The Influence of in Utero Cannabis Exposure on Neonatal Brain Morphology and Structural Connectivity

Study Overview
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Brief Summary
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Cannabis is the most commonly used drug by women during pregnancy with an estimated prevalence of use in Colorado of 5.7%. THC and its metabolites freely cross the placenta and blood-brain barrier to bind with cannabinoid receptors, disrupting the endogenous cannabinoid signaling system during a critical period of development of cortical circuitry structure and function. The density of cannabinoid receptors in the developing brain is high, especially in the limbic areas and prefrontal lobes. Research in animal models suggests synaptic plasticity in the prefrontal lobes as well the amygdala and hippocampus are impacted by the prenatal cannabis exposure; regions associated with both cognitive and emotional control, thus influencing long-term deficiencies in attention and impulsivity. This pilot study will collect preliminary data on the structural impact of in utero cannabis exposure on region-specific morphology and structural connectivity of white matter tracts that connect to the prefrontal lobes and the limbic regions shortly after birth, before confounding by the postnatal environment becomes a major influence.

Detailed Description
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Cannabis is the most commonly used psychoactive substance among pregnant women, with an estimated prevalence of use between 5 to 20% in in the United States. Little is known about the neurodevelopmental consequences for the fetus, particularly in the context of contemporary cannabis use patterns including high potency strains, cannabinoids and novel routes of administration. Colorado leads the nation in implementation of legalized medical and retail marijuana. Coupled with a growing pro-marijuana advocacy movement, marijuana may be perceived as safe to use during pregnancy. The local actions of endocannabinoids are in place in the placenta during fetal brain development and THC and its metabolites freely pass the placental barrier and the fetal blood-brain barrier. Furthermore, cannabinoid receptors appear to be more widespread in the fetal and neonatal prefrontal cortex (PFC) and the limbic areas (the amygdala and hippocampus) than in the adult brain, thus the in utero period may be a sensitive period of human brain development during which exogenous cannabinoids could permanently alter neurodevelopmental processes. Human epidemiologic studies across diverse populations have reported an emerging theme of deficiencies related to impulse control and executive functioning among offspring with in utero exposure to cannabis starting in adolescence. Only rudimentary aspects of executive function are present in infants, thus evidence of an impact during infancy and the toddler years is sparse, inconsistent and confounded by the postnatal environment (i.e., daycare, caregiver functioning). Research is needed to evaluate the proximal impact of in utero cannabis exposure on robust metrics of neonatal brain morphology and structural integrity of white matter tracts that connect to the PFC and the limbic regions before the influence of postnatal exposures become a major confounding influence. To address this challenge, a pilot prospective pre-birth cohort study will be conducted to investigate the impact of chronic in utero cannabis exposure by enrolling 110 mother-infant pairs (50 exposed and 60 unexposed controls) for a neonate neuroimaging scan within 2 weeks after birth. Chronic in utero cannabis exposure will be quantified using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS) of neonatal meconium. The associations between in utero cannabis exposure and neural morphological outcomes will be examined by structural MRI and diffusion tensor imaging (DTI). The central hypothesis is that in utero cannabis exposure will be associated with alterations in grey and white matter development in the prefrontal lobe and its connectivity to limbic regions. Specific Aim 1: To determine the magnitude of the association between in utero exposure to cannabis and neonate brain morphology and structural connectivity. Hypothesis: In utero exposure to cannabis (assessed by THC metabolites in meconium) will be associated with the following neonate brain structural outcomes: (1) Grey matter: reduced volume in the PFC and limbic regions (i.e. the amygdala, hippocampus); (2) White matter: reduced structural integrity (assessed by fractional anisotropy) of white matter tracts that connect to the PFC and the limbic regions including the uncinate fasciculus and the cingulum bundle. The associations will be independent of other maternal substance use (i.e. tobacco), postnatal feeding practices (i.e. breastfeeding), socio-demographic characteristics and maternal mental health.

Official Title
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The Influence of in Utero Cannabis Exposure on Neonatal Brain Morphology and Structural Connectivity

Conditions
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Cannabis Use Disorder, PREG1, Drug Use, Fetal Exposure During Pregnancy, Neurodevelopmental Abnormality

Intervention / Treatment
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* Other: no intervention, this is a purely observational study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: pregnant women who are receiving prenatal care at the University of Colorado Hospital at Anschutz (UCH) or Denver Health Medical Center. maternal positive urine toxicology screen for cannabis at any clinical prenatal visit or self-report of cannabis during pregnancy at a clinical visit greater than ≥ 28 weeks gestation, aged ≥18 years, expecting a singleton birth, live in Colorado, and plan to deliver at UCH or Denver Health Medical Center . Inclusion criteria for unexposed controls will be identical to that of exposed cases with the exception that they cannot have a positive toxicology screen for cannabis or self-reported cannabis use during pregnancy. Exclusion Criteria (for unexposed cases and controls): use of tobacco, alcohol or other drugs during pregnancy, serious chronic diseases (cancer, psychiatric diseases, steroid-dependent asthma, pre-existent diabetes mellitus of any kind), mothers who subsequently experience a fetal death or deliver a premature infant (< 37 weeks of gestation). Postnatal exclusions will include failure to collect meconium samples at birth, infant neurological trauma, other neurological conditions in the infant (e.g., epilepsy), suspicion of metal in body or other MRI contraindications in either the mother or infant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| prenatal exposed to cannabis<br>50 mother-infant pairs with self-reported maternal chronic cannabis use during pregnancy | Other: no intervention, this is a purely observational study<br>* No intervention<br>|
| prenatal not-exposed to cannabis<br>60 mother-infant pairs with no self-reported maternal cannabis use during pregnancy | Other: no intervention, this is a purely observational study<br>* No intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| region specific grey matter volume (mm^2) in the PFC and limbic regions | region specific volume (mm^2) | 2 weeks postnatal age | 
| structural integrity measured by fractional anisotrophy of white matter tracks that connect the PFC and limbic regions | mean fractional anisotrophy | 2 weeks postnatal age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Negative affectivity based on a subscale from the Infant Behavioral Questionnaire (Rothbart, 1981) | Four subscales on the IBQ-R will be combined to form a negative affectivity scale including scales of Sadness, Distress to Limitations, Fear, and Falling Reactivity/Rate of Recovery from Distress. | 1 year postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cannabis, fetal programming, pregnancy, infant neuroimaging