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Project

Reducing invasiveness of fetal spina bifida repair - Towards novel techniques.

Though not a lethal condition, the prenatal correction of open spina bifida aperta (SBA) was proposed, because it could halt its in utero progressive nature hence prevent severe postnatal morbidity. In 1995, fetal surgery was proven safe and effective in the fetal lamb model. After initial exploratory clinical trials demonstrating feasibility and safety, in 2011 the randomized clinical trial (Management Of Myelomeningocele Study, MOMS) demonstrated the efficacy of midgestational anatomical SBA fetal repair. Prenatal, rather than postnatal repair, reduces the brain shunt rate at 12 months, increases the likelihood of walking at 30 months and reduces intermittent catheterization rates at school age. This comes at the expense of an increased risk for prematurity and maternal morbidity, both in the index and subsequent pregnancies. The hysterotomy, through which the procedure is done, is responsible in subsequent pregnancies for a 10% risk of rupture with concomitant fetal death in nearly one in two cases. To reduce these side effects, the concept of fetoscopic SBA repair was reintroduced. Though theoretically attractive, we thought we could not embrace it clinically without proper preclinical validation.

We first conducted a systematic review in chapter 4 showing that in fetal lambs, a two-layer SBA repair through hysterotomy is safe and effective. However, functional assessment methods were lacking in this model, and the lesion was induced in different ways and used to study either the effects on the spinal cord or the brain. In chapter 5, we showed that motor evoked potentials recording and analysis in neonatal lambs is feasible and can reliably assess neuromotor function. Furthermore in chapter 6 we demonstrated that prenatal myelotomy replicates the full phenotype of a lumbar myeloschisis. We eventually reported in chapter 7 that a layered watertight compared to non-watertight fetal repair achieves in this model more neuroprotection and better brain and spinal cord neuromorphology.

In preparation for clinical implementation, we investigated whether such watertight repair could be done by fetoscopy. In chapter 8 a systematic review of the clinical literature indicated that, in its early experience, fetoscopy was not safe yet neuroprotective. One factor explaining lack of safety was the use of CO2 for amnio-insufflation, which in lambs induces fetal acidosis and hypercapnia. We therefore assessed the feasibility and safety of fetoscopic repair using humidified and heated CO2. In chapter 9, we showed this was feasible and safe using an anesthetic technique that maintains maternal physiological homeostasis.

In parallel, we performed in chapter 10 a meta-analysis to determine the learning curve of open and fetoscopic approaches and assess the need for training. Surgeons reach competency after 35 cases for standard hysterotomy. For percutaneous fetoscopy, competency is not reached prior to 56 cases. We then designed a five-step training program for fetoscopic SBA repair on a pelvic trainer, rabbit cadavers, a high-fidelity model in rabbits, fetal lambs and finally human fetuses. We trained three fetal surgeons and showed in chapter 11 that ≥33 procedures may be necessary to reach competency. Eventually, our fetal team successfully performed three human fetoscopic SBA repair and propose to implement this training program more broadly.

Date:9 Mar 2015 →  10 Nov 2020
Keywords:spina bifida, Neural tube defects, fetal therapy, Open fetal surgery, Fetoscopy, Training, Learning curve
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences
Project type:PhD project