<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/NCT04484441</url>
  </required_header>
  <id_info>
    <org_study_id>19-011382</org_study_id>
    <nct_id>NCT04484441</nct_id>
  </id_info>
  <brief_title>Maternal-fetal Immune Responses to Fetal Surgery</brief_title>
  <official_title>Maternal-fetal Immune Responses to Fetal Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Performing surgery in utero on fetuses with certain birth defects has led to significant&#xD;
      improvements in outcomes after birth; however, many of these infants are born preterm which&#xD;
      can decrease the effectiveness of these procedures. The investigators aim to understand the&#xD;
      effects of surgery on the maternal and fetal immune system and whether immune activation may&#xD;
      be causing some of these infants to be born prematurely.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Over 300,000 neonates worldwide die in their first month of life due to a congenital birth&#xD;
      defect. Thanks to advancements in diagnostic technology and imaging, the field of fetal&#xD;
      surgery was developed to treat some of these conditions in utero. Results have demonstrated&#xD;
      improved short and long-term outcomes following surgery, especially for those fetuses&#xD;
      diagnosed with congenital diaphragmatic hernia, lower urinary tract obstruction and spina&#xD;
      bifida. However, over 30% of the surgical cases will have preterm labor, leading to&#xD;
      complications related to neonatal prematurity. The cause of this surgery-induced preterm&#xD;
      birth is unknown; however, disruption in fetal-maternal tolerance may lead to immune&#xD;
      activation and inflammation of the maternal and fetal immune systems. Maintaining immunologic&#xD;
      tolerance is essential during pregnancy, as a women shares only half of her genetic material&#xD;
      with the fetus. Previous work has demonstrated that fetal surgery leads to an increase in&#xD;
      maternal cells identified in cord blood. Animal studies have also shown that in utero&#xD;
      intervention leads to the activation of maternal cells against fetal (paternal) antigen.&#xD;
      Based on this previous data, it is hypothesized that surgical trauma following in utero&#xD;
      intervention results in mixing of maternal and fetal cells leading to activation of systemic&#xD;
      (adaptive maternal immunity) and regional (fetal placental macrophages) immune responses that&#xD;
      disrupt fetal-maternal tolerance, which can result in preterm birth. Blood will be collected&#xD;
      from pregnant women and their partners. Blood and placental tissue will be collected from&#xD;
      infants that do and do not undergo in utero surgery to determine whether maternal T cells&#xD;
      specific to fetal antigen are activated and expand after in utero intervention; and 2) to&#xD;
      determine whether placental macrophages (Hofbauer Cells) and histology in the maternal-fetal&#xD;
      interface exhibit increased activation and inflammation in surgical cases born preterm (&lt;37&#xD;
      weeks) compared to term. Should this exploratory study reveal activation of maternal and/or&#xD;
      fetal immune responses following in utero surgery, modalities aimed at therapeutically&#xD;
      suppressing these acute responses may prolong gestation, significantly benefiting newborns&#xD;
      diagnosed with a congenital anomaly.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 24, 2022</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Maternal T cell activation following in utero intervention.</measure>
    <time_frame>Baseline, 1-2 days post intervention, 1 week post intervention, delivery</time_frame>
    <description>T cells from maternal blood will be isolated and CDR3 spectra typing will be completed. These samples will be compared to each other to identify high frequency T cell clones as well as longitudinal changes in the dynamics of clones.&#xD;
Blood collected at the four time points above will be profiled for changes in immune activation using mass cytometry (CyTOF) and plasma collected to measure changes in cytokine responses pre- and post-surgery by multiplex.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Placental histology in the maternal-fetal interface in term and preterm fetal intervention cases</measure>
    <time_frame>Delivery</time_frame>
    <description>Placental macrophages will be phenotyped for subtypes (M1 classical versus M2 repair), activation (CD25 and CD40), and apoptosis status by CyTOF. Comparisons will be made between those born before 37 weeks and those born after 37 weeks in the surgical group, as well as to those who didn't undergo surgery.&#xD;
From each placenta, 5 sections will be dissected and submitted for histological evaluation of placental villitis. Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus and Herpes (TORCH) infection panels will be completed to distinguish infectious villitis from immune-mediated villitis.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Spina Bifida</condition>
  <condition>Congenital Diaphragmatic Hernia</condition>
  <condition>Lower Urinary Tract Obstructive Syndrome</condition>
  <condition>Myelomeningocele</condition>
  <arm_group>
    <arm_group_label>Fetal surgical intervention group</arm_group_label>
    <description>Pregnant adult women carrying a fetus with a diagnosed congenital anomaly and scheduled to undergo fetal surgical intervention at Mayo Clinic.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group - normal pregnancy</arm_group_label>
    <description>Pregnant adult women with normal ultrasound findings. These women will be matched with the subjects enrolled in the intervention cohort for parity, maternal age, ethnicity, fetal sex and gestational age at time of surgical intervention.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood and placenta specimen collection.</intervention_name>
    <description>Collection of maternal and paternal blood. Collection of infant cord blood and placenta.</description>
    <arm_group_label>Control group - normal pregnancy</arm_group_label>
    <arm_group_label>Fetal surgical intervention group</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        The study population will compare two groups of pregnant women. Each group will be&#xD;
        comprised of maternal, paternal, fetal trios. The study cohort will be comprised of adult&#xD;
        women carrying a fetus with a diagnosed congenital anomaly and scheduled to undergo fetal&#xD;
        surgical intervention. The control cohort will enroll pregnant women with normal ultrasound&#xD;
        findings that will be matched with the subjects enrolled in the study cohort for parity,&#xD;
        maternal age, ethnicity, fetal sex and gestational age at time of surgical intervention.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria for study group:&#xD;
&#xD;
          -  Maternal age ≥18 years&#xD;
&#xD;
          -  Pregnant with a congenital anomaly diagnosis AND undergoing fetal intervention in&#xD;
             utero&#xD;
&#xD;
          -  Delivery planned at Mayo Clinic, Rochester MN&#xD;
&#xD;
        Inclusion Criteria for control group:&#xD;
&#xD;
          -  Maternal age ≥18 years&#xD;
&#xD;
          -  Pregnant with normal ultrasound findings&#xD;
&#xD;
          -  Delivery planned at Mayo Clinic, Rochester MN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Delivery planned elsewhere&#xD;
&#xD;
          -  Abnormal fetal karyotype&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mauro Schenone, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maureen A Lemens, BSN</last_name>
    <phone>507-293-1487</phone>
    <email>lemens.maureen@mayo.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Elizabeth Ann L Enninga, PhD</last_name>
    <phone>507-538-7615</phone>
    <email>enninga.elizabethann@mayo.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester, Minnesota</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maureen A Lemens, BSN, RN</last_name>
      <phone>507-293-1487</phone>
      <email>lemens.maureen@mayo.edu</email>
    </contact>
    <investigator>
      <last_name>Mauro Schenone, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Elizabeth Ann L Enninga, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Madeline Peters</last_name>
      <phone>513-517-7162</phone>
      <email>Madeline.Peters@cchmc.org</email>
    </contact>
    <contact_backup>
      <last_name>Erin Watters, BA</last_name>
      <phone>513-803-7024</phone>
      <email>Erin.Watters@cchmc.org</email>
    </contact_backup>
    <investigator>
      <last_name>Jose-Luis Peiro Ibanez, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Texas Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Percy N Pacora Portella, MD</last_name>
      <phone>713-500-6410</phone>
      <email>Percy.N.PacoraPortella@uth.tmc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Sunbola Ashimi, PhD</last_name>
      <phone>713-500-6410</phone>
      <email>Sunbola.S.Ashimi@uth.tmc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Eric Bergh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.mayo.edu/research/clinical-trials</url>
    <description>Mayo Clinic Clinical Trials</description>
  </link>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>August 7, 2023</last_update_submitted>
  <last_update_submitted_qc>August 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mayo Clinic</investigator_affiliation>
    <investigator_full_name>Mauro H. Schenone</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Fetal Surgery</keyword>
  <keyword>Fetal Intervention</keyword>
  <keyword>In Utero Surgery</keyword>
  <keyword>In Utero Intervention</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spinal Dysraphism</mesh_term>
    <mesh_term>Meningomyelocele</mesh_term>
    <mesh_term>Spina Bifida Cystica</mesh_term>
    <mesh_term>Hernias, Diaphragmatic, Congenital</mesh_term>
    <mesh_term>Hernia, Diaphragmatic</mesh_term>
  </condition_browse>
  <!-- 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/NCT04484441
org study id: 19-011382
nct id: NCT04484441
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Performing surgery in utero on fetuses with certain birth defects has led to significant
      improvements in outcomes after birth; however, many of these infants are born preterm which
      can decrease the effectiveness of these procedures. The investigators aim to understand the
      effects of surgery on the maternal and fetal immune system and whether immune activation may
      be causing some of these infants to be born prematurely.
Over 300,000 neonates worldwide die in their first month of life due to a congenital birth
      defect. Thanks to advancements in diagnostic technology and imaging, the field of fetal
      surgery was developed to treat some of these conditions in utero. Results have demonstrated
      improved short and long-term outcomes following surgery, especially for those fetuses
      diagnosed with congenital diaphragmatic hernia, lower urinary tract obstruction and spina
      bifida. However, over 30% of the surgical cases will have preterm labor, leading to
      complications related to neonatal prematurity. The cause of this surgery-induced preterm
      birth is unknown; however, disruption in fetal-maternal tolerance may lead to immune
      activation and inflammation of the maternal and fetal immune systems. Maintaining immunologic
      tolerance is essential during pregnancy, as a women shares only half of her genetic material
      with the fetus. Previous work has demonstrated that fetal surgery leads to an increase in
      maternal cells identified in cord blood. Animal studies have also shown that in utero
      intervention leads to the activation of maternal cells against fetal (paternal) antigen.
      Based on this previous data, it is hypothesized that surgical trauma following in utero
      intervention results in mixing of maternal and fetal cells leading to activation of systemic
      (adaptive maternal immunity) and regional (fetal placental macrophages) immune responses that
      disrupt fetal-maternal tolerance, which can result in preterm birth. Blood will be collected
      from pregnant women and their partners. Blood and placental tissue will be collected from
      infants that do and do not undergo in utero surgery to determine whether maternal T cells
      specific to fetal antigen are activated and expand after in utero intervention; and 2) to
      determine whether placental macrophages (Hofbauer Cells) and histology in the maternal-fetal
      interface exhibit increased activation and inflammation in surgical cases born preterm (<37
      weeks) compared to term. Should this exploratory study reveal activation of maternal and/or
      fetal immune responses following in utero surgery, modalities aimed at therapeutically
      suppressing these acute responses may prolong gestation, significantly benefiting newborns
      diagnosed with a congenital anomaly.
observational model: Case-Control
time perspective: Prospective
measure: Maternal T cell activation following in utero intervention.
time frame: Baseline, 1-2 days post intervention, 1 week post intervention, delivery
description: T cells from maternal blood will be isolated and CDR3 spectra typing will be completed. These samples will be compared to each other to identify high frequency T cell clones as well as longitudinal changes in the dynamics of clones.
Blood collected at the four time points above will be profiled for changes in immune activation using mass cytometry (CyTOF) and plasma collected to measure changes in cytokine responses pre- and post-surgery by multiplex.
measure: Placental histology in the maternal-fetal interface in term and preterm fetal intervention cases
time frame: Delivery
description: Placental macrophages will be phenotyped for subtypes (M1 classical versus M2 repair), activation (CD25 and CD40), and apoptosis status by CyTOF. Comparisons will be made between those born before 37 weeks and those born after 37 weeks in the surgical group, as well as to those who didn't undergo surgery.
From each placenta, 5 sections will be dissected and submitted for histological evaluation of placental villitis. Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus and Herpes (TORCH) infection panels will be completed to distinguish infectious villitis from immune-mediated villitis.
arm group label: Fetal surgical intervention group
description: Pregnant adult women carrying a fetus with a diagnosed congenital anomaly and scheduled to undergo fetal surgical intervention at Mayo Clinic.
arm group label: Control group - normal pregnancy
description: Pregnant adult women with normal ultrasound findings. These women will be matched with the subjects enrolled in the intervention cohort for parity, maternal age, ethnicity, fetal sex and gestational age at time of surgical intervention.
intervention type: Other
intervention name: Blood and placenta specimen collection.
description: Collection of maternal and paternal blood. Collection of infant cord blood and placenta.
arm group label: Control group - normal pregnancy
arm group label: Fetal surgical intervention group
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Mauro Schenone, MD
role: Principal Investigator
affiliation: Mayo Clinic
last name: Maureen A Lemens, BSN
phone: 507-293-1487
email: lemens.maureen@mayo.edu
last name: Elizabeth Ann L Enninga, PhD
phone: 507-538-7615
email: enninga.elizabethann@mayo.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
url: https://www.mayo.edu/research/clinical-trials
description: Mayo Clinic Clinical Trials
responsible party type: Principal Investigator
investigator affiliation: Mayo Clinic
investigator full name: Mauro H. Schenone
investigator title: Principal Investigator
mesh term: Spinal Dysraphism
mesh term: Meningomyelocele
mesh term: Spina Bifida Cystica
mesh term: Hernias, Diaphragmatic, Congenital
mesh term: Hernia, Diaphragmatic