4. Women of reproductive age Margaret Parker, MD, MPH, FAAP – Education work with their state and/ Program Chairperson who are pregnant or planning or local health departments to become pregnant and are if legalization of marijuana FORMER EXECUTIVE COMMITTEE MEMBER identified through universal is being considered or has Margreete Johnston, MD, MPH, FAAP screening as using marijuana occurred in their state to help should be counseled and, as with constructive, nonpunitive STAFF clinically indicated, receive brief policy and education for Ngozi Onyema-Melton, MPH, CHES intervention and be referred to families. treatment. RESOURCES 5. Although marijuana is legal ABBREVIATIONS in some states, pregnant women who use marijuana Additional resources include the can be subject to child welfare AAP Resources on Marijuana (www.​ AAP: American Academy of investigations if they have a aap/​marijuana), the AAP Section Pediatrics positive marijuana screen result. on Breastfeeding (www.​aap.​org/​ ACOG: American College of Health care providers should breastfeeding), the Academy of Obstetricians and emphasize that the purpose of Breastfeeding Medicine (www.​bfmed.​ Gynecologists ’ screening is to allow treatment org), the ACOG (www.​acog.​org/​ ECS: endocannabinoid system of the woman s substance use, About-​ACOG/​ACOG-​Departments/​ MHPCD: Maternal Health not to punish or prosecute her. Breastfeeding), and LactMed (toxnet.​ Practices and Child nlm.​nih.​gov/​newtoxnet/​lactmed.​htm). Development Study 6. Present data are insufficient to LEAD AUTHORS NSDUH: National Survey on Drug assess the effects of exposure of Sheryl A. Ryan, MD, FAAP Use and Health infants to maternal marijuana Seth D. Ammerman, MD, FAAP, FSAHM, DABAM Mary E. O Connor, MD, MPH, FAAP OPPS: Ottawa Prenatal use during breastfeeding. As ’ Prospective Study a result, maternal marijuana COMMITTEE ON SUBSTANCE USE AND PRAMS: Pregnancy Risk use while breastfeeding is PREVENTION, 2017–2018 Assessment Monitoring discouraged. Because the δ Sheryl A. Ryan, MD, FAAP, Chairperson System potential risks of infant exposure THC:  -9-tetrahydrocannabinol to marijuana metabolites are Downloaded from www.aappublications.org/news by guest on November 2, 2018 PEDIATRICS Volume 142, number 3, September 2018 11 All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

DOI: https://​doi.​org/​10.​1542/​peds.​2018-​1889

Address correspondence to Seth D. Ammerman, MD, FAAP, FSAHM, DABAM. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/142/3/e20181889 References This article cites 85 articles, 7 of which you can access for free at: http://pediatrics.aappublications.org/content/142/3/e20181889#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Nutrition http://www.aappublications.org/cgi/collection/nutrition_sub Breastfeeding http://www.aappublications.org/cgi/collection/breastfeeding_sub Substance Use http://www.aappublications.org/cgi/collection/substance_abuse_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on November 2, 2018 Marijuana Use During Pregnancy and Breastfeeding: Implications for Neonatal and Childhood Outcomes Sheryl A. Ryan, Seth D. Ammerman, Mary E. O'Connor, COMMITTEE ON SUBSTANCE USE AND PREVENTION and SECTION ON BREASTFEEDING Pediatrics 2018;142; DOI: 10.1542/peds.2018-1889 originally published online August 27, 2018;

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