MARIJUANA / CANNABIS | TERIS agent - 1068

TERIS Summary
TERIS Agent Number: 1068 Bibliographic Search Date: 06/2020
Agent Name: MARIJUANA / CANNABIS    

 

Marijuana (cannabis sativa) is widely used as a medicinal and recreational drug. There are many routes of exposure including smoking the flowers and leaves, vaping concentrates, applying a vaporized spray to the buccal area, ingesting capsules, liquids, or foods, and applying topical lotions. The principal psychoactive ingredient is delta-9-tetrahydrocannabinol (THC). The most common reasons pregnant women give for using marijuana are nausea and vomiting of pregnancy, chronic pain, and anxiety (Metz & Borgelt, 2018).



Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
   

MALFORMATIONS: NONE TO MINIMAL

NEURODEVELOPMENTAL OUTCOMES: MINIMAL


Quality and Quantity of Data on Which Risk Estimate is Based:
   

MALFORMATIONS: LIMITED TO FAIR

NEURODEVELOPMENTAL OUTCOMES: LIMITED TO FAIR


Comments:   

 

1) THE RATING PROVIDED FOR MARIJUANA/CANNABIS IS PRIMARILY BASED ON INFORMATION FROM OLDER EPIDEMIOLOGY STUDIES. THE CANNABIS PRODUCTS AVAILABLE TODAY ARE FAR MORE POTENT AND ROUTES OF EXPOSURE HAVE CHANGED OVER TIME. THE TERATOGENIC RISK ASSOCIATED WITH FETAL EXPOSURE TO HIGHER LEVELS OF THC IS NOT WELL STUDIED.

 

2) THIS SUMMARY APPLIES ONLY TO THE POSSIBLE RISKS ASSOCIATED WITH EXPOSURE TO THC DURING PREGNANCY. PLEASE SEE AGENT SUMMARY ON CANNABIDIOL FOR INFORMATION ON OTHER CHEMICAL COMPOUNDS FOUND IN THE CANNABIS PLANT.


Summary of Teratology Studies:

MAJOR CONGENITAL ANOMALIES

Many published epidemiological studies of infants born to women who used cannabis during pregnancy are compromised by poor or absent information on the dose, duration, and gestational timing of exposures. The influence of confounding variables such as maternal age, concurrent drug and medication use, smoking, parity, body mass index, prenatal care, folic acid intake, and socioeconomic status is likely to be significant in some investigations.

There was no increase in the frequency of congenital anomalies among the infants of approximately 13 regular cannabis users (one or more joints per week) during pregnancy in the longitudinal Ottawa Prenatal Prospective Study (Fried, 1982). Similarly, the frequency of congenital anomalies was no greater than expected among the infants of 103 women who used cannabis regularly (one or more joints per day) during the first trimester in the prospective Maternal Health Practices and Child Development Project (Day et al., 1991). The prevalence of congenital malformations was also no greater than expected among infants born to 283 women with a positive THC screen at any point during pregnancy in a retrospective observational study (Kharbanda et al., 2020) or in another cohort study of 361 infants whose mothers who self-reported cannabis use during pregnancy or had a positive urine screen (Warshak et al., 2015). In a large records study conducted in 2019, no association between prenatal cannabis exposure and congenital anomalies was found among the infants of 66,925 women reporting use during pregnancy (Petrangelo et al., 2019).

A 2016 meta-analysis of the published data on prenatal cannabis exposure, including subjects from some of the cohort studies cited above, found that the frequency of major malformations was no greater than expected among the infants of mothers who used cannabis during pregnancy (approximately 3100 exposed cases) (Gunn et al., 2016).

Maternal cannabis use in pregnancy has been associated with the development of gastroschisis in the infants in two case-control studies using state health records--one that included 55 affected infants (odds ratio=2.2, 95% confidence interval 1.0-4.8) (Lam & Torfs, 2006) and another that included 109 affected infants (rate ratio=23.1, 95% confidence interval 4.7-69.3) (Forrester & Merz, 2007). Furthermore, another study of 114 gastroschisis cases, from the Canadian Pediatric Surgery Network database, reported an increased severity of the malformation in infants whose mothers used cannabis in pregnancy (odds ratio=4.0, 95% confidence interval 1.0-15.7) (Weinsheimer & Yanchar, 2008).

First trimester cannabis exposure has also been associated with an increased risk of anencephaly (adjusted odds ratio=2.2, 95% confidence interval 1.3-3.7) in an updated analysis of data from the National Birth Defects Prevention Study that identified 329 cases (van Gelder et al., 2014). In a separate case-control study of birth defects records, a significant relationship between maternal and paternal cannabis use during pregnancy and frequency of isolated simple ventricular septal defects (122 affected cases) was found (odds ratio=1.9, 95% confidence interval 1.3-2.8) (Williams et al., 2004).

ADVERSE PREGNANCY AND NEONATAL OUTCOMES

An increased frequency of composite neonatal morbidity or death was found among infants born to 48 women who used cannabis during pregnancy in a record-linkage study from the Stillbirth Collaborative Research Network cohort (adjusted odds ratio=3.11, 95% confidence interval 1.40-6.91) (Metz et al., 2017). The overall prevalence of intrapartum stillbirth was higher among the neonates of 5801 women who used cannabis during pregnancy in an observational cohort study using medical records (adjusted hazards ratio=2.84; 95% confidence interval 1.18–6.82) but rates of overall stillbirth and antepartum stillbirth were not affected (Luke et al., 2019). In a separate retrospective cohort study, the risk of intrauterine fetal demise was significantly elevated among the infants of 66,925 women who reported cannabis abuse or dependence while pregnant (adjusted odds ratio=1.50, 95% confidence interval 1.39-1.62) (Petrangelo et al., 2019).

An association was found with maternal cannabis use during pregnancy and spontaneous preterm birth in several large retrospective cohort studies with a combined total of 94,104 women who used cannabis during pregnancy (odds ratio/relative risk range from 1.27-1.5) (Baer et al., 2019; Corsi et al., 2019; Luke et al., 2019; Petrangelo et al., 2019).

Evidence of adverse effects on fetal growth has been found in some studies (see below) but not in others (van Gelder et al., 2010; Conner et al., 2015; Sturrock et al., 2020).

In a 2020 observational cohort study that included 283 women with a positive urine screen for THC, in utero cannabis exposure was associated with a 70% increase in risk for small for gestational age birth (adjusted rate ratio=1.69, 95% confidence interval 1.22-2.34) (Kharbanda et al., 2020). An elevated risk of small for gestational age birth has been found in a number of other cohort studies with a combined total of 12,012 women who used cannabis during pregnancy (odds ratio range from 1.30-1.69) (Warshak et al., 2015; Corsi et al., 2019; Luke et al., 2019; Rodriguez et al., 2019).

In a retrospective medical record review, cannabis use during pregnancy was negatively correlated with fetal birth weight (up to 450 g less) in 491 women with positive THC urine screens when compared to non-users (p<.001) (Howard et al., 2019). Additional evidence of adverse effects on fetal growth was found in the prospective cohort study Generation R where fetal weights in mid- and late-pregnancy (-14.44 g/week, 95% confidence interval -22.94 to -5.94; p=.001) and birth weight were reduced among the infants of women who used cannabis during early pregnancy (n=173) or throughout pregnancy (n=41) (El Marroun et al., 2009).

A 2016 meta-analysis of the published literature on maternal cannabis use and neonatal outcomes, including some of the individual studies cited in this summary, found two significant relationships; infants prenatally exposed to cannabis showed a decrease in birth weight (odds ratio=1.77, 95% confidence interval 1.04-3.01) and were more likely to require admittance to the Neonatal Intensive Care Unit (odds ratio=2.02, 95% confidence interval 1.27-3.21) (Gunn et al., 2016). However, some important confounding variables were not included in this meta-analysis and the role that cannabis played in the outcomes is difficult to discern.

NEURODEVELOPMENTAL OUTCOMES

The findings on prenatal exposure and child development often lack consistency and methodological limitations make it difficult to fully understand the effects of cannabis on postnatal neurodevelopmental outcomes.

During infancy, data are limited but suggest that prenatal cannabis exposure has no robust effect on early mental development (Fried & Watkinson, 1988; Astley & Little, 1990; Richardson et al., 1995). Disturbances in sleep cycling have been reported (Scher et al., 1988) as have increased aggression and attentional problems in exposed female infants (El Marroun et al., 2011).

During early and middle-childhood, disturbances in sleep cycling continue to be reported (Dahl et al., 1995). It is unlikely that prenatal exposure has an effect on global IQ but subtle deficits in verbal reasoning, memory, and/or attention have been reported and may impact success in school (Fried & Watkinson, 1990; Fried et al., 1992a, b; Day et al., 1994; Richardson et al., 2002; Goldschmidt et al., 2004, 2008). There is some evidence that symptoms of anxiety and depression are elevated in exposed children (Gray et al., 2005; Leech et al., 2006) as are rates of externalizing behaviors such as aggression and impulsivity (Leech et al., 1999; Goldschmidt et al., 2000).

Adolescents with a history of prenatal cannabis exposure have normal long-term physical growth trajectories and the attainment of pubertal milestones appears to be unaffected (Fried et al., 2001). Reduced scores on tests of academic achievement have been reported and suggest the possibility of diminished executive functioning skills (Fried & Smith, 2001; Fried et al., 2003; Goldschmidt et al., 2012; Smith et al., 2016).

ANIMAL TERATOLOGY STUDIES

No congenital anomalies were described in term infant monkeys exposed to 2.5 mg/kg/day THC in-utero during the second and third period of gestation (Asch & Smith, 1986). In the same study, exposure during the first period of gestation resulted in spontaneous abortions for three of five pregnancies and one of the two remaining infants was delivered stillborn.

In rodent models, malformations have not been reported in multiple studies of offspring born to dams treated with varying doses of THC during pregnancy (Harbison et al., 1977; Hutchings et al., 1987; Moreno et al., 2003; Campolongo et al., 2007; Benevenuto et al., 2017). In some of these investigations, there was evidence of fetal growth restrictions but recent data in mice suggest that significant postnatal catch-up growth normalizes the early effects of exposure (Natale et al., 2020).

Some investigations using rodent models have found that neurobehavioral development is not disrupted by prenatal cannabis exposure (Abel, 1984; Hutchings et al., 1991; Hutchings & Dow-Edwards, 1991) while other studies have identified persistent changes in learning and memory (Gianutsos & Abbatiello, 1972; Campolongo et al., 2007). Altered social interactions and increased anxiety-like behaviors have also been reported (Trezza et al., 2008, 2012).

Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)

Abel EL: Effects of delta 9-THC on pregnancy and offspring in rats. Neurobehav Toxicol Teratol 6(1):29-32, 1984. [A]

Asch RH, Smith CG: Effects of delta 9-THC, the principal psychoactive component of marijuana, during pregnancy in the rhesus monkey. J Reprod Med 31(12):1071-1081, 1986. [A]

Astley SJ, Little RE: Maternal marijuana use during lactation and infant development at one year. Neurotoxicol Teratol 12(2):161-168, 1990. [E]

Baer RJ, Chambers CD, Ryckman KK, Oltman SP, Rand L, Jelliffe-Pawlowski LL: Risk of preterm and early term birth by maternal drug use. J Perinatol 39(2):286-294, 2019. [E]

Benevenuto SG, Domenico MD, Martins MAG, Costa NS, de Souza ARL, Costa JL, Tavares MFM, Dolhnikoff M, Veras MM: Recreational use of marijuana during pregnancy and negative gestational and fetal outcomes: An experimental study in mice. Toxicology 376:94-101, 2017. [A]

Campolongo P, Trezza V, Cassano T, Gaetani S, Morgese MG, Ubaldi M, Soverchia L, Antonelli T, Ferraro L, Massi M, Ciccocioppo R, Cuomo V: Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol. 2007 Sep;12(3-4):485-495, 2007. [A]

Conner SN, Carter EB, Tuuli MG, Macones GA, Cahill AG: Maternal marijuana use and neonatal morbidity. Am J Obstet Gynecol. 2015 Sep;213(3):422.e1-422.e4, 2015. [E]

Corsi DJ, Walsh L, Weiss D, Hsu H, El-Chaar D, Hawken S, Fell DB, Walker M: Association between self-reported prenatal cannabis use and maternal, perinatal, and neonatal outcomes. JAMA 322(2):145-152, 2019. [E]

Dahl RE, Scher MS, Williamson DE, Robles N, Day N: A longitudinal study of prenatal marijuana use. Effects on sleep and arousal at age 3 years. Arch Pediatr Adolesc Med 149(2):145-150, 1995. [E]

Day N, Sambamoorthi U, Taylor P, Richardson G, Robles N, Jhon Y, Scher M, Stoffer D, Cornelius M, Jasperse D: Prenatal marijuana use and neonatal outcome. Neurotoxicol Teratol 13(3):329-334, 1991. [E]

Day NL, Richardson GA, Goldschmidt L, Robles N, Taylor PM, Stoffer DS, Cornelius MD, Geva D: Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicol Teratol 16(2):169-175, 1994. [E]

El Marroun H, Hudziak JJ, Tiemeier H, Creemers H, Steegers EAP, Jaddoe VWV, Hofman A, Verhulst FC, van den Brink W, Huizink AC: Intrauterine cannabis exposure leads to more aggressive behavior and attention problems in 18-month-old girls. Drug Alcohol Depend 118(2-3):470-474, 2011. [E]

El Marroun H, Tiemeier H, Steegers EAP, Jaddoe VWV, Hofman A, Verhulst FC, van den Brink W, Huizink AC: Intrauterine cannabis exposure affects fetal growth trajectories: the Generation R Study. J Am Acad Child Adolesc Psychiatry 48(12):1173-1181, 2009. [E]

Forrester MB, Merz RD: Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986-2002. J Toxicol Environ Health A 70(1):7-18, 2007. [E]

Fried PA: Marihuana use by pregnant women and effects on offspring: an update. Neurobehav Toxicol Teratol 4(4):451-454, 1982. [E]

Fried PA, James DS, Watkinson B: Growth and pubertal milestones during adolescence in offspring prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 23(5):431-436, 2001. [E]

Fried PA, O'Connell CM, Watkinson B: 60- and 72-month follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol: cognitive and language assessment. J Dev Behav Pediatr 13(6):383-391, 1992a. [E]

Fried PA, Smith AM: A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function. Neurotoxicol Teratol 23(1):1-11, 2001. [R]

Fried PA, Watkinson B: 12- and 24-month neurobehavioural follow-up of children prenatally exposed to marihuana, cigarettes and alcohol. Neurotoxicol Teratol 10(4):305-313, 1988. [E]

Fried PA, Watkinson B: 36- and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes, and alcohol. J Dev Behav Pediatr 11(2):49-58, 1990. [E]

Fried PA, Watkinson B, Gray R: A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes, and alcohol. Neurotoxicol Teratol 14(5):299-311, 1992b. [E]

Fried PA, Watkinson B, Gray R: Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 25(4):427-436, 2003. [E]

Gianutsos G, Abbatiello ER: The effect of pre-natal Cannabis sativa on maze learning ability in the rat. Psychopharmacologia 27(2):117-122, 1972. [A]

Goldschmidt L, Day NL, Richardson GA: Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol 22(3):325-336, 2000. [E]

Goldschmidt L, Richardson GA, Cornelius MD, Day NL: Prenatal marijuana and alcohol exposure and academic achievement at age 10. Neurotoxicol Teratol 26(4):521-532, 2004. [E]

Goldschmidt L, Richardson GA, Willford J, Day NL: Prenatal marijuana exposure and intelligence test performance at age 6. J Am Acad Child Adolesc Psychiatry 47(3):254-263, 2008. [E]

Goldschmidt L, Richardson GA, Willford JA, Severtson SG, Day NL: School achievement in 14-year-old youths prenatally exposed to marijuana. Neurotoxicol Teratol 34(1):161-167, 2012. [E]

Gray KA, Day NL, Leech S, Richardson GA: Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol Teratol 27(3):439-448, 2005. [E]

Gunn JKL, Rosales CB, Center KE, Nunez A, Gibson SJ, Christ C, Ehiri JE: Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open 6(4):e009986, 2016. [R]

Harbison RD, Mantilla-Plata B, Lubin DJ: Alteration of delta 9-tetrahydrocannabinol-induced teratogenicity by stimulation and inhibition of its metabolism. J Pharmacol Exp Ther 202(2):455-465, 1977. [A]

Howard DS, Dhanraj DN, Devaiah CG, Lambers DS: Cannabis use based on urine drug screens in pregnancy and its association with infant birth weight. J Addict Med 13(6):436-441, 2019. [E]

Hutchings DE, Brake SC, Banks AN, Nero TJ, Dick LS, Zmitrovich AC: Prenatal delta-9-tetrahydrocannabinol in the rat: effects on auditory startle in adulthood. Neurotoxicol Teratol 13(4):413-416, 1991. [A]

Hutchings DE, Dow-Edwards D: Animal models of opiate, cocaine, and cannabis use. Clin Perinatol 18(1):1-22, 1991. [A]

Hutchings DE, Morgan B, Brake SC, Shi T, Lasalle E: Delta-9-tetrahydrocannabinol during pregnancy in the rat: I. Differential effects on maternal nutrition, embryotoxicity, and growth in the offspring. Neurotoxicol Teratol 9(1):39-43, 1987. [A]

Kharbanda EO, Vazquez-Benitez G, Kunin-Batson A, Nordin JD, Olsen A, Romitti PA: Birth and early developmental screening outcomes associated with cannabis exposure during pregnancy. J Perinatol 40(3):473-480, 2020. [E]

Lam PK, Torfs CP: Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. Birth Defects Res A Clin Mol Teratol 76(3):182-186, 2006. [E]

Leech SL, Larkby CA, Day R, Day NL: Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10. J Am Acad Child Adolesc Psychiatry 45(2):223-230, 2006. [E]

Leech SL, Richardson GA, Goldschmidt L, Day NL: Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds. Neurotoxicol Teratol 21(2):109-118, 1999. [E]

Luke S, Hutcheon J, Kendall T: Cannabis use in pregnancy in British Columbia and selected birth outcomes. J Obstet Gynaecol Can 41(9):1311-1317, 2019. [E]

Metz TD, Allshouse AA, Hogue CJ, Goldenberg RL, Dudley DJ, Varner MW, Conway DL, Saade GR, Silver RM: Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity. Am J Obstet Gynecol 217(4):478.e1-478.e8, 2017. [E]

Metz TD, Borgelt LM: Marijuana use in pregnancy and while breastfeeding. Obstet Gynecol 132(5):1198-1210, 2018. [R]

Moreno M, Trigo JM, Escuredo L, Rodriguez de Fonseca F, Navarro M: Perinatal exposure to delta 9-tetrahydrocannabinol increases presynaptic dopamine D2 receptor sensitivity: a behavioral study in rats. Pharmacol Biochem Behav 75(3):565-575, 2003. [A]

Natale BV, Gustin KN, Lee K, Holloway AC, Laviolette SR, Natale DRC, Hardy DB: ?9-tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta. Sci Rep 10(1):544, 2020. [A]

Petrangelo A, Czuzoj-Shulman N, Balayla J, Abenhaim HA: Cannabis abuse or dependence during pregnancy: a population-based cohort study on 12 million births. J Obstet Gynaecol Can 41(5):623-630, 2019. [E]

Richardson GA, Day NL, Goldschmidt L: Prenatal alcohol, marijuana, and tobacco use: infant mental and motor development. Neurotoxicol Teratol 17(4):479-487, 1995. [E]

Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L: Prenatal alcohol and marijuana exposure: effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol 24(3):309-20, 2002. [E]

Rodriguez CE, Sheeder J, Allshouse AA, Scott S, Wymore E, Hopfer C, Hermesch A, Metz TD: Marijuana use in young mothers and adverse pregnancy outcomes: a retrospective cohort study. BJOG 126(12):1491-1497, 2019. [E]

Scher MS, Richardson GA, Coble PA, Day NL, Stoffer DS: The effects of prenatal alcohol and marijuana exposure: disturbances in neonatal sleep cycling and arousal. Pediatr Res. 1988 Jul;24(1):101-105, 1988. [E]

Smith AM, Mioduszewski O, Hatchard T, Byron-Alhassan A, Fall C, Fried PA: Prenatal marijuana exposure impacts executive functioning into young adulthood: An fMRI study. Neurotoxicol Teratol 58:53-59, 2016. [R]

Sturrock S, Williams E, Ambulkar H, Dassios T, Greenough A: Maternal smoking and cannabis use during pregnancy and infant outcomes. J Perinat Med 48(2):168-172, 2020. [E]

Trezza V, Campolongo P, Cassano T, Macheda T, Dipasquale P, Carratu MR, Gaetani S, Cuomo V: Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology 198(4):529-537, 2008. [A]

Trezza V, Campolongo P, Manduca A, Morena M, Palmery M, Vanderschuren LJMJ, Cuomo V: Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance. Front Behav Neurosci 6:2, 2012. [A]

van Gelder MMHJ, Donders ART, Devine O, Roeleveld N, Reefhuis J: Using Bayesian models to assess the effects of under-reporting of cannabis use on the association with birth defects, National Birth Defects Prevention Study, 1997-2005. Paediatr Perinat Epidemiol 28(5):424-433, 2014. [E]

van Gelder MMHJ, Reefhuis J, Caton AR, Werler MM, Druschel CM, Roeleveld N: Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study. Drug Alcohol Depend 109(1-3):243-247, 2010. [E]

Warshak CR, Regan J, Moore B, Magner K, Kritzer S, Van Hook J: Association between marijuana use and adverse obstetrical and neonatal outcomes. J Perinatol 35(12):991-995, 2015. [E]

Weinsheimer RL, Yanchar NL: Impact of maternal substance abuse and smoking on children with gastroschisis. J Pediatr Surg 43(5):879-883, 2008. [E]

Williams LJ, Correa A, Rasmussen S: Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res Part A Clin Mol Teratol 70(2):59-64, 2004. [E]