D. A. L. Pedreira

Endoscopic surgery for the antenatal treatment of myelomeningocele: the CECAM trial

BACKGROUNDnA recent randomized clinical trial named Management of Myelomeningocele Study (MOMS trial) showed that prenatal correction of open spina bifida (OSB) via open fetal surgery was associated with improved infant neurological outcomes relative to postnatal repair, but at the expense of increased maternal morbidity.nnnOBJECTIVEnWe sought to report the final results of our phase I trial (Cirurgia Endoscópica para Correção Antenatal da Meningomielocele [CECAM]) on the feasibility, safety, potential benefits, and side effects of the fetoscopic treatment of OSB using our unique surgical technique.nnnSTUDY DESIGNnTen consecutive pregnancies with lumbosacral OSB were enrolled in the study. Surgeries were performed percutaneously under general anesthesia with 3 ports and partial carbon dioxide insufflation. After appropriate surgical positioning of the fetus, the neuroplacode was released with scissors and the skin was undermined to place a biocellulose patch over the lesion. The skin was closed over the patch using a single running stitch. Preoperative, postoperative, and postnatal magnetic resonance imaging were performed to assess hindbrain herniation. Neurodevelopmental evaluation was performed before discharge and at 3, 6, and 12 months. All cases were delivered by cesarean delivery, at which time the uterus was assessed for evidence of thinning or dehiscence.nnnRESULTSnThe median gestational age at the time of surgery was 27 weeks (range 25-28 weeks). Endoscopic repair was completed in 8 of 10 fetuses. Two cases were unsuccessful due to loss of uterine access. The mean gestational age at birth was 32.4 weeks with a mean latency of 5.6 weeks between surgery and delivery (range 2-8 weeks). There was 1 fetal and 1 neonatal demise, and 1 unsuccessful case underwent postnatal repair. Of the 7 infants available for analysis, complete reversal of hindbrain herniation occurred in 6 of 7 babies. Three babies required ventriculoperitoneal shunting or third ventriculostomy. Functional motor level was the same or better than the anatomical level in 6 of 7 cases. There was no significant maternal morbidity and no evidence of myometrial thinning or dehiscence. However, surgeries were complicated by premature rupture of membrane and prematurity.nnnCONCLUSIONnOur study suggests that the antenatal treatment of OSB using a fetoscopic approach and our unique surgical technique can result in a watertight seal, reversal of the hindbrain herniation, and better than expected motor function. Our technique differs substantially from the classic repair of OSB used in prior open fetal surgery and fetoscopic studies, in which the dura mater is dissected and the defect is closed in multiple layers. Instead, we use a biocellulose patch placed over the lesion and simple closure of the skin. As such, our technique is an alternative to the current paradigms in the antenatal treatment of OSB. Our clinical outcomes are in line with the results of our extensive prior animal work. Maternal benefits of our approach and technique include minimal morbidity and no myometrial legacy. Current limitations of the approach include potential loss of access, premature rupture of membranes, and attendant prematurity. Phase II trials are needed to prevent these complications and to further assess the risks and benefits of our distinct surgical approach and technique.

Biosynthetic cellulose induces the formation of a neoduramater following pre-natal correction of meningomyelocele in fetal sheep

PURPOSEnThe aim of this study was to compare the effectiveness of two dura-mater substitutes, namely human acellular dermal matrix (HADM) and biosynthetic cellulose (BC), in repairing, in utero, surgically-induced meningomyelocele (MMC) in fetal sheep.nnnMETHODSnA neural tube defect was created at 74-77 days gestation in 36 fetal sheep. They were divided into 3 groups, the control group that did not receive pre-natal corrective surgery, and the other two groups that received corrective surgery using HADM (Group A) or BC (Group B). Both materials were used as a dura-mater substitutes between the neural tissue and the sutured skin. Correction was performed at gestation day 100 and the fetuses were maintained in utero until term. Sheep were sacrificed on gestation day 140. The fetal spine was submitted to macro and microscopic analysis. At microscopy, adherence of the material to the skin and neural tissue was analyzed.nnnRESULTSnIn the initial phase (pilot), experimentally-induced MMC was performed on 11 fetuses and 4 survived (37%). In the second phase (study), 25 fetuses received surgery and 17 survived (68%). In the study group, 6 fetuses did not undergo repair (control group), 11 cases were submitted to corrective surgery (experimental group) and one fetal loss occurred. Of the surviving cases in the experimental group, 4 constituted Group A and 6 in Group B. Macroscopically, skin and underlying tissues where easily displaced from the BC in all cases it was used; in contrast, HADM adhered to these tissues. To compare the adherence, 4 cases from Group A and 4 in Group B were studied. We observed adherence, host cell migration and vessel proliferation into the HADM all sections from Group A and this aspect was not present in any cases in Group B (p < 0.05). In Group B, we also observed that a new fibroblast layer formed around the BC thus protecting the medulla and constituting a neoduramater.nnnCONCLUSIONnThe use of BC seems to be more adequate as a dura-mater substitute to cover the damaged neural tissue than HADM. It seems promising for use in the in utero correction of MMC because to does not adhere to neural tissue of superficial and deep layers (tethered spinal cord). Thus, BC minimizes the mechanical and chemical intrauterine damage to the spinal medulla.

Validation of the ovine fetus as an experimental model for the human myelomeningocele defect

PURPOSEnTo produce a myelomeningocele-like human defect in the ovine fetus and validate this experimental model in our population.nnnMETHODSnA prospective study on 12 pregnant sheep of a crossed Hampshire/Down breed where a spinal defect was surgically created between Day 75 and Day 77 after conception. The technique consisted of a hysterotomy with exposure of fetal hind limbs and tail up to the mid spine. Fetal skin, paravertebral muscles, and 4 posterior spinal arches were excised, exposing the spinal cord. Duramater was opened and the medulla was incised until the medullar canal. Animals were euthanized at 139 days of gestation for fetal evaluation. The central nervous system was submitted to post-mortem magnetic resonance imaging (MRI) and the spine was submitted to pathological examination.nnnRESULTSnThe defect was created in 13 fetuses and 5 survived. Mean gestational age at necropsy was 121.6 days (varying from 93 to 145 days). Macroscopically, the defect was present in 4 cases. Microscopy revealed a flattened medulla with disappearance of the medullar canal and disruption of normal medullar architecture with neuronal apoptosis and/or fusion of the piamater and duramater. The MRI showed herniation of the cerebellum into the cervical canal and syringomyelia.nnnCONCLUSIONSnThe surgically produced defect mimics the defect found in the human fetus, including the Arnold-Chiari malformation. Post-mortem MRI was used for the first time in our study and proved an excellent alternative for demonstrating the cerebellar herniation. We standardized the technique for creating the defect in our population.

Laser for the treatment of twin to twin transfusion syndrome

PURPOSEnTo report the initial experience in our country with a new technique for twin to twin transfusion syndrome (TTTS) treatment, using laser to coagulate the placental vessels responsible for the twin transfusion during gestation.nnnMETHODSnProspective study of eight cases diagnosed with TTTS evaluated in our service from january 2001 to june 2005. Through percutaneous introduction of a 2,0mm diameter fetoscope in the uterine cavity, placental surface vessels where directly visualized. Those identified as responsible for the transfusion were laser coagulated. The procedure combines ultrasonography and fetoscopy, in a so-called sonoendoscopic technique (FETENDO).nnnRESULTSnAmong the eight pregnancies evaluated, five cases were submitted to the procedure (10 fetuses). All fetuses survived for at least five weeks after surgery. A total of eight fetuses were born alive and five survived the neonatal period. In a 18 months follow-up after birth, all five are still alive and well and their mean age is now 10,6 months. The total survival rate was 50% and in three pregnancies, at least one fetus survived.nnnCONCLUSIONSnLaser fetoscopy is actually the gold-standard treatment of TTTS. Nevertheless is a sophisticated technique that depends of proper training. Our service is the first in our country to offer this therapeutic technique. Our success rate is comparable with the international literature.

Fetoscopic repair of spina bifida: safer and better?

†Fetal Therapy Program, Albert Einstein Hospital, São Paulo, Brazil; ‡Office of the Dean and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; §Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; ¶Department of Obstetrics and Gynecology, University of Missouri, Kansas City, MO, USA; **Elizabeth J. Ferrell Fetal Health Center, Fetal Therapy, Children’s Mercy Hospital, Kansas City, MO, USA *Correspondence. (e-mail: denise.pedreira@gmail.com)

OC124: A different technique for the correction of a ‘myelomeningocele-like’ defect in ovine fetus

Objective: To evaluate the accuracy of three-dimensional ultrasonography in predicting the level of the defect in spine bifida. Patients and Methods: Between January 2005 and January 2006, the level of spine bifida was evaluated prenatally on three-dimensional ultrasonography (3DUS) using the rendered bone mode. All cases underwent postnatal surgery immediately after birth. Prenatal results obtained on 3DUS were compared to surgical level and to radiological level. Results: Up to now, 21 cases were completely evaluated. The correct surgical level was predicted in 9 (42.86%) cases; difference of one level was observed in 9 (42.86%) fetuses and difference of 2 levels in 3 (14.28%). Up to 1 and to 2 levels of agreement were observed in 18 (85.71%) and 21 (100%) cases. Using the postnatal radiological diagnosis, the correct level was predicted in 9 (42.86%) cases; difference of one level was observed in 9 (42.86%) fetuses and difference of 2 levels in 2 (14.29%). Up to 1 and to 2 levels of agreement were observed in 18 (85.71%) and 21 (100%) cases respectively. Conclusions: In our experience, 3DUS (rendered skeletal mode) is a good method to evaluate the level of spine bifida, with difference of two levels in 14.29% of cases when compared to postnatal surgical and radiological diagnosis.

OC16.01: Fetoscopic repair of spina bifida also improves postnatal motor outcomes

Objectives: The uptake of cell-free DNA (cfDNA) testing has resulted in a decrease in invasive prenatal diagnosis (IPD), but atypical chromosomal abnormalities may be missed. We analyzed the chromosomal abnormalities detected by cfDNA as a contingent approach in a single public centre with universal Down syndrome screening (DSS). Methods: In this retrospective cohort study, we compared the types of chromosomal abnormalities detected by IPD using cytogenetic +/chromosomal microarray analysis (CMA) after a positive cfDNA testing as a contingent approach (group 1) versus a positive DSS (group 2) from August 2011 to July 2016 using descriptive analysis and Chi-square test. IPD was publicly funded while cfDNA was self-financed. Results: Of 2,132 women with a positive DSS, 721 chose cfDNA testing and 1,411 direct IPD. Of 721 cfDNA testing (group 1), two failed, one showed an inconclusive result and 29 (4.0%) abnormal results. Of the latter, 27 had known outcomes after IPD including 74.1% common Trisomies, 3.7% mosaicism, 14.8% sex chromosomal abnormalities (SCA), 3.7% atypical aneuploidy, and 3.7% confined placental mosacism. Of 1,411 direct IPD (group 2), 193 (13.7%) showed chromosomal abnormalities including 66.8% common Trisomies, 11.9% mosaicism, 7.8% SCA, 5.3% atypical aneuploidies including those by CMA and 8.3% balanced translocation. Compared to direct IPD (group 2), the proportion and types of chromosomal abnormalities detected by IPD after a positive cfDNA testing (group 1) was different (p < 0.001) with a low/no detection rate of mosacism, atypical aneuploidies and balanced translocations though comparable detection rate of common Trisomies and SCA. Conclusions: The detection rate of mosaicism, atypical aneuploidies, and balanced translocation after using cfDNA as contingent approach was low/no. This could be related to women’ characteristics or limitation of cfDNA. Women should be carefully assessed and adequately counselled on cfDNA vs. IPD after a positive DSS.

P40.03: Three‐dimensional sonographic assessment of the fetal face with Prader‐Willy syndrome

The test for pulmonary vascular reactivity in the fetus compares changes in branch pulmonary artery Doppler flow patterns with the mother breathing room air with maternal hyperoxygenation. A normal response to oxygen is to increase the pulmonary flow patterns and is seen in fetuses greater than 30 weeks’ gestation. Fetuses with severe growth restriction have redistribution of cardiac output to the brain, coronary and adrenal circulations. In fetuses greater than 30 weeks’ gestation with absent or reversed diastolic flow in the free loop of the umbilical artery and increased diastolic flow in the middle cerebral artery, the pulsatility of the flow in the branch pulmonary artery did not change with maternal hyperoxygenation. This indicates a fixed pulmonary vasoconstriction similar to what is seen in fetuses with pulmonary hypoplasia, yet these fetuses had normal respiratory function for gestational age after delivery. In fifteen fetuses hospitalized for growth less than 10% of prediction for age with abnormal umbilical artery Doppler flow patterns, the hyperoxygenation test was offered to mothers after obtaining consent. The results from these studies were compared to 15 fetuses whose mothers were hospitalized for pre-eclampsia, premature rupture of the membranes and abruption. Those fetuses whose growth biometry was within normal limits had normal pulmonary vascular response to the maternal hyperoxygenation test while those with severe growth restriction did not. Of those fetuses who had received antenatal steroids prior to the hyperoxygenation test, there was no effect on pulmonary vasodilatation in those with severe growth restriction but those fetuses with normal growth appeared to have an exaggerated positive response.

OC125: New “suspension” endoscopic technique to correct fetal myelomeningocele: a pilot study in the ovine model

days 74 and 78 after conception. At 98 to 112 days an attempt to correct the defect was made in 11 cases and 6 fetuses remained uncorrected (control group). Using an open uterine approach the fetus was partially exposed from its tail to the lumbar spine. The skin around the defect was dissected below the dermis to permit the placement of an interface material over the exposed neural tissue and the skin. The skin was then completely closed over the defect using a separated suture. Pregnancy was allowed to continue and lambs were sacrificed between 137–145 days of gestation. The specimens were submitted to macroscopic and microscopic analysis. The correction was considered successful when more then 70% of the skin was closed. Results: The survival rate after the creation of the defect was 68% (17/25) and 90% (10/11) after correction. Macroscopically the skin was completely closed in 7 out of 10 cases in the corrected group and in 2 out of 6 cases in the control group. Neverthless 80% (8/10) were considered successful in the corrected cases. Transverse sections of fetal spine were microscopically analyzed in average 132 days of gestation (range 118–145 days) and the medulla had been reached in all fetuses in both groups. Conclusions: The new simplified technique was successful in the correction of the defect. We believe it can be more easily applied in an endoscopic approach for correction a human myelomeningocele.

P09.28: Laser therapy for fetal treatment in complicated monochorionic twin pregnancies: experience in Brazil

rupture of the membranes, the median gestational age at delivery was 36.1 weeks (range 34.1–39.1), with a median weight of 2215 gr (range 1750–2850). No single case of brain damage was detected among the survivors, as assessed by both clinical examination and imaging techniques. Conclusion: Although the number of cases is small, our initial results doing cord occlusion by bipolar forceps are comparable with those reported by others.