Patch vs. No Patch Fetoscopic Meningomyelocele Repair Study

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.

In this protocol, the repair of the open neural tube defect will follow the same principles
as use in open repairs done at Texas Children's Fetal Center. 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 it
is not possible to complete the procedure with full skin closure of the defect, the option of
performing/completing the repair as an open procedure exists and will be offered to the
patient. The patient will be 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.

Inclusion Criteria:

1. Pregnant women - maternal age 18 years or older and capable of consenting for their
own participation in this study.

2. Singleton pregnancy.

3. MMC with the upper boundary located between T1 and S1.

4. Evidence of hindbrain herniation (confirmed on MRI to have an Arnold-Chiari type II
malformation). An exception will be made for patients unable to have an MRI due to
implants or any medical reasons. These patients will have the Arnold-Chiari type II
malformation reviewed by ultrasonography.

5. Absence of chromosomal abnormalities and associated anomalies

6. Gestational age at the time of the procedure will be between 19 0/7 weeks and 25 6/7
weeks.

7. Normal karyotype and/or normal chromosomal microarray (CMA) by invasive testing
(amniocentesis or Chorionic Villus Sampling (CVS)). If there is a balanced
translocation with normal CMA with no other anomalies the candidate can be included.
Patients declining invasive testing will be excluded.

8. The family has considered and declined the option of termination of the pregnancy at
less than 24 weeks.

9. The family meets psychosocial criteria (sufficient social support, ability to
understand the requirements of the study).

10. Parental/guardian permission (informed consent) for follow up of the child after
birth.

Exclusion Criteria:

1. Fetal anomaly unrelated to MMC.

2. Severe kyphosis.

3. Increased risk for preterm labor including short cervical length (<1.5 cm), history of
incompetent cervix with or without cerclage, and previous preterm birth.

4. Placental abnormalities (previa, abruption, accreta) known at time of enrollment.

5. A pre-pregnancy body-mass index ≥40.

6. Contraindications to surgery including previous hysterotomy (whether from a previous
classical cesarean, uterine anomaly such as an arcuate or bicornuate uterus, major
myomectomy resection, or previous fetal surgery) in active uterine segment.

7. Technical limitations precluding fetoscopic surgery, such as uterine fibroids, fetal
membrane separation, or uterine anomalies.

8. Maternal-fetal Rh alloimmunization, Kell sensitization or neonatal alloimmune
thrombocytopenia affecting the current pregnancy.

9. Maternal HIV, Hepatitis-B, Hepatitis-C status positive because of the increased risk
of transmission to the fetus during maternal-fetal surgery. If the patients HIV or
Hepatitis status is unknown, the patient must be tested and found to have negative
results before enrollment.

10. Maternal medical condition that is a contraindication to surgery or anesthesia.

11. Low amniotic fluid volume (Amniotic Fluid Index less than 6 cm) if deemed to be due to
fetal anomaly, poor placental perfusion or function, or membrane rupture. Low amniotic
fluid volume that responds to maternal hydration is not an exclusion criterion.

12. Patient does not have a support person (i.e. Spouse, partner, mother) available to
support the patient for the duration of the pregnancy.

13. Inability to comply with the travel and follow-up requirements of the trial.

14. Participation in another intervention study that influences maternal and fetal
morbidity and mortality or participation in this trial in a previous pregnancy.

15. Patient scores as severely depressed on the Edinburgh Postnatal Depression Scale

16. Maternal hypersensitivity to collagen.

17. Umbilical Cord hypercoiling or velamentous cord insertion