6. Cannabis use in human pregnancy
Cannabis is the most commonly used illicit drug among women of reproductive age and in the United States the self-reported use of this substance is 2.9% during pregnancy (National Pregnancy and Health Survey, 1996 and Ebrahim and Gfroerer, 2003).
Fried (2002) has reviewed the studies on behavioral teratologic consequences of prenatal exposure to cannabis. Only two longitudinal cohorts with very different sample characteristics were found that examined the possible impact of cannabis exposure in utero on neurobehavioral and cognitive outcomes in offspring beyond early school age. The Ottawa Prenatal Prospective Study (OPPS; Fried, 2002) examines the consequences of cannabis (and smoking) use during pregnancy in a sample of low-risk, white, predominantly middle-class families, as yet up to the age of 18–22 years. The Maternal Health Practices and Child Development Study (MHPCD; Richardson and Day, 1998) has been following a high-risk cohort of low socioeconomic status, started in 1982, and has reported offspring outcome up to the age of 10. These cohorts have mainly described the impact of heavy cannabis use on offspring outcome. At present there are no studies that have focused on moderate cannabis use during pregnancy.
6.1. Neurobehavioral outcomes after prenatal cannabis exposure
In the neonatal period, findings from the OPPS and MHPCD showed that there may be an association between aspects of nervous system functioning and prenatal exposure to marijuana, reflected by increased tremors that were typically accompanied by exaggerated and prolonged startles (Fried and Makin, 1987) or altered sleep patterns (Richardson et al., 1989). The Maternal Life Style study, a clinical prospective study of acute neonatal events and long-term health and developmental outcomes associated with prenatal cocaine exposure, also included prenatal marijuana exposure. More stress/abstinence signs were found in 1-month-old infants of mothers who used low to moderate amounts of cannabis in pregnancy (Lester et al., 2002).
At the 6-year-follow up, the OPPS reported more impulsive and hyperactive behavior of children prenatally exposed to cannabis (Fried et al., 1992b). The MHPCD cohort showed that at 6 years of age, prenatally cannabis exposed children were rated by their teachers as showing more delinquent behavior (Leech et al., 1999). Moreover, the 6-year-old children showed more impulsive behavior at a continuous performance task (Leech et al., 1999). At age 10, these children had hyperactivity, increased inattention, impulsivity and delinquency symptoms as reported by their mother and their teachers (Goldschmidt et al., 2000). Also, attention deficits were found, which may mediate the relation between prenatal cannabis exposure and delinquency (Goldschmidt et al., 2000).
None of these studies have focused on substance (ab)use by the offspring after prenatal exposure to cannabis.
6.2. Cognitive function after prenatal cannabis exposure
In the OPPS, no association was found between prenatal cannabis exposure and infant mental or motor development at 1 year of age (Fried and Watkinson, 1988). The high-risk MHPCD cohort, however, showed an association between the use of 1 or more joints per day in third trimester pregnancy and a decrease in mental scores of the Bayley Scales of Infant Development (Bayley, 1969) at 9 months of age, which disappeared at 18 months (Richardson et al., 1995).
When the offspring of OPPS reached the age of 4, associations between regular (more than 5 joints a week) prenatal cannabis exposure and significantly lower scores on several verbal and memory subscales of the McCarthy Scales of Children's Ability were noted (Fried and Watkinson, 1990 and McCarthy, 1972). Similar findings applied to the offspring of the MHPCD cohort at 3 years of age, in which an impairment on short-term memory, verbal and abstract/visual reasoning was found after in utero exposure to cannabis (Day et al., 1994).
As the children get older, the most striking finding is that ‘executive function’ (EF), an overarching cognitive domain reflecting the ability to organize and integrate specific cognitive and output processes over an interval of time, may be hampered. EF is involved in, e.g. cognitive flexibility in problem solving, sustained and focused attention, and working memory. Specific tests from the WISC-II, such as the Block Design and Picture Completion, requiring higher order cognitive processes which are part of EF, were performed less well by prenatal cannabis exposed 9- and 12-year-olds from the OPPS cohort (Fried et al., 1998). This is consistent with findings from the MHPCD cohort, that showed problems in abstract and visual reasoning, and more inattention and impulsivity, at 10 years of age after prenatal cannabis exposure (Richardson and Day, 1997 and Richardson et al., 2002). Fried and Watkinson (2000) examined visuoperceptual functioning in greater detail in the 9–12-year-old OPPS subjects and found more support for impaired aspects of EF (e.g. visual-motor integration, non-verbal concept formation, and inhibition of prepotent responses) after prenatal cannabis exposure. At 13–16 years of age, however, prenatal cannabis exposure was not associated with aspects of attention, such as flexibility, encoding and focusing (Fried et al., 2003).
6.3. Cannabis effects in animal pregnancy
Navarro et al. (1995) have reviewed behavioral consequences of maternal exposure to cannabinoids in rat models and concluded that it resulted in alteration in the pattern of ontogeny of spontaneous locomotor and exploratory behavior in the offspring. Adult animals exposed during gestational and early neonatal periods, when lactation took place, showed persistent alterations in the behavioral response to novelty, social interactions, sexual orientation and sexual behavior. They also exhibited a lack of habituation and reactivity to a variety of stimuli. Also, visual developmental milestones were delayed in rodents after prenatal exposure to cannabis (Borgen et al., 1973 and Fried, 1976). In addition, Mereu et al. (2003) found a disruption of memory retention and hyperactive behavior in offspring of rats who were administered with a cannabinoid receptor agonist during pregnancy. Moreover, the offspring appeared to be sensitized to reinforcing effects of morphine, suggesting an increased sensitivity to addictive behavior.
6.4. Mechanisms related to prenatal cannabis use and offspring outcomes
Cannabinoids, the psychoactive ingredients of cannabis, can cross the placental barrier (Gomez et al., 2003). This way, cannabinoids are able to affect the expression of key genes for neural development leading to neurotransmitter and behavioral disturbances (Gomez et al., 2003). Furthermore, the early presence of cannabinoid receptors during fetal brain development provides a mechanism by which cannabinoids might produce the effects found in the offspring (Navarro et al., 1995). Animal research indicates that endogenous cannabinoids and their cannabinoid CB1 and CB2 receptors are involved in embryonal implantation, neural development, and the initiation of suckling in the newborn (Fride, 2004). Also, cannabinoid CB1 receptors have been found in the human placenta (Park et al., 2003), and may mediate adverse actions of prenatal cannabis exposure. One of the major cannabinoid receptor sites in the human brain is in that part of the forebrain that is associated with higher cognitive functions (Glass et al., 1997 N. Glass, M. Dragunow and R.L.M. Faull, Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal, and adult human brain, Neuroscience 77 (1997), pp. 299–318.Glass et al., 1997) as well as in the cerebellum. This may support the suggestions that prenatal cannabis exposure is related to deficits in specific higher order cognitive functions. In line with this theory are findings from a recent study on the OPPS offspring aged 18–22-years-old, using fMRI to test prefrontal cortex activity by using Go/No–Go paradigms to assess response inhibition (Smith et al., 2004). An increased activity in the left orbital frontal gyrus and right dorsolateral of the prefrontal cortex was found. The authors suggested that this result might reflect increased effort to perform the response inhibition task, which may be caused by a delayed development of this brain area. However, more studies are needed.
Other mechanisms that have been proposed originate from animal models. For instance, prenatal cannabinoid exposure influences gene expression on a key protein for brain development, the neural adhesion molecule L1, which plays an important role in processes of cell proliferation and migration, and synaptogenesis (Gomez et al., 2003). Furthermore, prenatal cannabinoid exposure altered the normal development of nigrostriatal and mesolimbic dopaminergic neurons (Rodriguez de Fonseca et al., 1991). These mechanisms may underlie the associations between prenatal exposure to cannabis and neurobehavioral and cognitive outcomes.
With regard to the HPA-axis, Del Acro et al. (2000) observed long-lasting changes in the HPA axis reactivity in rat offspring exposed in utero to a synthetic cannabinoid compound. Offspring prenatally exposed to high levels of a synthetic cannabinoid compound showed a decreased responsiveness of the HPA axis to stressors at adult ages, whereas offspring prenatally exposed to low levels of the same cannabinoid compound showed a sensitization of the HPA axis. The latter may underlie some of the behavioral changes found in the moderately exposed offspring.
Source: Neuroscience & Biobehavioral Reviews
Volume 30, Issue 1
, 2006, Pages 24-41
Available online (but you have to pay $36 to read): https://linkinghub.elsevier.com/retri...49763405000953