<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04422600</url>
  </required_header>
  <id_info>
    <org_study_id>239611</org_study_id>
    <nct_id>NCT04422600</nct_id>
  </id_info>
  <brief_title>Fetal Exposure to Cannabinoids: Exposure, Methylation and Neurodevelopmental Effects</brief_title>
  <official_title>Fetal Exposure to Cannabinoids: Exposure, Methylation and Neurodevelopmental Effects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Arkansas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Arkansas</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cannabis is a very popular drug for both recreational and medicinal use. An estimated 20% of&#xD;
      adults in the United States report using cannabis in the past month, and this number&#xD;
      continues to increase each year. As of 2018, medical use of cannabis is legal in 33 states&#xD;
      and the District of Columbia. Recreational use is legal in 10 states, and it is&#xD;
      decriminalized in 15 states. Hemp-derived cannabidiol (CBD) is legal in all states. Due to&#xD;
      the rapidly changing legal status across the country, the demand for cannabinoids (which are&#xD;
      specific components of cannabis), such as THC and CBD, are also rapidly increasing. Studies&#xD;
      have shown a significant increase in marijuana use among pregnant and parenting women&#xD;
      following state-wide legalization, and this could have significant implications for the&#xD;
      health and development of children born to these women.&#xD;
&#xD;
      While there is a growing effort to evaluate the health effects of cannabinoids, especially&#xD;
      during pregnancy, there is still relatively little known about the long term&#xD;
      neurodevelopmental outcomes, such as emotional regulation, attention, and intelligence, in&#xD;
      children born to mothers who used any sort of cannabinoid during pregnancy. The few studies&#xD;
      that have been performed that look at longer term outcomes were epidemiological and&#xD;
      self-reported in nature, and cannot accurately correlate neurodevelopmental outcomes with&#xD;
      precise dosage and exposure levels during pregnancy.&#xD;
&#xD;
      Importantly, the THC content of marijuana has dramatically increased in recent years, with&#xD;
      THC concentration and purity being the highest in history. It is estimated that cannabis&#xD;
      potency has increased 3-fold over the past 2 decades. Many of the previous studies examining&#xD;
      prenatal cannabis use and fetal outcomes reflected lower potency cannabis, which is not&#xD;
      relevant to today's exposure levels. Additionally, there are no published studies to-date&#xD;
      that evaluate fetal exposure to CBD or neurodevelopmental outcomes in infants who were&#xD;
      exposed to CBD prenatally.&#xD;
&#xD;
      Finally, the causes behind possible neurodevelopmental changes in children exposed to&#xD;
      cannabis prenatally have not been thoroughly explored, particularly in humans. It is thought&#xD;
      that epigenetic modifications, or changes to DNA, may play a role in changes to the&#xD;
      developing fetal brain after prenatal exposure to cannabis, but few studies have evaluated&#xD;
      this quantitatively in humans.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cannabis is a very popular drug for both recreational and medicinal use. An estimated 20% of&#xD;
      adults in the United States report using cannabis in the past month, and this number&#xD;
      continues to increase each year. As of 2018, medicinal use of cannabis is legal in 33 states&#xD;
      and the District of Columbia. Recreational use is legal in 10 states, and it is&#xD;
      decriminalized in 15 states. Hemp-derived cannabidiol (CBD) is legal in all states. Due to&#xD;
      the rapidly changing legal status across the country, the demand for tetrahydrocannabinoid&#xD;
      (THC) and CBD products is also rapidly increasing. Studies have shown a significant increase&#xD;
      in marijuana use among pregnant and parenting women following state-wide legalization, and&#xD;
      this could have significant implications for the health and development of children born to&#xD;
      these women.&#xD;
&#xD;
      Despite its widespread use, and increased interests in THC for medical treatment, significant&#xD;
      gaps exist in the investigator's scientific knowledge of the pharmacology and&#xD;
      pharmacokinetics of THC and its metabolites. When inhaled, THC and CBD reach maximum&#xD;
      concentrations within seconds. Bioavailability varies widely and is a function of inhalation&#xD;
      time, number, interval, and duration of puffs, as well as within product variability.&#xD;
      Importantly, smokers have greater bioavailability of THC than non-smokers. When THC and CBD&#xD;
      are orally consumed, the bioavailability is relatively low (&lt; 20%). However, the&#xD;
      lipophilicity of both THC and CBD make these compounds of great interest with respect to&#xD;
      tissue distribution. CBD is more lipophilic than THC and thus more likely to be absorbed with&#xD;
      topic application. THC is known to cross the placenta and can reach the fetus]. The&#xD;
      metabolism of both THC and CBD is complex. Following absorption, THC and CBD are rapidly&#xD;
      distributed to tissues with high blood flow. Metabolism occurs in the liver via CYP2C9,&#xD;
      CYP2C19, and CYP3A4, as well as the brain, small intestine, heart and lung. Primary&#xD;
      metabolites undergo glucuronidation or conjugation reactions. The elimination half-lives are&#xD;
      prolonged due to the deposition of drug and metabolites in fat.&#xD;
&#xD;
      Some previous epidemiological studies have shown that children born to mothers who report&#xD;
      using THC during their pregnancy have a higher prevalence of neurodevelopmental and&#xD;
      behavioral abnormalities. While these studies are sparse, there have been some studies that&#xD;
      follow longitudinal cohorts worldwide. These epidemiological, survey-based studies have&#xD;
      reported an increase in executive functioning deficits in infants who were exposed to THC in&#xD;
      utero. These studies have also shown an increase in attention problems and hyperactivity in&#xD;
      these children during early childhood and later adolescence. However, these studies have&#xD;
      reported inconsistent outcomes. Some have reported negative effects on cognitive or executive&#xD;
      functioning, and others have reported no significant changes. One possibility for these&#xD;
      discrepancies is that survey-based epidemiological studies do not accurately capture the&#xD;
      exact levels of fetal exposure due to the unreliable nature of self-reporting, making it&#xD;
      difficult to accurately correlate prenatal exposure levels to neurodevelopment. This makes&#xD;
      the need for a well-designed, quantitative exposure study that is followed by longitudinal&#xD;
      neurodevelopmental outcome measurement imperative to determining true correlations between&#xD;
      prenatal THC use and developmental outcomes in children.&#xD;
&#xD;
      It has also previously been established that cannabis use during pregnancy can be detrimental&#xD;
      to the developing fetus. Prenatal use of THC has been shown to cause low birth weight in the&#xD;
      absence of any change in neonatal length or head circumference, as well as increased tremors&#xD;
      and disrupted sleep patterns. It has also been correlated with an increased need for&#xD;
      placement in the neonatal intensive care unit. In addition to human studies, animal studies&#xD;
      have shown changes in the endocannabinoid system (ECS) in the fetal brain during development.&#xD;
      The ECS is present in the developing brain from the time of 5 weeks gestation, and is&#xD;
      required for proliferation, differentiation, and migration of neurons. Any changes to this&#xD;
      system during development could have important implications for further neural development.&#xD;
      Several studies have observed changes in postsynaptic target selectivity, differentiation of&#xD;
      developing axons, and disruption of position in the ECS in animal fetuses that were exposed&#xD;
      to THC in utero. These central nervous system alterations could potentially point to&#xD;
      long-term neurodevelopmental changes in children born to mothers who used cannabis during&#xD;
      pregnancy. However, while animal studies are able to report exact dosing levels, animal&#xD;
      models of prenatal cannabinoid use often do not accurately reflect human use.&#xD;
&#xD;
      While some detrimental effects to the fetus following prenatal cannabis use have been&#xD;
      observed in both animal models and human studies, there remains the mechanistic question of&#xD;
      what is causing these changes. Some studies have proposed epigenetic reprogramming that may&#xD;
      occur in the mothers and the babies following prenatal cannabis use. Prior studies have&#xD;
      focused on the effects of prenatal cannabis use increasing the likelihood of the children's&#xD;
      substance abuse later in life, and have found positive correlations to DNA methylation and&#xD;
      histone modification in these cases. Additionally, it has been shown that paternal cannabis&#xD;
      use alters DNA methylation in sperm of rats and humans, which could also have important&#xD;
      implications for development. However, to-date, there have not been any studies correlating&#xD;
      epigenetic changes and neurodevelopmental changes in infants prenatally exposed to cannabis.&#xD;
&#xD;
      Additionally, many of the prior human studies were done at a time when THC content in&#xD;
      marijuana was not as high as is in today's market, which could have major implications for&#xD;
      actual exposure levels in the fetus. The initial studies that evaluated the effects of&#xD;
      prenatal cannabis use on fetal outcomes were done in the early 1990s, at a time when average&#xD;
      THC potency in seized marijuana in the United States was approximately 4%. The most recently&#xD;
      reported potency of seized illicit cannabis plant material is approximately 12%.&#xD;
      Additionally, the ratio of psychoactive THC content to non-psychoactive cannabidiol content&#xD;
      has increased from approximately 14 to 80 between 1995 and 2014. These factors suggest a need&#xD;
      for more updated studies that examine the effects of current high potency levels of fetal&#xD;
      exposure to cannabis, as an increase in potency may have greater effects on the developing&#xD;
      fetus.&#xD;
&#xD;
      While there have been some prior studies measuring the effects of fetal exposure to THC&#xD;
      specifically, there have been no studies to-date that have evaluated the effects of CBD&#xD;
      exposure on the developing fetus. CBD (also known as hemp) supposedly lacks psychoactive THC&#xD;
      components, making it legal, widely available, and generally perceived to be safe.CBD is&#xD;
      touted as a treatment for a number of conditions, including depression, anxiety, pain, and&#xD;
      cancer. These factors, in addition to strong marketing campaigns, have most likely caused an&#xD;
      increase in prenatal CBD use in recent years. A recent study conducted in mice found that CBD&#xD;
      activates a large range of CYPP450 enzymes. While these data are preliminary, CYPP450&#xD;
      activation raises the concern of drug-drug interactions and suggests that biologic activity&#xD;
      of CBD is not fully understood. However, there are no published studies evaluating the&#xD;
      effects of prenatal CBD use on fetal outcomes or neurodevelopment. Additionally, many CBD&#xD;
      products have been shown to contain varying concentrations of CBD, or are contaminated with&#xD;
      synthetic cannabinoids (e.g. K2, &quot;spice&quot;) or THC. The investigators will establish the exact&#xD;
      composition of the products the pregnant women are taking in order to properly evaluate&#xD;
      potential exposure levels in the developing fetus. The investigators will then correlate that&#xD;
      exposure with neurodevelopmental outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 26, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2023</completion_date>
  <primary_completion_date type="Actual">May 1, 2023</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>12 Months</target_duration>
  <primary_outcome>
    <measure>THC and CBD metabolite levels in maternal neonatal blood</measure>
    <time_frame>Within three months prior to the estimated due date</time_frame>
    <description>Levels of THC and CBD metabolites will be measured in maternal blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>THC and CBD metabolite level in umbilical cord blood</measure>
    <time_frame>Immediately after birth</time_frame>
    <description>Levels of THC and CBD metabolites will be measured umbilical cord blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>THC and CBD metabolite levels in neonatal blood</measure>
    <time_frame>24 hours after birth</time_frame>
    <description>Levels of THC and CBD metabolites will be measured in neonatal blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Infant motor, cognitive, and social development at 6 months of age using the Ages and Stages Questionnaire</measure>
    <time_frame>6 months after birth</time_frame>
    <description>To measure infant neurodevelopment, we will use the Ages and Stages Questionnaire (ASQ). The ASQ measures 5 domains/scales of child development: communication, gross motor, fine motor, problem solving, and personal-social. Each scale ranges from 0 to 60, with lower scores being indicative of deficits or poor outcomes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Infant motor, cognitive, and social development at 12 months of age using the Ages and Stages Questionnaire</measure>
    <time_frame>12 months after birth</time_frame>
    <description>To measure infant neurodevelopment, we will use the Ages and Stages Questionnaire (ASQ). The ASQ measures 5 domains/scales of child development: communication, gross motor, fine motor, problem solving, and personal-social. Each scale ranges from 0 to 60, with lower scores being indicative of deficits or poor outcomes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Infant motor, cognitive, and social development at 6 months of age using the Bayley Scales of Infant Development</measure>
    <time_frame>6 months after birth</time_frame>
    <description>To measure infant neurodevelopment, we will use the Bayley Scales of Infant and Toddler Development. The Bayley Scales measures 5 domains of child development: adaptive behavior, cognitive, language, motor, and social-emotional. Each scale ranges from 40-160, with higher scores indicative of better outcomes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Infant motor, cognitive, and social development at 12 months of age using the Bayley Scales of Infant Development</measure>
    <time_frame>12 months after birth</time_frame>
    <description>To measure infant neurodevelopment, we will use the Bayley Scales of Infant and Toddler Development. The Bayley Scales measures 5 domains of child development: adaptive behavior, cognitive, language, motor, and social-emotional. Each scale ranges from 40-160, with higher scores indicative of better outcomes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DNA methylation profiles in infants at 12 months of age</measure>
    <time_frame>12 months after birth</time_frame>
    <description>Buccal samples from infants at 12 months of age will be used to evaluate DNA methylation profiles.</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">72</enrollment>
  <condition>Fetal Exposure Timing Unspecified</condition>
  <arm_group>
    <arm_group_label>Mothers who report use of THC with or without CBD</arm_group_label>
    <description>Mothers who report THC and CBD usage during the trimester month of pregnancy, at a frequency of at least three time per week. Information will be collected from mothers receiving their obstetrical care at UAMS and will include data on the exact products used and the frequency of use.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mothers who report use of CBD only</arm_group_label>
    <description>Mothers who report CBD usage during the trimester month of pregnancy, at a frequency of at least three time per week. Information will be collected from mothers receiving their obstetrical care at UAMS and will include data on the exact products used and the frequency of use.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Mothers</arm_group_label>
    <description>Recruitment of pregnant women who do not use THC or CBD will be conducted using the Epic MyChart research participant recruitment tool</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Five (5) mL of blood will be collected from mothers at some point in the third trimester of&#xD;
      pregnancy. Five (5) mL of umbilical cord blood will be collected from the baby immediately&#xD;
      after birth, followed by a 1 mL venous blood sample collected 24 hours or later following&#xD;
      birth during the routine blood sample collection for newborn screening.&#xD;
&#xD;
      Buccal swabs will be collected from infants at 6 and 12 months of age for DNA methylation.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Mothers who report use of THC and /or CBD and pregnant women who do not use THC or CBD.&#xD;
        Babies will be enrolled (consent given by mothers) following birth.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Age 18 and older&#xD;
&#xD;
          -  Must plan to give birth at UAMS&#xD;
&#xD;
          -  Report regular (at least 3x per week) use of THC- and/or CBD-containing product&#xD;
             anytime during pregnancy (for experimental groups). Women who discontinue use of&#xD;
             marijuana and/or CBD during pregnancy will still be allowed in the study.&#xD;
&#xD;
          -  Pregnant women who do not use THC or CBD will be enrolled as controls.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any other illicit drug use during pregnancy&#xD;
&#xD;
          -  Plan to give birth anywhere other than UAMS&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women and infants</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stefanie Kennon McGill, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Arkansas</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Arkansas for Medical Sciences</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>May 1, 2023</last_update_submitted>
  <last_update_submitted_qc>May 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Fetal Exposure</keyword>
  <keyword>Cannabinoids</keyword>
  <keyword>Methylation</keyword>
  <keyword>Neurodevelopmental Effects</keyword>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04422600
org study id: 239611
nct id: NCT04422600
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Cannabis is a very popular drug for both recreational and medicinal use. An estimated 20% of
      adults in the United States report using cannabis in the past month, and this number
      continues to increase each year. As of 2018, medical use of cannabis is legal in 33 states
      and the District of Columbia. Recreational use is legal in 10 states, and it is
      decriminalized in 15 states. Hemp-derived cannabidiol (CBD) is legal in all states. Due to
      the rapidly changing legal status across the country, the demand for cannabinoids (which are
      specific components of cannabis), such as THC and CBD, are also rapidly increasing. Studies
      have shown a significant increase in marijuana use among pregnant and parenting women
      following state-wide legalization, and this could have significant implications for the
      health and development of children born to these women.

      While there is a growing effort to evaluate the health effects of cannabinoids, especially
      during pregnancy, there is still relatively little known about the long term
      neurodevelopmental outcomes, such as emotional regulation, attention, and intelligence, in
      children born to mothers who used any sort of cannabinoid during pregnancy. The few studies
      that have been performed that look at longer term outcomes were epidemiological and
      self-reported in nature, and cannot accurately correlate neurodevelopmental outcomes with
      precise dosage and exposure levels during pregnancy.

      Importantly, the THC content of marijuana has dramatically increased in recent years, with
      THC concentration and purity being the highest in history. It is estimated that cannabis
      potency has increased 3-fold over the past 2 decades. Many of the previous studies examining
      prenatal cannabis use and fetal outcomes reflected lower potency cannabis, which is not
      relevant to today's exposure levels. Additionally, there are no published studies to-date
      that evaluate fetal exposure to CBD or neurodevelopmental outcomes in infants who were
      exposed to CBD prenatally.

      Finally, the causes behind possible neurodevelopmental changes in children exposed to
      cannabis prenatally have not been thoroughly explored, particularly in humans. It is thought
      that epigenetic modifications, or changes to DNA, may play a role in changes to the
      developing fetal brain after prenatal exposure to cannabis, but few studies have evaluated
      this quantitatively in humans.
Cannabis is a very popular drug for both recreational and medicinal use. An estimated 20% of
      adults in the United States report using cannabis in the past month, and this number
      continues to increase each year. As of 2018, medicinal use of cannabis is legal in 33 states
      and the District of Columbia. Recreational use is legal in 10 states, and it is
      decriminalized in 15 states. Hemp-derived cannabidiol (CBD) is legal in all states. Due to
      the rapidly changing legal status across the country, the demand for tetrahydrocannabinoid
      (THC) and CBD products is also rapidly increasing. Studies have shown a significant increase
      in marijuana use among pregnant and parenting women following state-wide legalization, and
      this could have significant implications for the health and development of children born to
      these women.

      Despite its widespread use, and increased interests in THC for medical treatment, significant
      gaps exist in the investigator's scientific knowledge of the pharmacology and
      pharmacokinetics of THC and its metabolites. When inhaled, THC and CBD reach maximum
      concentrations within seconds. Bioavailability varies widely and is a function of inhalation
      time, number, interval, and duration of puffs, as well as within product variability.
      Importantly, smokers have greater bioavailability of THC than non-smokers. When THC and CBD
      are orally consumed, the bioavailability is relatively low (< 20%). However, the
      lipophilicity of both THC and CBD make these compounds of great interest with respect to
      tissue distribution. CBD is more lipophilic than THC and thus more likely to be absorbed with
      topic application. THC is known to cross the placenta and can reach the fetus]. The
      metabolism of both THC and CBD is complex. Following absorption, THC and CBD are rapidly
      distributed to tissues with high blood flow. Metabolism occurs in the liver via CYP2C9,
      CYP2C19, and CYP3A4, as well as the brain, small intestine, heart and lung. Primary
      metabolites undergo glucuronidation or conjugation reactions. The elimination half-lives are
      prolonged due to the deposition of drug and metabolites in fat.

      Some previous epidemiological studies have shown that children born to mothers who report
      using THC during their pregnancy have a higher prevalence of neurodevelopmental and
      behavioral abnormalities. While these studies are sparse, there have been some studies that
      follow longitudinal cohorts worldwide. These epidemiological, survey-based studies have
      reported an increase in executive functioning deficits in infants who were exposed to THC in
      utero. These studies have also shown an increase in attention problems and hyperactivity in
      these children during early childhood and later adolescence. However, these studies have
      reported inconsistent outcomes. Some have reported negative effects on cognitive or executive
      functioning, and others have reported no significant changes. One possibility for these
      discrepancies is that survey-based epidemiological studies do not accurately capture the
      exact levels of fetal exposure due to the unreliable nature of self-reporting, making it
      difficult to accurately correlate prenatal exposure levels to neurodevelopment. This makes
      the need for a well-designed, quantitative exposure study that is followed by longitudinal
      neurodevelopmental outcome measurement imperative to determining true correlations between
      prenatal THC use and developmental outcomes in children.

      It has also previously been established that cannabis use during pregnancy can be detrimental
      to the developing fetus. Prenatal use of THC has been shown to cause low birth weight in the
      absence of any change in neonatal length or head circumference, as well as increased tremors
      and disrupted sleep patterns. It has also been correlated with an increased need for
      placement in the neonatal intensive care unit. In addition to human studies, animal studies
      have shown changes in the endocannabinoid system (ECS) in the fetal brain during development.
      The ECS is present in the developing brain from the time of 5 weeks gestation, and is
      required for proliferation, differentiation, and migration of neurons. Any changes to this
      system during development could have important implications for further neural development.
      Several studies have observed changes in postsynaptic target selectivity, differentiation of
      developing axons, and disruption of position in the ECS in animal fetuses that were exposed
      to THC in utero. These central nervous system alterations could potentially point to
      long-term neurodevelopmental changes in children born to mothers who used cannabis during
      pregnancy. However, while animal studies are able to report exact dosing levels, animal
      models of prenatal cannabinoid use often do not accurately reflect human use.

      While some detrimental effects to the fetus following prenatal cannabis use have been
      observed in both animal models and human studies, there remains the mechanistic question of
      what is causing these changes. Some studies have proposed epigenetic reprogramming that may
      occur in the mothers and the babies following prenatal cannabis use. Prior studies have
      focused on the effects of prenatal cannabis use increasing the likelihood of the children's
      substance abuse later in life, and have found positive correlations to DNA methylation and
      histone modification in these cases. Additionally, it has been shown that paternal cannabis
      use alters DNA methylation in sperm of rats and humans, which could also have important
      implications for development. However, to-date, there have not been any studies correlating
      epigenetic changes and neurodevelopmental changes in infants prenatally exposed to cannabis.

      Additionally, many of the prior human studies were done at a time when THC content in
      marijuana was not as high as is in today's market, which could have major implications for
      actual exposure levels in the fetus. The initial studies that evaluated the effects of
      prenatal cannabis use on fetal outcomes were done in the early 1990s, at a time when average
      THC potency in seized marijuana in the United States was approximately 4%. The most recently
      reported potency of seized illicit cannabis plant material is approximately 12%.
      Additionally, the ratio of psychoactive THC content to non-psychoactive cannabidiol content
      has increased from approximately 14 to 80 between 1995 and 2014. These factors suggest a need
      for more updated studies that examine the effects of current high potency levels of fetal
      exposure to cannabis, as an increase in potency may have greater effects on the developing
      fetus.

      While there have been some prior studies measuring the effects of fetal exposure to THC
      specifically, there have been no studies to-date that have evaluated the effects of CBD
      exposure on the developing fetus. CBD (also known as hemp) supposedly lacks psychoactive THC
      components, making it legal, widely available, and generally perceived to be safe.CBD is
      touted as a treatment for a number of conditions, including depression, anxiety, pain, and
      cancer. These factors, in addition to strong marketing campaigns, have most likely caused an
      increase in prenatal CBD use in recent years. A recent study conducted in mice found that CBD
      activates a large range of CYPP450 enzymes. While these data are preliminary, CYPP450
      activation raises the concern of drug-drug interactions and suggests that biologic activity
      of CBD is not fully understood. However, there are no published studies evaluating the
      effects of prenatal CBD use on fetal outcomes or neurodevelopment. Additionally, many CBD
      products have been shown to contain varying concentrations of CBD, or are contaminated with
      synthetic cannabinoids (e.g. K2, "spice") or THC. The investigators will establish the exact
      composition of the products the pregnant women are taking in order to properly evaluate
      potential exposure levels in the developing fetus. The investigators will then correlate that
      exposure with neurodevelopmental outcomes.
observational model: Cohort
time perspective: Prospective
measure: THC and CBD metabolite levels in maternal neonatal blood
time frame: Within three months prior to the estimated due date
description: Levels of THC and CBD metabolites will be measured in maternal blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.
measure: THC and CBD metabolite level in umbilical cord blood
time frame: Immediately after birth
description: Levels of THC and CBD metabolites will be measured umbilical cord blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.
measure: THC and CBD metabolite levels in neonatal blood
time frame: 24 hours after birth
description: Levels of THC and CBD metabolites will be measured in neonatal blood following prenatal drug use. These levels will be measured via liquid chromatography-mass spectrometry.
measure: Infant motor, cognitive, and social development at 6 months of age using the Ages and Stages Questionnaire
time frame: 6 months after birth
description: To measure infant neurodevelopment, we will use the Ages and Stages Questionnaire (ASQ). The ASQ measures 5 domains/scales of child development: communication, gross motor, fine motor, problem solving, and personal-social. Each scale ranges from 0 to 60, with lower scores being indicative of deficits or poor outcomes.
measure: Infant motor, cognitive, and social development at 12 months of age using the Ages and Stages Questionnaire
time frame: 12 months after birth
description: To measure infant neurodevelopment, we will use the Ages and Stages Questionnaire (ASQ). The ASQ measures 5 domains/scales of child development: communication, gross motor, fine motor, problem solving, and personal-social. Each scale ranges from 0 to 60, with lower scores being indicative of deficits or poor outcomes.
measure: Infant motor, cognitive, and social development at 6 months of age using the Bayley Scales of Infant Development
time frame: 6 months after birth
description: To measure infant neurodevelopment, we will use the Bayley Scales of Infant and Toddler Development. The Bayley Scales measures 5 domains of child development: adaptive behavior, cognitive, language, motor, and social-emotional. Each scale ranges from 40-160, with higher scores indicative of better outcomes.
measure: Infant motor, cognitive, and social development at 12 months of age using the Bayley Scales of Infant Development
time frame: 12 months after birth
description: To measure infant neurodevelopment, we will use the Bayley Scales of Infant and Toddler Development. The Bayley Scales measures 5 domains of child development: adaptive behavior, cognitive, language, motor, and social-emotional. Each scale ranges from 40-160, with higher scores indicative of better outcomes.
measure: DNA methylation profiles in infants at 12 months of age
time frame: 12 months after birth
description: Buccal samples from infants at 12 months of age will be used to evaluate DNA methylation profiles.
arm group label: Mothers who report use of THC with or without CBD
description: Mothers who report THC and CBD usage during the trimester month of pregnancy, at a frequency of at least three time per week. Information will be collected from mothers receiving their obstetrical care at UAMS and will include data on the exact products used and the frequency of use.
arm group label: Mothers who report use of CBD only
description: Mothers who report CBD usage during the trimester month of pregnancy, at a frequency of at least three time per week. Information will be collected from mothers receiving their obstetrical care at UAMS and will include data on the exact products used and the frequency of use.
arm group label: Control Mothers
description: Recruitment of pregnant women who do not use THC or CBD will be conducted using the Epic MyChart research participant recruitment tool
Five (5) mL of blood will be collected from mothers at some point in the third trimester of
      pregnancy. Five (5) mL of umbilical cord blood will be collected from the baby immediately
      after birth, followed by a 1 mL venous blood sample collected 24 hours or later following
      birth during the routine blood sample collection for newborn screening.

      Buccal swabs will be collected from infants at 6 and 12 months of age for DNA methylation.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women and infants
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Stefanie Kennon McGill, Ph.D.
role: Principal Investigator
affiliation: University of Arkansas
facility: 
country: United States
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responsible party type: Sponsor