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
]. 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
]. Nevertheless, prenatal cannabis exposure has been found to be associated with fetal growth restriction [41
], and learning disabilities and memory impairment in the exposed offspring [43
]. 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 refected 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.
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 (). 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
Prenantal marijuana exposure studies in humans.
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
]. Altered sleep patterns were found in the MHPCD study, and the authors also reported a non-significant 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
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
], 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
], 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
]. 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 can not 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
]. 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 neuro-development [48
]. In the mid gestation 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