<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/NCT02230072</url>
  </required_header>
  <id_info>
    <org_study_id>H-34680</org_study_id>
    <nct_id>NCT02230072</nct_id>
  </id_info>
  <brief_title>Fetoscopic Meningomyelocele Repair Study</brief_title>
  <acronym>fMMC</acronym>
  <official_title>Minimally Invasive Fetal Neural Tube Defect Repair Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to evaluate the maternal and fetal outcomes of a new technique&#xD;
      for the fetoscopic repair of fetal MMC at Texas Children's Hospital Pavilion for Women.&#xD;
&#xD;
      The investigators hypothesis is that this minimally invasive technique is feasible, and that&#xD;
      this approach will have the same efficacy as open fetal surgery for MMC, but with&#xD;
      significantly less maternal-fetal risk. Both mother and baby will benefit from the surgery.&#xD;
      The fetus will have a repaired MMC defect, and the mother will not have a uterine incision&#xD;
      (hysterotomy). A hysterotomy increases the risk of uterine rupture and requires that all&#xD;
      subsequent deliveries are by cesarean section. There may also be a decreased risk of Pre-term&#xD;
      Premature Rupture Of Membranes (PPROM) and prematurity when compared with the current open&#xD;
      operation. Finally, a vaginal delivery is possible following the fetoscopic fetal surgery if&#xD;
      the baby is shown to have a skin covered repair.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Spina bifida can be a devastating neurological congenital anomaly . It results from&#xD;
      incomplete closure of the neural tube between 22 and 28 embryological days. Its incidence is&#xD;
      approximately 1-2 per 1,000 births. It is considered the most common congenital anomaly of&#xD;
      the central nervous system that is compatible with life.&#xD;
&#xD;
        1. The most frequent form is myelomeningocele (MMC), characterized by the extrusion of the&#xD;
           spinal cord into a sac filled with cerebrospinal fluid (CSF), and is associated with&#xD;
           lower limb paralysis and bowel and bladder dysfunction.&#xD;
&#xD;
        2. The majority of MMCs can be diagnosed between 14 and 20 weeks of gestation. MMC is&#xD;
           associated with Chiari II malformation, which includes a constellation of anomalies such&#xD;
           as hindbrain herniation, brainstem abnormalities, low-lying venous sinuses and a small&#xD;
           posterior fossa.The Chiari II malformation can have deleterious effects on motor,&#xD;
           cranial nerve and cognitive functions. Postnatally most MMC patients develop&#xD;
           hydrocephalus and require a ventriculoperitoneal shunt. Shunts require lifelong&#xD;
           monitoring and have a high failure rate due to infection, obstruction, and fracture.&#xD;
&#xD;
      Experimental studies using animal models have shown that prenatal coverage of a spina&#xD;
      bifida-like lesion can preserve neurological function and reduce or reverse hindbrain&#xD;
      herniation.These studies suggest a &quot;two-hit&quot; hypothesis in which the ultimate neurologic&#xD;
      deficit results from a combination of the failure of normal neural-tube closure (first hit)&#xD;
      with secondary spinal cord injury resulting from prolonged exposure of sensitive neural&#xD;
      elements to the amniotic fluid (second hit mechanism).&#xD;
&#xD;
      Based on this hypothesis, open fetal surgical repair of MMC was proposed, and the recent&#xD;
      publication of the NICHD sponsored randomized controlled trial demonstrated clear neonatal&#xD;
      benefit of open in-utero fetal surgical repair of MMC. The study showed a reduction in the&#xD;
      incidence of hydrocephalus and in the radiographic severity of hindbrain herniation (relative&#xD;
      risk: 0.67; 95% confidence interval: 0.56-0.81).&#xD;
&#xD;
      Open in-utero fetal surgery is not without risk and the NICHD study (MOMS Trial) showed an&#xD;
      elevation in maternal-fetal morbidity/risk when compared to the postnatally treated group,&#xD;
      including higher risk for chorioamniotic separation (26% vs. 0%, respectively), maternal&#xD;
      pulmonary edema (6% vs. 0%), oligohydramnios (21% vs. 0%), placental abruption (6% vs. 0%),&#xD;
      spontaneous membrane rupture (46%; RR: 6.15; 95% CI: 2.75-13.78), spontaneous labor (38%; RR:&#xD;
      2.80, 95%CI: 1.51-5.18), maternal blood transfusion (9%; RR: 7.18; 95%CI: 0.90-57.01), and&#xD;
      preterm delivery before 34 weeks (46%; RR: 9.2; 95%CI: 3.81-22.19). The reason for the&#xD;
      increased incidence of these complications is related to the nature of the open fetal&#xD;
      procedure, which involves a multi-faceted invasive approach including maternal laparotomy,&#xD;
      large hysterotomy with uterine edge stapling, and open fetal repair of the spina bifida&#xD;
      defect that may involve manipulation and exposure of the fetus for a significant amount of&#xD;
      time.&#xD;
&#xD;
      Fetal endoscopic surgery has progressed rapidly over the past decades and the investigators&#xD;
      are now able to perform a number of intricate procedures inside the uterus with specially&#xD;
      designed instruments. These procedures include laser therapy for Twin-twin-transfusion&#xD;
      syndrome, fetal cystoscopy and fulguration of posterior urethral valves, release of amniotic&#xD;
      bands, and placement of various shunts and balloons inside fetal structures and cavities&#xD;
      (peritoneal, pleural, cardiac, and trachea).&#xD;
&#xD;
      Fetoscopy offers a less invasive therapeutic option that could reduce a number of the&#xD;
      morbidities (both maternal and fetal) related to open fetal procedures.&#xD;
&#xD;
      A few animal studies and some clinical human experience with fetoscopic repair of MMC have&#xD;
      been reported showing the feasibility of covering the defect with a patch and sealant, or&#xD;
      even in performing a full repair. These repairs have been accomplished using at least two&#xD;
      (and sometimes more) entry ports through the uterine wall. Kohl et al. in Germany, have&#xD;
      demonstrated the feasibility of performing a complete percutaneous fetoscopic repair of MMC&#xD;
      using carbon dioxide to distend the uterus and provide a dry working area for the surgeon to&#xD;
      perform the repair.&#xD;
&#xD;
      These investigators described a two-layer covering technique using an absorbable patch&#xD;
      (Durasis, Cook, Germany) and sutures. However, while they showed that the procedure is&#xD;
      feasible, their percutaneous technique with complete two layer surgical closure of the defect&#xD;
      using sutures was associated with prolonged operative time and significant maternal and&#xD;
      obstetrical morbidities.&#xD;
&#xD;
      Fetoscopy in a CO2 gas filled uterus has been recently reported by groups in Bonn, Germany&#xD;
      (Kohl et al) and Sao Paulo, Brazil (Pedreira et al). The fetoscopic technique the&#xD;
      investigators use has been developed and tested in a fetal sheep model of MMC by the&#xD;
      investigators group and others (Peiro et al).&#xD;
&#xD;
      This fetoscopy technique has evolved over time to a 2-port technique developed by our team in&#xD;
      Houston, Texas and its feasibility and applicability to the human uterus and fetus have been&#xD;
      demonstrated and published (Belfort et al, 2017) and demonstrate an improved degree of&#xD;
      flexibility in terms of access to the fetus regardless of placental location. The technique&#xD;
      is designed to decrease the maternal risks of open uterus fetal surgery while maintaining a&#xD;
      similar level of fetal benefit as seen in the MOMS trial.&#xD;
&#xD;
      The investigators technique employs an open abdomen/exteriorized (but closed) uterus&#xD;
      methodology that allows the minimally invasive multi-layer closure of the fetal neural tube&#xD;
      using the same closed skin repair currently employed at Baylor College of Medicine/Texas&#xD;
      Children's Fetal Center using the open uterus approach. The technique employs a novel&#xD;
      approach to low pressure uterine distention using the same carbon dioxide gas 8-12 mmHg that&#xD;
      others attempting fetoscopic repair have used, but employing a much lower gas flow rate and&#xD;
      pressure. In addition, our technique (as compared with the percutaneous method) allows&#xD;
      improved access to the fetus in anterior placentation, ability to manipulate and maintain the&#xD;
      fetus in the required position, and optimal port placement resulting from the exteriorized&#xD;
      maternal uterus.&#xD;
&#xD;
      In addition, because of the exteriorized uterus and the optimal placement this allows, we&#xD;
      require only two access ports and these can be sutured into the uterus allowing a closed seal&#xD;
      and minimizing gas leakage. The use of humidified, warmed CO2, which we pioneered in fetal&#xD;
      surgery, decreases membrane disruption and may prolong gestation without rupture of the&#xD;
      membranes. Finally, recent advances in miniature surgical instruments (Storz 1.5 - 3mm&#xD;
      surgical sets) allow unprecedented flexibility which enables a full surgical repair to be&#xD;
      performed via a fetoscopic approach.&#xD;
&#xD;
      In preparation for the human trial we were able to perform, in a sheep model, dual access&#xD;
      port fetoscopic neural tube closure using a 12 F cannula, a second 9F cannula, a cover patch,&#xD;
      and a medical sealant with similar results to that seen with open fetal surgical repair in&#xD;
      the same sheep model.26&#xD;
&#xD;
      We have now completed almost 50 cases using our 2 port exteriorized technique with results&#xD;
      that are reflect our initial hypothesis (Belfort et al , 2017). As with any technique there&#xD;
      have been advances in instrumentation and technique and the study is ongoing investigating&#xD;
      the multilayer closure technique.&#xD;
&#xD;
      In this protocol, the repair of the open neural tube defect will follow the same principles&#xD;
      as we use in open repairs currently being done at this institution. This involves release of&#xD;
      the placode, dissection of the surrounding skin and attempted primary closure of the defect&#xD;
      using a Durepair patch, a muscle or duro-fascial flap, and available skin. In those cases&#xD;
      where we are able to complete the procedure with full skin closure of the defect, the only&#xD;
      difference between the open uterus procedure and the fetoscopic procedure, will be that the&#xD;
      surgery will be done fetoscopically rather than through an open uterine incision. If we are&#xD;
      unable to close the skin primarily despite best fetoscopic efforts, the option of&#xD;
      performing/completing the repair as an open procedure exists and will be offered to the&#xD;
      patient. The patient is monitored in hospital until ready for discharge.&#xD;
&#xD;
      Approximately 6 weeks after the surgery a post-procedure fetal MRI will be performed. If&#xD;
      there is evidence of good closure of the neural tube defect and reversal of the Chiari II&#xD;
      malformation, a vaginal delivery can be attempted based on obstetric criteria. Patients will&#xD;
      be followed in person every 3-4 months after birth to 12 months at the Spina Bifida Clinic at&#xD;
      TCH. Remaining visits will be yearly up to 5 years. If this is not possible, questionnaire(s)&#xD;
      will be mailed to the child's parents and records will be requested from the treating&#xD;
      neurosurgeon on this same schedule.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 2014</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">March 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility</measure>
    <time_frame>Time of procedure</time_frame>
    <description>Whether the minimally invasive technique can be technically performed in human patients (success of primary skin closure) in a safe and effective manner.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reversal of the Chiari II malformation with complete closure of the spinal defect.</measure>
    <time_frame>at birth</time_frame>
    <description>Whether the minimally invasive technique results in an acceptable fetal outcome as defined by reversal of the Chiari II malformation, a reduced need for ventriculoperitoneal shunting or other procedures to avoid or treat hydrocephalus, and complete closure of the spinal defect with protection of the placode. In addition the procedure will be assessed as to whether it prevents loss of neurological level during intra-uterine life.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Neural Tube Defect</condition>
  <arm_group>
    <arm_group_label>fetoscopic surgical repair</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single arm study. All patients will receive the fetoscopic repair.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>fetoscopy</intervention_name>
    <description>The fetoscopic arm is described above. All patients will have a laparotomy, exteriorization of the uterus, and a fetoscopic repair of the fetal open neural tube defect.</description>
    <arm_group_label>fetoscopic surgical repair</arm_group_label>
    <other_name>Karl Storz, Tuttlingen, Germany</other_name>
    <other_name>Richard Wolf Medical Instruments, Corp.</other_name>
    <other_name>Karl Storz Endoscopy-America, Inc.</other_name>
    <other_name>Cook Medical, Inc.</other_name>
    <other_name>Lexion Medical, LLC.</other_name>
    <other_name>Terumo Pinnacle</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Pregnant women - maternal age 18 years or older and capable of consenting for their&#xD;
             own participation in this study,&#xD;
&#xD;
          2. Singleton pregnancy,&#xD;
&#xD;
          3. MMC with the upper boundary located between T1 and S1,&#xD;
&#xD;
          4. Evidence of hindbrain herniation (confirmed on MRI to have an Arnold-Chiari type II&#xD;
             malformation),&#xD;
&#xD;
          5. Absence of chromosomal abnormalities and associated anomalies,&#xD;
&#xD;
          6. Gestational age at the time of the procedure will be between 19 0/7 weeks and 25 6/7&#xD;
             weeks,&#xD;
&#xD;
          7. Normal karyotype and/or normal chromosomal microarray (CMA) by invasive testing&#xD;
             (amniocentesis or CVS). If there is a balanced translocation with normal MCA with no&#xD;
             other anomalies the candidate can be included. Patients declining invasive testing&#xD;
             will be excluded.&#xD;
&#xD;
          8. Family has considered and declined the option of termination of the pregnancy at less&#xD;
             than 24 weeks,&#xD;
&#xD;
          9. Family meets psychosocial criteria (sufficient social support, ability to understand&#xD;
             requirements of the study), and&#xD;
&#xD;
         10. Parental/guardian permission (informed consent) for follow up of child after birth.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Fetal anomaly unrelated to MMC,&#xD;
&#xD;
          2. Severe kyphosis,&#xD;
&#xD;
          3. Increased risk for preterm labor including short cervical length (&lt;1.5 cm), history of&#xD;
             incompetent cervix with or without cerclage, and previous preterm birth,&#xD;
&#xD;
          4. Placental abnormalities (previa, abruption, accreta) known at time of enrollment,&#xD;
&#xD;
          5. A pre-pregnancy body-mass index ≥40,&#xD;
&#xD;
          6. Contraindications to surgery including previous hysterotomy (whether from a previous&#xD;
             classical cesarean, uterine anomaly such as an arcuate or bicornuate uterus, major&#xD;
             myomectomy resection, or previous fetal surgery) in active uterine segment,&#xD;
&#xD;
          7. Technical limitations precluding fetoscopic surgery, such as uterine fibroids, fetal&#xD;
             membrane separation, and uterine anomalies,&#xD;
&#xD;
          8. Maternal-fetal Rh isoimmunization, Kell sensitization or neonatal alloimmune&#xD;
             thrombocytopenia affecting the current pregnancy,&#xD;
&#xD;
          9. Maternal HIV, Hepatitis-B, Hepatitis-C status positive because of the increased risk&#xD;
             of transmission to the fetus during maternal-fetal surgery. If the patient's HIV or&#xD;
             Hepatitis status is unknown, the patient must be tested and found to have negative&#xD;
             results before enrollment,&#xD;
&#xD;
         10. Maternal medical condition that is a contraindication to surgery or anesthesia,&#xD;
&#xD;
         11. Low amniotic fluid volume (Amniotic Fluid Index less than 6cm) if deemed to be due to&#xD;
             fetal anomaly, poor placental perfusion or function, or membrane rupture. Low amniotic&#xD;
             fluid volume that responds to maternal hydration is not an exclusion criterion,&#xD;
&#xD;
         12. Patient does not have a support person (e.g. Spouse, partner, mother) available to&#xD;
             support the patient for the duration of the pregnancy,&#xD;
&#xD;
         13. Inability to comply with the travel and follow-up requirements of the trial,&#xD;
&#xD;
         14. Participation in another intervention study that influences maternal and fetal&#xD;
             morbidity and mortality or participation in this trial in a previous pregnancy, and&#xD;
&#xD;
         15. Patient scores as severely depressed on the BDI-II questionnaire; a score of 29 or&#xD;
             above.&#xD;
&#xD;
         16. Maternal hypersensitivity to collagen.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael A. Belfort, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University: Lucille Packard's Childrens Hospital</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Childrens Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>August 22, 2014</study_first_submitted>
  <study_first_submitted_qc>September 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <last_update_submitted>March 28, 2023</last_update_submitted>
  <last_update_submitted_qc>March 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>Michael A Belfort</investigator_full_name>
    <investigator_title>Professor and Chairman, Department of Obstetrics and Gynecology</investigator_title>
  </responsible_party>
  <keyword>myelomeningocele</keyword>
  <keyword>MMC</keyword>
  <keyword>NTD</keyword>
  <keyword>neural</keyword>
  <keyword>defect</keyword>
  <keyword>Spina bifida</keyword>
  <keyword>Neural Tube Defect</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neural Tube Defects</mesh_term>
    <mesh_term>Spinal Dysraphism</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/NCT02230072
org study id: H-34680
nct id: NCT02230072
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
The purpose of the study is to evaluate the maternal and fetal outcomes of a new technique
      for the fetoscopic repair of fetal MMC at Texas Children's Hospital Pavilion for Women.

      The investigators hypothesis is that this minimally invasive technique is feasible, and that
      this approach will have the same efficacy as open fetal surgery for MMC, but with
      significantly less maternal-fetal risk. Both mother and baby will benefit from the surgery.
      The fetus will have a repaired MMC defect, and the mother will not have a uterine incision
      (hysterotomy). A hysterotomy increases the risk of uterine rupture and requires that all
      subsequent deliveries are by cesarean section. There may also be a decreased risk of Pre-term
      Premature Rupture Of Membranes (PPROM) and prematurity when compared with the current open
      operation. Finally, a vaginal delivery is possible following the fetoscopic fetal surgery if
      the baby is shown to have a skin covered repair.
Spina bifida can be a devastating neurological congenital anomaly . It results from
      incomplete closure of the neural tube between 22 and 28 embryological days. Its incidence is
      approximately 1-2 per 1,000 births. It is considered the most common congenital anomaly of
      the central nervous system that is compatible with life.

        1. The most frequent form is myelomeningocele (MMC), characterized by the extrusion of the
           spinal cord into a sac filled with cerebrospinal fluid (CSF), and is associated with
           lower limb paralysis and bowel and bladder dysfunction.

        2. The majority of MMCs can be diagnosed between 14 and 20 weeks of gestation. MMC is
           associated with Chiari II malformation, which includes a constellation of anomalies such
           as hindbrain herniation, brainstem abnormalities, low-lying venous sinuses and a small
           posterior fossa.The Chiari II malformation can have deleterious effects on motor,
           cranial nerve and cognitive functions. Postnatally most MMC patients develop
           hydrocephalus and require a ventriculoperitoneal shunt. Shunts require lifelong
           monitoring and have a high failure rate due to infection, obstruction, and fracture.

      Experimental studies using animal models have shown that prenatal coverage of a spina
      bifida-like lesion can preserve neurological function and reduce or reverse hindbrain
      herniation.These studies suggest a "two-hit" hypothesis in which the ultimate neurologic
      deficit results from a combination of the failure of normal neural-tube closure (first hit)
      with secondary spinal cord injury resulting from prolonged exposure of sensitive neural
      elements to the amniotic fluid (second hit mechanism).

      Based on this hypothesis, open fetal surgical repair of MMC was proposed, and the recent
      publication of the NICHD sponsored randomized controlled trial demonstrated clear neonatal
      benefit of open in-utero fetal surgical repair of MMC. The study showed a reduction in the
      incidence of hydrocephalus and in the radiographic severity of hindbrain herniation (relative
      risk: 0.67; 95% confidence interval: 0.56-0.81).

      Open in-utero fetal surgery is not without risk and the NICHD study (MOMS Trial) showed an
      elevation in maternal-fetal morbidity/risk when compared to the postnatally treated group,
      including higher risk for chorioamniotic separation (26% vs. 0%, respectively), maternal
      pulmonary edema (6% vs. 0%), oligohydramnios (21% vs. 0%), placental abruption (6% vs. 0%),
      spontaneous membrane rupture (46%; RR: 6.15; 95% CI: 2.75-13.78), spontaneous labor (38%; RR:
      2.80, 95%CI: 1.51-5.18), maternal blood transfusion (9%; RR: 7.18; 95%CI: 0.90-57.01), and
      preterm delivery before 34 weeks (46%; RR: 9.2; 95%CI: 3.81-22.19). The reason for the
      increased incidence of these complications is related to the nature of the open fetal
      procedure, which involves a multi-faceted invasive approach including maternal laparotomy,
      large hysterotomy with uterine edge stapling, and open fetal repair of the spina bifida
      defect that may involve manipulation and exposure of the fetus for a significant amount of
      time.

      Fetal endoscopic surgery has progressed rapidly over the past decades and the investigators
      are now able to perform a number of intricate procedures inside the uterus with specially
      designed instruments. These procedures include laser therapy for Twin-twin-transfusion
      syndrome, fetal cystoscopy and fulguration of posterior urethral valves, release of amniotic
      bands, and placement of various shunts and balloons inside fetal structures and cavities
      (peritoneal, pleural, cardiac, and trachea).

      Fetoscopy offers a less invasive therapeutic option that could reduce a number of the
      morbidities (both maternal and fetal) related to open fetal procedures.

      A few animal studies and some clinical human experience with fetoscopic repair of MMC have
      been reported showing the feasibility of covering the defect with a patch and sealant, or
      even in performing a full repair. These repairs have been accomplished using at least two
      (and sometimes more) entry ports through the uterine wall. Kohl et al. in Germany, have
      demonstrated the feasibility of performing a complete percutaneous fetoscopic repair of MMC
      using carbon dioxide to distend the uterus and provide a dry working area for the surgeon to
      perform the repair.

      These investigators described a two-layer covering technique using an absorbable patch
      (Durasis, Cook, Germany) and sutures. However, while they showed that the procedure is
      feasible, their percutaneous technique with complete two layer surgical closure of the defect
      using sutures was associated with prolonged operative time and significant maternal and
      obstetrical morbidities.

      Fetoscopy in a CO2 gas filled uterus has been recently reported by groups in Bonn, Germany
      (Kohl et al) and Sao Paulo, Brazil (Pedreira et al). The fetoscopic technique the
      investigators use has been developed and tested in a fetal sheep model of MMC by the
      investigators group and others (Peiro et al).

      This fetoscopy technique has evolved over time to a 2-port technique developed by our team in
      Houston, Texas and its feasibility and applicability to the human uterus and fetus have been
      demonstrated and published (Belfort et al, 2017) and demonstrate an improved degree of
      flexibility in terms of access to the fetus regardless of placental location. The technique
      is designed to decrease the maternal risks of open uterus fetal surgery while maintaining a
      similar level of fetal benefit as seen in the MOMS trial.

      The investigators technique employs an open abdomen/exteriorized (but closed) uterus
      methodology that allows the minimally invasive multi-layer closure of the fetal neural tube
      using the same closed skin repair currently employed at Baylor College of Medicine/Texas
      Children's Fetal Center using the open uterus approach. The technique employs a novel
      approach to low pressure uterine distention using the same carbon dioxide gas 8-12 mmHg that
      others attempting fetoscopic repair have used, but employing a much lower gas flow rate and
      pressure. In addition, our technique (as compared with the percutaneous method) allows
      improved access to the fetus in anterior placentation, ability to manipulate and maintain the
      fetus in the required position, and optimal port placement resulting from the exteriorized
      maternal uterus.

      In addition, because of the exteriorized uterus and the optimal placement this allows, we
      require only two access ports and these can be sutured into the uterus allowing a closed seal
      and minimizing gas leakage. The use of humidified, warmed CO2, which we pioneered in fetal
      surgery, decreases membrane disruption and may prolong gestation without rupture of the
      membranes. Finally, recent advances in miniature surgical instruments (Storz 1.5 - 3mm
      surgical sets) allow unprecedented flexibility which enables a full surgical repair to be
      performed via a fetoscopic approach.

      In preparation for the human trial we were able to perform, in a sheep model, dual access
      port fetoscopic neural tube closure using a 12 F cannula, a second 9F cannula, a cover patch,
      and a medical sealant with similar results to that seen with open fetal surgical repair in
      the same sheep model.26

      We have now completed almost 50 cases using our 2 port exteriorized technique with results
      that are reflect our initial hypothesis (Belfort et al , 2017). As with any technique there
      have been advances in instrumentation and technique and the study is ongoing investigating
      the multilayer closure technique.

      In this protocol, the repair of the open neural tube defect will follow the same principles
      as we use in open repairs currently being done at this institution. This involves release of
      the placode, dissection of the surrounding skin and attempted primary closure of the defect
      using a Durepair patch, a muscle or duro-fascial flap, and available skin. In those cases
      where we are able to complete the procedure with full skin closure of the defect, the only
      difference between the open uterus procedure and the fetoscopic procedure, will be that the
      surgery will be done fetoscopically rather than through an open uterine incision. If we are
      unable to close the skin primarily despite best fetoscopic efforts, the option of
      performing/completing the repair as an open procedure exists and will be offered to the
      patient. The patient is monitored in hospital until ready for discharge.

      Approximately 6 weeks after the surgery a post-procedure fetal MRI will be performed. If
      there is evidence of good closure of the neural tube defect and reversal of the Chiari II
      malformation, a vaginal delivery can be attempted based on obstetric criteria. Patients will
      be followed in person every 3-4 months after birth to 12 months at the Spina Bifida Clinic at
      TCH. Remaining visits will be yearly up to 5 years. If this is not possible, questionnaire(s)
      will be mailed to the child's parents and records will be requested from the treating
      neurosurgeon on this same schedule.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Feasibility
time frame: Time of procedure
description: Whether the minimally invasive technique can be technically performed in human patients (success of primary skin closure) in a safe and effective manner.
measure: Reversal of the Chiari II malformation with complete closure of the spinal defect.
time frame: at birth
description: Whether the minimally invasive technique results in an acceptable fetal outcome as defined by reversal of the Chiari II malformation, a reduced need for ventriculoperitoneal shunting or other procedures to avoid or treat hydrocephalus, and complete closure of the spinal defect with protection of the placode. In addition the procedure will be assessed as to whether it prevents loss of neurological level during intra-uterine life.
arm group label: fetoscopic surgical repair
arm group type: Experimental
description: Single arm study. All patients will receive the fetoscopic repair.
intervention type: Device
intervention name: fetoscopy
description: The fetoscopic arm is described above. All patients will have a laparotomy, exteriorization of the uterus, and a fetoscopic repair of the fetal open neural tube defect.
arm group label: fetoscopic surgical repair
other name: Karl Storz, Tuttlingen, Germany
other name: Richard Wolf Medical Instruments, Corp.
other name: Karl Storz Endoscopy-America, Inc.
other name: Cook Medical, Inc.
other name: Lexion Medical, LLC.
other name: Terumo Pinnacle
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Michael A. Belfort, M.D.
role: Principal Investigator
affiliation: Baylor College of Medicine
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: Michael A Belfort
investigator title: Professor and Chairman, Department of Obstetrics and Gynecology
mesh term: Neural Tube Defects
mesh term: Spinal Dysraphism