Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03794011 |
| Other study ID # |
H-43359 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
December 18, 2018 |
| Est. completion date |
August 2026 |
Study information
| Verified date |
March 2024 |
| Source |
Baylor College of Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
