<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/NCT03794011</url>
  </required_header>
  <id_info>
    <org_study_id>H-43359</org_study_id>
    <nct_id>NCT03794011</nct_id>
  </id_info>
  <brief_title>Patch vs. No Patch Fetoscopic Meningomyelocele Repair Study</brief_title>
  <official_title>Study to Compare 2 Minimally Invasive Fetal Neural Tube Defect Repair Techniques: Repair Using Durepair Patch vs. Repair Without Durepair Patch</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 compare the maternal, fetal and neonatal outcomes of a cohort&#xD;
      of 60 patients in whom a multilayer closure with a Durepair patch is performed with a prior&#xD;
      cohort of patients in whom a standardized repair without patch (n = 32) was performed using&#xD;
      the same minimally invasive fetoscopic repair technique.&#xD;
&#xD;
      The hypothesis is that there will be a thicker repair (as measured by MRI at 6 weeks post&#xD;
      surgery) and less MMC repair dehiscence and/or CSF leak with the patch repair.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Spina bifida can be a devastating neurological congenital anomaly. It results from incomplete&#xD;
      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 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 2011&#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 investigators are&#xD;
      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 growing clinical human experience with fetoscopic repair of MMC have&#xD;
      demonstrated the feasibility of covering the defect and performing a full repair. These&#xD;
      repairs have been accomplished using at least two (and sometimes more) entry ports through&#xD;
      the uterine wall. Kohl et al. in Germany, have demonstrated the feasibility of performing a&#xD;
      complete percutaneous fetoscopic repair of MMC using carbon dioxide to distend the uterus and&#xD;
      provide a dry working area for the surgeon to 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 the 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&#xD;
      pressure) that others attempting fetoscopic repair have used, but employing a much lower gas&#xD;
      flow rate. In addition, the exteriorized uterus technique used by the Baylor investigators&#xD;
      (as compared with the percutaneous method) allows improved access to the fetus in cases of&#xD;
      anterior placentation, ability to manipulate and maintain the fetus in the required position,&#xD;
      and optimal port placement resulting from the exteriorized maternal uterus.&#xD;
&#xD;
      In addition, because of the exteriorized uterus and the optimal placement this allows, only&#xD;
      two access ports are needed and these can be sutured into the uterus allowing a closed seal&#xD;
      and minimizing gas leakage. The use of humidified, warmed CO2, pioneered by the Baylor group,&#xD;
      in fetal surgery, decreases membrane disruption and may prolong gestation without rupture of&#xD;
      the 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 the Barcelona group of Peiro et al tested their patch and&#xD;
      sealant technique in a sheep model using single or double port access. Fetoscopic neural tube&#xD;
      closure using a 12 F cannula, and when needed a second 9F cannula, a cover patch, and a&#xD;
      medical sealant . They had similar results to that seen with open fetal surgical repair in&#xD;
      the same sheep model.26 When they progressed to human trials this success in closing the&#xD;
      lesion was not seen and they abandoned this approach&#xD;
&#xD;
      The team at Baylor College of Medicine/Texas Children's Fetal Center have now completed 53&#xD;
      cases using a 2 port exteriorized technique with results that support the initial hypothesis&#xD;
      (Belfort et al , 2017). As with any technique there have been advances in instrumentation and&#xD;
      technique and a multilayer closure (with or without a patch) has now been developed. The&#xD;
      current study is designed to investigate the multilayer closure technique using a Durepair&#xD;
      patch and to compare results to those achieved with the single layer closure.&#xD;
&#xD;
      We have recently added a percutaneous approach option for those patients with an anterior&#xD;
      uterine window (i.e. an area of the uterine surface under the maternal anterior abdominal&#xD;
      wall that is completely free of placenta (i.e. there is a posterior placenta or placenta that&#xD;
      is located laterally and posterior such that the anterior uterine wall is free of placental&#xD;
      tissue). The rationale for this is that in some selected cases, it will be possible to access&#xD;
      the uterine surface in such a way that exactly the same port placement, membrane plication&#xD;
      sutures and surgical repair as we currently perform, can be done through two smaller openings&#xD;
      than the currently utilized large lower abdominal laparotomy that we use. The benefits of&#xD;
      this proposed percutaneous approach are: Maternal - it will avoid the larger incision and&#xD;
      reduce potential blood loss and infection risk from a long incision, reduce hospital length&#xD;
      of stay, decrease maternal recovery and pain, and possibly give a better cosmetic outcome by&#xD;
      avoiding a large scar. The fetal benefits will potentially include decreased heat loss from&#xD;
      an open abdomen and thus reduced fetal hypothermia, decreased uterine artery manipulation and&#xD;
      thus reduced risk of ischemia during the procedure, and a shortened surgery because of a much&#xD;
      smaller length of abdominal opening to be closed.&#xD;
&#xD;
      In this protocol, All women who have an appropriate window and choose fetoscopic surgery will&#xD;
      be offered (along with the standard open hysterotomy approach) the two fetoscopic options,&#xD;
      (i) laparotomy assisted and, (ii) totally percutaneous expandable port assisted. In this new&#xD;
      aspect of our protocol, the repair of the open neural tube defect will continue to follow the&#xD;
      same principles used in open repairs currently being done at this institution and at others&#xD;
      around the world. This involves release of the placode, dissection of the surrounding skin,&#xD;
      development of myofascial flaps on either side of the defect, suture of the flaps over the&#xD;
      freed placode, and attempted primary closure of the defect using available skin. The&#xD;
      additional step in this protocol will add introduction of the Durepair patch to be laid on&#xD;
      top of the placode prior to closure of the myofascial flaps. If necessary we will use&#xD;
      relaxing incisions to provide additional mobility to the skin to be closed over the defect -&#xD;
      an accepted technique routinely used in open procedures at our institution. 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, the laparotomy assisted fetoscopic procedure,&#xD;
      and the totally percutaneous expandable port assisted procedure will be the approach inside&#xD;
      the uterus. In the event of expandable port assisted repair being deemed too difficult or too&#xD;
      risky, we will revert to laparotomy assisted fetoscopic repair, or to open repair (as has&#xD;
      always been our alternative for any abandoned fetoscopic case).&#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 performed over the phone with the child's parents and records will be requested from&#xD;
      the treating neurosurgeon on this same schedule.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 18, 2018</start_date>
  <completion_date type="Anticipated">August 2026</completion_date>
  <primary_completion_date type="Anticipated">August 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>MMC Repair Dehiscence and/or CSF leak</measure>
    <time_frame>at birth</time_frame>
    <description>Rate of MMC repair dehiscence and/or CSF leak in each group</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">38</enrollment>
  <condition>Neural Tube Defects</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. Patients who have an appropriate window (posterior placenta) and choose fetoscopic surgery will be offered the two fetoscopic options, (i) laparotomy assisted and, (ii) totally percutaneous expandable port assisted. Patients with an anterior placenta will only be offered the lapartotomy assisted approach. All patients will undergo a fetoscopic repair of the fetal open neural tube defect including a the use of a Durepair patch.</description>
    <arm_group_label>fetoscopic surgical repair</arm_group_label>
    <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>
    <other_name>Pare Surgical, Inc.</other_name>
    <other_name>Medtronic Neurosurgery</other_name>
    <other_name>Canon Medical</other_name>
    <other_name>Applied Medical</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). An exception will be made for patients unable to have an MRI due to&#xD;
             implants or any medical reasons. These patients will have the Arnold-Chiari type II&#xD;
             malformation reviewed by ultrasonography.&#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 Chorionic Villus Sampling (CVS)). If there is a balanced&#xD;
             translocation with normal CMA with no other anomalies the candidate can be included.&#xD;
             Patients declining invasive testing will be excluded. Results by flouorescence in situ&#xD;
             hybridization (FISH) will be acceptable if the patient is at 24 weeks or more.&#xD;
&#xD;
          8. The family has considered and declined the option of termination of the pregnancy at&#xD;
             less than 24 weeks.&#xD;
&#xD;
          9. The family meets psychosocial criteria (sufficient social support, ability to&#xD;
             understand the requirements of the study).&#xD;
&#xD;
         10. Parental/guardian permission (informed consent) for follow up of the child after&#xD;
             birth.&#xD;
&#xD;
         11. For totally percutaneous expandable port assisted cases: Appropriate anterior window&#xD;
             on the uterus free of placental tissue, as assessed by ultrasound, such that direct&#xD;
             access to the fetus through the maternal abdominal wall is possible. If this criteria&#xD;
             is not met, patient may still be eligible for laparotomy assisted fetoscopic repair if&#xD;
             all other inclusion criteria and no exclusion criteria are met.&#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, or uterine anomalies.&#xD;
&#xD;
          8. Maternal-fetal Rh alloimmunization, 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 patients 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 6 cm) 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 (i.e. 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.&#xD;
&#xD;
         15. Patient scores as severely depressed on the Edinburgh Postnatal Depression Scale&#xD;
&#xD;
         16. Maternal hypersensitivity to collagen.&#xD;
&#xD;
         17. Umbilical Cord hypercoiling or velamentous cord insertion&#xD;
&#xD;
         18. For totally percutaneous expandable port assisted cases: total anterior placentation&#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., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University: Lucille Packard's Children's 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>January 2, 2019</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 4, 2019</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>Spinal 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/NCT03794011
org study id: H-43359
nct id: NCT03794011
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 compare the maternal, fetal and neonatal outcomes of a cohort
      of 60 patients in whom a multilayer closure with a Durepair patch is performed with a prior
      cohort of patients in whom a standardized repair without patch (n = 32) was performed using
      the same minimally invasive fetoscopic repair technique.

      The hypothesis is that there will be a thicker repair (as measured by MRI at 6 weeks post
      surgery) and less MMC repair dehiscence and/or CSF leak with the patch 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 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 2011
      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 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 growing clinical human experience with fetoscopic repair of MMC have
      demonstrated the feasibility of covering the defect and 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 the 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
      pressure) that others attempting fetoscopic repair have used, but employing a much lower gas
      flow rate. In addition, the exteriorized uterus technique used by the Baylor investigators
      (as compared with the percutaneous method) allows improved access to the fetus in cases of
      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, only
      two access ports are needed and these can be sutured into the uterus allowing a closed seal
      and minimizing gas leakage. The use of humidified, warmed CO2, pioneered by the Baylor group,
      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 the Barcelona group of Peiro et al tested their patch and
      sealant technique in a sheep model using single or double port access. Fetoscopic neural tube
      closure using a 12 F cannula, and when needed a second 9F cannula, a cover patch, and a
      medical sealant . They had similar results to that seen with open fetal surgical repair in
      the same sheep model.26 When they progressed to human trials this success in closing the
      lesion was not seen and they abandoned this approach

      The team at Baylor College of Medicine/Texas Children's Fetal Center have now completed 53
      cases using a 2 port exteriorized technique with results that support the initial hypothesis
      (Belfort et al , 2017). As with any technique there have been advances in instrumentation and
      technique and a multilayer closure (with or without a patch) has now been developed. The
      current study is designed to investigate the multilayer closure technique using a Durepair
      patch and to compare results to those achieved with the single layer closure.

      We have recently added a percutaneous approach option for those patients with an anterior
      uterine window (i.e. an area of the uterine surface under the maternal anterior abdominal
      wall that is completely free of placenta (i.e. there is a posterior placenta or placenta that
      is located laterally and posterior such that the anterior uterine wall is free of placental
      tissue). The rationale for this is that in some selected cases, it will be possible to access
      the uterine surface in such a way that exactly the same port placement, membrane plication
      sutures and surgical repair as we currently perform, can be done through two smaller openings
      than the currently utilized large lower abdominal laparotomy that we use. The benefits of
      this proposed percutaneous approach are: Maternal - it will avoid the larger incision and
      reduce potential blood loss and infection risk from a long incision, reduce hospital length
      of stay, decrease maternal recovery and pain, and possibly give a better cosmetic outcome by
      avoiding a large scar. The fetal benefits will potentially include decreased heat loss from
      an open abdomen and thus reduced fetal hypothermia, decreased uterine artery manipulation and
      thus reduced risk of ischemia during the procedure, and a shortened surgery because of a much
      smaller length of abdominal opening to be closed.

      In this protocol, All women who have an appropriate window and choose fetoscopic surgery will
      be offered (along with the standard open hysterotomy approach) the two fetoscopic options,
      (i) laparotomy assisted and, (ii) totally percutaneous expandable port assisted. In this new
      aspect of our protocol, the repair of the open neural tube defect will continue to follow the
      same principles used in open repairs currently being done at this institution and at others
      around the world. This involves release of the placode, dissection of the surrounding skin,
      development of myofascial flaps on either side of the defect, suture of the flaps over the
      freed placode, and attempted primary closure of the defect using available skin. The
      additional step in this protocol will add introduction of the Durepair patch to be laid on
      top of the placode prior to closure of the myofascial flaps. If necessary we will use
      relaxing incisions to provide additional mobility to the skin to be closed over the defect -
      an accepted technique routinely used in open procedures at our institution. 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, the laparotomy assisted fetoscopic procedure,
      and the totally percutaneous expandable port assisted procedure will be the approach inside
      the uterus. In the event of expandable port assisted repair being deemed too difficult or too
      risky, we will revert to laparotomy assisted fetoscopic repair, or to open repair (as has
      always been our alternative for any abandoned fetoscopic case).

      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 performed over the phone with 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: MMC Repair Dehiscence and/or CSF leak
time frame: at birth
description: Rate of MMC repair dehiscence and/or CSF leak in each group
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. Patients who have an appropriate window (posterior placenta) and choose fetoscopic surgery will be offered the two fetoscopic options, (i) laparotomy assisted and, (ii) totally percutaneous expandable port assisted. Patients with an anterior placenta will only be offered the lapartotomy assisted approach. All patients will undergo a fetoscopic repair of the fetal open neural tube defect including a the use of a Durepair patch.
arm group label: fetoscopic surgical repair
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
other name: Pare Surgical, Inc.
other name: Medtronic Neurosurgery
other name: Canon Medical
other name: Applied Medical
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Michael A. Belfort, M.D., Ph.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