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Table 1.  

right brain regions – medial PFC, DLPFC and ventrolateral PFC
Age† Cohort‡ Category Results/outcomes Exposure
details
Ref.
Fetus
17–22 GW Growth Reduced foot length and bodyweight ≥0.4 J/day [48]
18–22 GW Dopamine signaling Decreased D2 mRNA in amygdala of males only ≥0.4 J/day [152]
18–22 GW Endorphin signaling Decreased opioid peptide (PENK) and receptor (κ) in caudal putamen and thalamus, respectively;
increased opioid receptor (µ) in the amygdala
[74]
Neonatal
Neonatal OPPS Neurobehavior Increased tremors, exaggerated startles and diminished responsiveness to light [46]
Neonatal MHPCD Growth Decreased body length ≥1 J/day, first
Trim
[49]
Neonatal Growth
Neurobehavior
No effect on birthweight, length or gestational age
No effect

[54]
Neonatal VIPS Growth No effect on birthweight, preterm delivery or abruptio placentae [35]
Neonatal Growth
Behavior
No effect on birthweight, length or gestational age
More irritable, less responsive to calming, increased jitters and startles

[52]
Neonatal NBDPS Growth No effect on birthweight, gestational age or preterm delivery [40]
1 mo Behavior Less irritable, more alert, more robust autonomic and motor systems, more autonomically stable and
increased orientation
≥2.86 J/day [54]
Toddler
8 mo MHPCD Growth No effect [49]
9 mo MHPCD Mental/motor skills Delayed mental development ≥1 J/day, third
Trim
[26]
1 y OPPS Mental/motor skills No effect [55]
1 y Mental/motor skills Decreased motor scores, no effect on mental development ≥0.5 J/day, first
Trim
[149]
19 mo MHPCD Mental/motor skills No effect [26]
2 y OPPS Mental/motor skills No effect [55]
3 y MHPCD Intelligence
Cognition
No effect on overall IQ for entire cohort
For African–Americans: decrease in short-term memory and verbal reasoning

≥1 J/day,
first/second Trim
[57]
3 y MHPCD Sleep and arousal Lowered sleep efficiency, more nocturnal arousals and more awake time after sleep onset [153]
Childhood
4 y Sustained attention Increased number of omission errors First Trim [45]
4 y MHPCD Motor skills No effect on balance and coordination skills [154]
5–6 y OPPS Cognition and
language
No effect [155]
6 y MHPCD Growth No effect [156]
6 y OPPS Memory
Attention
Behavior
No effect
Increased number of omission errors
Described as more impulsive and hyperactive
≥0.86 J/day [58]
6 y MHPCD Impulsivity
Sustained attention
Decrease in errors of omission
Lower overall composite score
Second Trim [60]
6 y MHPCD Intelligence
Cognition
Lower overall composite score
Lower verbal reasoning, quantitative reasoning and short-term memory
≥1 J/day,
first/second Trim
[59]
9–12 y OPPS Reading and language No effect in regards to reading or language [68]
9–12 y OPPS Intelligence
Executive function
No effect in terms of full scale IQ
Impulse control and visual hypothesis aspects are negatively impacted

> 0.86 J/day
[63]
Adolescence
10 y MHPCD Behavior and emotion
Behavior and emotion
Fewer internalizing problems, although not correlated with teacher’s report
Predicted lower scores in design memory and screening index
≥0.4 J/day
second Trim
≥0.89 J/day,
first Trim
[47]
10 y MHPCD Learning and memory
Sustained attention
Predicted lower scores in design memory and screening index
Increase in errors of commission
≥0.89 J/day,
first Trim
≥0.89 J/day,
second Trim
[47]
10 y MHPCD Depression Increased levels of depressive symptoms >0.89 J/day,
first/third Trim
[64]
12 y Psychotic symptoms No effect [66]
10–14 y Volumetric MRI No effect on cortical gray matter volume, white matter volume, cerebral spinal fluid or
parenchymal volume
[69]
10 y

14 y
MHPCD Behavior and
cognition
Delinquent behaviors
Negatively associated with depressive symptoms, IQ, learning and memory

Increased delinquent behaviors
≥0.89 J/day,
first/second Trim
≥0.89 J/day
[61]
13–16 y OPPS Sustained attention Decreased stability of attention over time ≥0.86 J/day [71]
13–16 y OPPS Growth No changes in weight, height or puberty symptoms [157]
13–16 y OPPS Visual memory Lower scores in abstract designs and Peabody spelling ≥0.86 J/day [27]
16 y MHPCD Fine motor
coordination
Visual–motor
coordination
Various light deficits in processing speed and interhemispheric motor coordination

Slight increase in visual–motor coordination
≥2 J/mo [158]
Young adult
18–22 y OPPS Response inhibition
Response inhibition
by fMRI
Intelligence
Working memory
by fMRI
Slightly more errors of commission
Increased bilateral PFC activity, right premotor cortex activity; decreased activity in left cerebellum

No effect
Increased activity in left medial PFC, inferior frontal gyrus and left cerebellum; decreased activity in




[72]



[73]

Prenatal Marijuana Exposure Studies in Humans

†Exposed offspring study age.
‡Specified conditions of prenatal exposure.
DLPFC: Dorsolateral prefrontal cortex; GW: Gestation week(s); J: Joint; MHPCD: Maternal Health Practices and Child Development Project; mo: Month(s); NBDPS: National Birth Defects Prevention Study; OPPS: Ottawa Prenatal Prospective Study; PENK: Proenkephalin; PFC: Prefrontal cortex; Trim: Trimester; VIPS: Vaginal Infections and Prematurity Study; y: Year(s).

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

  • Authors: Chia-Shan Wu, PhD; Christopher P. Jew; Hui-Chen Lu, PhD
  • CME Released: 7/1/2011
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This activity is intended for primary care clinicians, obstetricians, neurologists, psychiatrists, pediatricians, and other healthcare providers advising pregnant women regarding the effects of prenatal marijuana exposure and/or caring for their offspring.

The goal of this activity is to review the interaction of prenatal exposure to marijuana with endocannabinoid effects on neural development.

Upon completion of this activity, participants will be able to:

  1. Describe the epidemiology of prenatal exposure to marijuana, based on a review
  2. Describe the neurodevelopmental effects of prenatal exposure to marijuana
  3. Describe the effects of endocannabinoids on neural development and how prenatal exposure to marijuana influences these effects


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  • Chia-Shan Wu, PhD

    The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital

    Disclosures

    Disclosure: Chia-Shan Wu, PhD, has disclosed no relevant financial relationships.

  • Christopher P. Jew

    The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas

    Disclosures

    Disclosure: Christopher P. Jew has disclosed no relevant financial relationships.

  • Hui-Chen Lu, PhD

    The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Pediatrics; Program in Developmental Biology; Department of Neuroscience, Baylor College of Medicine, Houston, Texas

    Disclosures

    Disclosure: Hui-Chen Lu, PhD, is supported by NIH grants: NS048884 (NINDS), DA029381 (NIDA) and HD065561 (NICHD).

Editor(s)

  • Elisa Manzotti

    Editorial Director, Future Science Group, London, United Kingdom

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  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

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    CME Clinical Director, Medscape, LLC

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    CME Program Manager, Medscape, LLC

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CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain: Adverse Effect of Prenatal Exposure to Marijuana

processing....

Adverse Effect of Prenatal Exposure to Marijuana

Cannabis use during 2010 for those aged 15–64 was estimated to be between 2.9 and 4.3% worldwide, with a high but steady occurrence in North America and Western/Central Europe.[203] The Substance Abuse and Mental Health Services Administration estimates that 7.1% of pregnant women aged 18–25 have used illicit drugs in the month prior to being surveyed.[201] Marijuana was the most prevalent substance abused, ranging from 2–6% usage as determined by interview or self-report[33,34]. However, one study on cannabis usage during pregnancy found an 11% usage rate by measuring serum metabolites[35] close to that seen in age-matched, non-pregnant women (10.9%,[201]). Moore et al. found that within a British population, marijuana was the only illicit drug pregnant women were likely to continue using to term.[36]

Available data linking prenatal cannabis exposure to congenital anomalies or preterm delivery are weak. While fetal alcohol syndrome-like features in prenatally cannabis-exposed newborns have been reported,[37] a number of other studies have failed to replicate this finding.[38–40] Nevertheless, prenatal cannabis exposure has been found to be associated with fetal growth restriction,[41,42] and learning disabilities and memory impairment in the exposed offspring.[43–45] The mean potency of cannabis preparations, in terms of contents of its psychoactive constituent, THC, has increased from 3.4% in 1993 to 8.8% in 2008, and can reach as high as 30% in certain hashish preparations.[23] This fact is important since THC effects are dose related and classical studies carried out in the 1970s used doses that reflected cannabis intake at that period of time. Key findings from human and animal studies regarding behavioral consequences of cannabis exposure during pregnancy and/or lactation will be summarized in the following section.

Human Studies

Despite the fact that marijuana is the most widely used illicit drug by pregnant women, there are few studies on the prevalence of prenatal drug exposure. Most information is derived from two longitudinal cohort studies, the Ottawa Prenatal Prospective Study (OPPS) and the Maternal Health Practices and Child Development Study (MHPCD). OPPS, initiated in 1978, focused on assessing prenatal exposure effects of tobacco and marijuana in a low-risk, mainly Caucasian, predominantly middle-class Canadian cohort.[46] Initiated in 1982, the MHPCD focused mainly on prenatal alcohol and marijuana exposure in a group of women from Pittsburgh, Pennsylvania. These women were generally of low socioeconomic status and comprised of approximately half Caucasian and half African–American ethnicity.[47] In both the OPPS and MHPCD studies, cannabis use during pregnancy was not associated with increased miscarriage rates, premature deliveries or any other complications ( Table 1 ). Physically, marijuana exposure was not correlated with any changes in head circumference at the mid-gestational stage (17–22 weeks), although a significant reduction in foot length and bodyweight at this gestational period was reported.[48] These changes in bodyweight and foot length were not present at birth,[35] although head circumference was reportedly larger in the exposed cohort at 8 months.[49] These anthropometric measurements were used as an indication of normal fetal development, which correlates with brain development.[50]

The OPPS study found that prenatal marijuana exposure was highly correlated with an increase in exaggerated startles and tremors as well as with a significant reduction in habituation to light at the neonatal stage.[46,51] Altered sleep patterns were found in the MHPCD study, and the authors also reported a nonsignificant trend towards increased irritability.[49] A study on neonates from adolescent mothers found in cannabis-exposed infants transiently increased irritability, excitability and arousal 24–72 h after birth.[52] However, these symptoms were not reported within the MHPCD cohort[53] or in an ethnographic field study based in Jamaica.[54] The MHPCD cohort also demonstrated that a higher amount of cannabis use per day (defined as more than one joint per day) during the third trimester of pregnancy was associated with decreased mental scores of the Bayley Scales of Infant Development at 9 months of age, a difference that disappeared by 18 months.[26] No cognitive deficit was observed during early childhood in the OPPS study, particularly between the ages of 1 and 3 years, suggesting that CNS abnormalities might be absent or subclinical in toddlers.[55,56]

For 3–4 year old children, prenatal marijuana exposure negatively affected the verbal and memory domains in both the OPPS and MHPCD studied groups. Cognitive development assessed by the Stanford-Binet Intelligence Scale demonstrated a negative association of short-term memory and verbal reasoning with first and/or second trimester marijuana usage.[57] Similarly, memory and verbal domains, measured by the McCarthy Scales of Children’s Abilities, decreased with daily marijuana usage.[56] However, composite intelligence scores in both studies were not impacted at this age by maternal marijuana use.

When children reach school age at around 5–6 years old, reports on the consequences of prenatal marijuana exposure begin to diverge. Exposed children from the OPPS cohort appear to have no memory deficits,[58] while those from the MHPCD cohort report short-term memory deficits that correlate strongly with heavy second trimester exposure.[59] Cannabis-exposed children in the OPPS cohort scored significantly lower in tests for sustained attention, while those from the MHPCD group actually displayed increased attention (measured by fewer errors of omission in a continuous performance task) from second trimester exposure.[60] Both groups reported an increase in impulsive and hyperactive behaviors. Follow-up studies found that problems of depression, hyperactivity, inattention and impulsivity persist into the 9–12 year age range,[47,61–64] raising speculation of deficits in higher cognitive processes such as executive function.[65]

Upon closer inspection, the impact of prenatal marijuana exposure is a little more difficult to discern. For example, one report from the MHPCD cohort found that heavy first- and third-trimester exposure (rated as >0.89 joints/day) was associated with increased hyperactivity and impulsivity,[62] while another found that heavy second trimester exposure was significantly associated with increased impulsivity.[47] First- and third-trimester exposure also predicted increased levels of depressive symptoms, assessed by the Children’s Depression Inventory,[61,64] whereas second-trimester usage was associated with some depressive, but fewer internalizing, symptoms compared with the extent observed in first- and third-trimester exposure groups.[62] Verbal IQ, reading comprehension, overall IQ, presence of psychotic symptoms and sleep patterns do not seem to be impacted.[63,66–68] A recent study has assessed volumetric changes using functional MRI (fMRI) in the brains of children exposed to a number of drugs, including marijuana, during pregnancy. This study found evidence of reduced cortical gray matter and parenchymal volume in children (aged 10- to 14-years old) with intra-uterine marijuana exposure.[69]

Executive functions comprise capacities such as cognitive flexibility, sustained and focused attention, and working memory; these cannot be assessed with global, standardized tests of cognition.[70] Data from both OPPS and MHPCD cohorts demonstrated deficits in executive functions, which seemed to persist into late adolescence and young adulthood in children of cannabis users.[47,63] The two tests that were found to be negatively affected in marijuana-exposed children both involve the visual analysis and impulse control aspects of executive functions.[63] In the OPPS cohort, 13–16 year olds that were heavily exposed (rated as >0.86 joints/day) displayed deficits in visual memory, visual analysis[27] and the ability to maintain attention (referred to as stability).[71] fMRI studies with Go/No–Go paradigms conducted to assess response inhibition with 18–22 year-old subjects from the OPPS group found that prenatal exposure was associated with alterations of neural activity in various brain areas during certain tasks.[72] fMRI analysis of visuospatial working memory tasks with the same group also revealed significant changes in levels of activity in the cannabis-exposed group.[73] Peculiarly, prenatal exposure had both positive and negative associations with fMRI response; whereas mostly left brain regions experienced an increase in activity, right brain regions experienced the opposite during tasks. Whether these differences in regional activation/deactivation are a result of various compensatory mechanisms, or if these changes reflect a behavioral alteration that can only be observed with different or more sensitive testing requires further investigation.

Data addressing whether prenatal marijuana exposure can clearly alter the structural and molecular composition of the fetal brain are scarce. Hurd et al. developed a post-mortem human fetal brain collection of midgestational subjects with maternal cannabis use that has begun to provide the first insights into the molecular and biochemical alterations associated with prenatal cannabis exposure on human neurodevelopment.[48] In the midgestation human fetus, prenatal cannabis exposure was associated with decreased pro-enkephalin mRNA levels in the striatum, increased µ-opioid receptor expression in the amygdala and reduced κ-opioid receptor mRNA levels in the mediodorsal thalamus.[74] These data suggest that striatal enkephalin/D2 receptor and the opioid system in the limbic-related structures are vulnerable to prenatal cannabis exposure.

In summary, cannabis consumption during pregnancy has profound but variable effects on offspring in several areas of cognitive development.[28] Most of the information on the long-term consequences of prenatal exposure to cannabis comes from longitudinal studies of the OPPS and MHPCD cohorts. By comparing data from the cohorts, a pattern emerges where maternal cannabis use is associated with impaired high-order cognitive function in the offspring, including attention deficits and impaired visuoperceptual integration. It is possible that genetic and environmental interactions may affect the extent of long-term neurobehavioral deficits resulting from prenatal exposure. Recent advances in methodology in prenatal substance use research employ novel approaches to disentangle the exposure to substance effects from correlated risk factors.[75] For example, in the prospective Generation R Study, where 7452 mothers were enrolled during pregnancy and information on substance use and ultrasound measures of fetal growth in early, mid- and late pregnancy were collected, information on paternal cannabis use was also included.[41] Thus, maternal cannabis use during pregnancy was associated with growth restriction in mid and late pregnancy, and also with lower birthweight, while no such association was found for paternal cannabis use in the same period, demonstrating a direct biological effect of maternal intrauterine exposure to cannabis on fetal growth.[41] Refined study designs and novel approaches will assist in confirming and extending the findings of associations between prenatal cannabis exposure and offspring outcomes.[75]

Animal Studies

Epidemiological studies on long-term neurobehavioral effects of drugs of abuse are subject to a number of confounding factors such as dosage, poly-substance abuse, length and frequency of drug usage, pregnancy stage and environmental factors such as maternal nutrition and socioeconomic problems, commonly associated with drug abuse. Animal models provide tighter experimental control over these factors and a wealth of data have been generated on the behavioral and molecular changes associated with prenatal exposure to cannabis preparations or synthetic compounds (termed ‘cannabinoids’ for the following discussion). Overall, pre- and early post-natal exposure to cannabinoids lead to changes in social interactions, novelty responses and memory in the adult offspring.[29–32] In addition, drug addictive behaviors are modified in cannabinoid-exposed offspring, as indicated by sensitized responses to the reinforcing effects of heroin and morphine in conditioned place preference tests.[76,77] While the exact molecular pathways underlying these behavioral changes are not clear, numerous studies demonstrated that prenatal cannabinoid exposure may lead to alterations in GABAergic, glutamatergic, dopaminergic, serotoninergic and opioidergic systems in offspring.[28,32,78] In addition, perinatal cannabinoid exposure disrupts neurodevelopment through modifications of gene expression[79] involved in neuronal specification and synapse physiology.[80]