Background
A 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.
Objective
We 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.
Study Design
Ten 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.
Results
The 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.
Conclusion
Our 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.
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Introduction
Open spina bifida (OSB) results in injury of spinal cord tissue at the level of the bone lesion as well as in hindbrain herniation. Affected individuals require lifelong support and rehabilitation. Early work had suggested that prenatal repair of OSB could prevent or ameliorate damage to the medulla and reverse the hindbrain herniation. A recent randomized clinical trial named Management of Myelomeningocele Study (MOMS trial) showed that prenatal correction of OSB via open fetal surgery resulted in improved infant neurological outcomes relative to postnatal repair, but at the expense of increased maternal morbidity. Therefore, efforts to reduce maternal risk in the antenatal treatment of OSB are warranted.
Initial attempts to treat OSB using a fetoscopic approach were not encouraging. However, Kohl and his group reported the use of a percutaneous endoscopic technique with 3 ports and partial carbon dioxide (CO 2 ) insufflation. The outcomes of the 19 initial patients and the subsequent 51 patients treated by the same group with this technique have been recently reported. Although less invasive than open fetal surgery, this endoscopic technique seemed laborious because it requires dissection of the dura mater and multiple-layer closure.
Our group first tested the use of biocellulose in rabbit and ovine models of OSB. The technique involved placing (but not suturing) a biocellulose patch over the spinal defect, followed by skin closure. The biocellulose patch produced a watertight seal by inducing the formation of neoduramater. Translation of this animal work into a clinically applicable fetoscopic technique required a joint effort between our group (Brazilian Fetal Network) and the USFetus Consortium. In 2013, we were approved by the Brazilian National Ethics Committee to begin a phase I trial with 10 patients. The results of the first 4 cases were reported as a preliminary experience to justify continuation of the trial. In this article we provide the final results of the Cirurgia Endoscópica para Correção Antenatal da Meningomielocele (CECAM) trial in a total of 10 patients.
Materials and Methods
The research protocol (CECAM) ( http://redefetalbrasileira.med.br/meningomielocele ) was approved by the Brazilian National Ethics Committee (CONEP-16799) for a total of 10 cases. The objective of the study was to evaluate the feasibility of completing the surgery, maternal safety, fetal risks, and potential fetal benefits. Technical success was defined as fetoscopic closure of the OSB. Fetal outcome variables included perinatal survival, reversal of hindbrain herniation, and evidence of complete skin closure at the time of birth. Postnatal outcomes included need for postnatal repair, evaluation of motor function, and need for ventriculoperitoneal (VP) shunting.
Inclusion and exclusion criteria
Table 1 shows the inclusion and exclusion criteria for the study. Patients with a prior cesarean delivery were excluded until an interim analysis was performed by the Brazilian National Ethics Committee after the first 5 surgeries had been completed. Fetal evaluation included a complete sonographic anatomical survey, fetal echocardiography, genetic amniocentesis, and fetal magnetic resonance imaging (MRI). After maternal counseling by a multidisciplinary team (fetal therapy specialist, pediatric neurosurgeon, neonatologist, and obstetrician), candidates were invited to participate in this pilot study and they gave written informed consent.
| Inclusion criteria | Exclusion criteria |
|---|---|
| Level of lesion: T1–S1 | Anterior placenta (complete) |
| Gestational age: 19–27.9 wk | Multiple gestation |
| Hindbrain herniation | Kyphosis >30 degrees |
| Maternal age >18 y | Cervical length <2 cm |
| No other major anomalies | Low-lying placenta |
| Normal karyotype | Placental abruption |
| History of preterm birth <37 wk | |
| History of incompetent cervix | |
| Alloimmunization | |
| Positive serology (HIV, hepatitis B) | |
| Large uterine fibroids | |
| Body mass index >35 kg/m 2 | |
| Maternal diabetes, hypertension (with increased risk of preeclampsia) | |
| Prior cesarean delivery a |
a This exclusion was removed after first 4 patients underwent surgery.
Surgical technique
Surgery was done under general maternal-fetal anesthesia using intravenous (IV) propofol 3.0 μg/kg, IV remifentanil 1 μg/kg, and IV rocuronium 0.6 mg/kg for induction followed by IV remifentanil 0.2 μg/kg/min and sevoflurane 0.5 minimal alveolar concentration for maintenance. The uterine cavity was accessed using a percutaneous Seldinger technique. Two 11F vascular introducers (Terumo, Tokyo, Japan) and a third 14F or 16F vascular introducer (Cook Medical, Bloomington, IN) or a 5-mm balloon-tipped laparoscopic trocar (Applied Medical, Rancho Santa Margarita, CA) were placed. Partial amniotic CO 2 insufflation was performed as described by Kohl et al. The fetus was positioned using standard 3.0-mm laparoscopic instruments and a 2.7- to 4-mm 30-degree endoscope (Karl Storz, Tüttlingen, Germany). The neural placode was released with a circumferential incision at the transition zone and the skin was further undermined to allow approximation at the midline. The placode was covered with a biocellulose patch (Bionext, Paraná, Brazil). The skin was closed over the patch with a 2-0 monofilament (nonabsorbable polypropylene) single running stitch (Quill SRS; Angiotech, Reading, PA) ( Figure 1 ). If the defect was too large, a 2-layer closure was performed, using a skin substitute (Dermal Regeneration Template; Integra, Plainsboro, NJ) placed over the biocellulose patch. No uterine closure devices were placed to seal the puncture sites, except in the first case. IV cefazolin 1 g was given 1 hour before surgery, intraamniotically, and every 8 hours after surgery for 24 hours.
Postoperative care
Patients received prophylactic tocolysis with atosiban (Ferring, Lausanne, Switzerland) (6.75 mg IV bolus, followed by 300 μg/min for 3 hours and 100 μg/min for 21 hours) for 24 hours. Patients were allowed to ambulate after the first postoperative day and were discharged on postoperative day 3-4. Discharge medications included progesterone 200 mg orally every 12 hours as well as vaginal metronidazole and imidazole. Patients were followed with weekly ultrasounds. An MRI was scheduled 3-4 weeks after surgery. Patients were scheduled for delivery by cesarean delivery at 39 weeks, or at 34 weeks in cases of premature rupture of membranes (PROM).
Postnatal assessment
An MRI was performed in the neonatal period and a repeat MRI was scheduled 12 months after birth. Table 2 shows the criteria for postnatal VP shunt placement. Neurodevelopmental assessment at the time of neonatal discharge, and at 3, 6, and 12 months of corrected age were performed with Test of Infant Motor Performance (first 2 appointments), Alberta Infant Motor Scale (at all appointments), and Bayley Scales of Infant and Toddler Development (at 12 months of age). The functional level of the lesion was assessed by considering the active movement of the lower limbs (muscle contraction able to overcome gravity) and sensibility preservation. The anatomical lesion level and a central nervous system targeted evaluation were performed by 2 independent neuroradiologists using the most recent MRI. A comparison between the functional and the anatomical level was done.
|
Statistical analysis was performed using software (SPSS Statistics for Windows, Version 22.0; IBM Corp, Armonk, NY). Continuous variables were checked for normality using the Kolmogorov-Smirnov test. Categorical variables were compared using the χ 2 or Fisher exact test as appropriate. A P value (2-tailed) ≤.05 was considered statistically significant.
Materials and Methods
The research protocol (CECAM) ( http://redefetalbrasileira.med.br/meningomielocele ) was approved by the Brazilian National Ethics Committee (CONEP-16799) for a total of 10 cases. The objective of the study was to evaluate the feasibility of completing the surgery, maternal safety, fetal risks, and potential fetal benefits. Technical success was defined as fetoscopic closure of the OSB. Fetal outcome variables included perinatal survival, reversal of hindbrain herniation, and evidence of complete skin closure at the time of birth. Postnatal outcomes included need for postnatal repair, evaluation of motor function, and need for ventriculoperitoneal (VP) shunting.
Inclusion and exclusion criteria
Table 1 shows the inclusion and exclusion criteria for the study. Patients with a prior cesarean delivery were excluded until an interim analysis was performed by the Brazilian National Ethics Committee after the first 5 surgeries had been completed. Fetal evaluation included a complete sonographic anatomical survey, fetal echocardiography, genetic amniocentesis, and fetal magnetic resonance imaging (MRI). After maternal counseling by a multidisciplinary team (fetal therapy specialist, pediatric neurosurgeon, neonatologist, and obstetrician), candidates were invited to participate in this pilot study and they gave written informed consent.
| Inclusion criteria | Exclusion criteria |
|---|---|
| Level of lesion: T1–S1 | Anterior placenta (complete) |
| Gestational age: 19–27.9 wk | Multiple gestation |
| Hindbrain herniation | Kyphosis >30 degrees |
| Maternal age >18 y | Cervical length <2 cm |
| No other major anomalies | Low-lying placenta |
| Normal karyotype | Placental abruption |
| History of preterm birth <37 wk | |
| History of incompetent cervix | |
| Alloimmunization | |
| Positive serology (HIV, hepatitis B) | |
| Large uterine fibroids | |
| Body mass index >35 kg/m 2 | |
| Maternal diabetes, hypertension (with increased risk of preeclampsia) | |
| Prior cesarean delivery a |
a This exclusion was removed after first 4 patients underwent surgery.
Surgical technique
Surgery was done under general maternal-fetal anesthesia using intravenous (IV) propofol 3.0 μg/kg, IV remifentanil 1 μg/kg, and IV rocuronium 0.6 mg/kg for induction followed by IV remifentanil 0.2 μg/kg/min and sevoflurane 0.5 minimal alveolar concentration for maintenance. The uterine cavity was accessed using a percutaneous Seldinger technique. Two 11F vascular introducers (Terumo, Tokyo, Japan) and a third 14F or 16F vascular introducer (Cook Medical, Bloomington, IN) or a 5-mm balloon-tipped laparoscopic trocar (Applied Medical, Rancho Santa Margarita, CA) were placed. Partial amniotic CO 2 insufflation was performed as described by Kohl et al. The fetus was positioned using standard 3.0-mm laparoscopic instruments and a 2.7- to 4-mm 30-degree endoscope (Karl Storz, Tüttlingen, Germany). The neural placode was released with a circumferential incision at the transition zone and the skin was further undermined to allow approximation at the midline. The placode was covered with a biocellulose patch (Bionext, Paraná, Brazil). The skin was closed over the patch with a 2-0 monofilament (nonabsorbable polypropylene) single running stitch (Quill SRS; Angiotech, Reading, PA) ( Figure 1 ). If the defect was too large, a 2-layer closure was performed, using a skin substitute (Dermal Regeneration Template; Integra, Plainsboro, NJ) placed over the biocellulose patch. No uterine closure devices were placed to seal the puncture sites, except in the first case. IV cefazolin 1 g was given 1 hour before surgery, intraamniotically, and every 8 hours after surgery for 24 hours.
Postoperative care
Patients received prophylactic tocolysis with atosiban (Ferring, Lausanne, Switzerland) (6.75 mg IV bolus, followed by 300 μg/min for 3 hours and 100 μg/min for 21 hours) for 24 hours. Patients were allowed to ambulate after the first postoperative day and were discharged on postoperative day 3-4. Discharge medications included progesterone 200 mg orally every 12 hours as well as vaginal metronidazole and imidazole. Patients were followed with weekly ultrasounds. An MRI was scheduled 3-4 weeks after surgery. Patients were scheduled for delivery by cesarean delivery at 39 weeks, or at 34 weeks in cases of premature rupture of membranes (PROM).
Postnatal assessment
An MRI was performed in the neonatal period and a repeat MRI was scheduled 12 months after birth. Table 2 shows the criteria for postnatal VP shunt placement. Neurodevelopmental assessment at the time of neonatal discharge, and at 3, 6, and 12 months of corrected age were performed with Test of Infant Motor Performance (first 2 appointments), Alberta Infant Motor Scale (at all appointments), and Bayley Scales of Infant and Toddler Development (at 12 months of age). The functional level of the lesion was assessed by considering the active movement of the lower limbs (muscle contraction able to overcome gravity) and sensibility preservation. The anatomical lesion level and a central nervous system targeted evaluation were performed by 2 independent neuroradiologists using the most recent MRI. A comparison between the functional and the anatomical level was done.
|
Statistical analysis was performed using software (SPSS Statistics for Windows, Version 22.0; IBM Corp, Armonk, NY). Continuous variables were checked for normality using the Kolmogorov-Smirnov test. Categorical variables were compared using the χ 2 or Fisher exact test as appropriate. A P value (2-tailed) ≤.05 was considered statistically significant.
Results
Maternal outcomes
Ten cases met inclusion criteria and are reported in the present study (including 4 cases previously published). Table 3 shows the surgical and perinatal characteristics of the cases. There were no maternal deaths, pulmonary edema, need for central line placement, nor admission to the intensive care unit. None of the patients required a blood transfusion and none developed chorioamnionitis. None of the patients had significant uterine contractions after surgery, and all were discharged home in 3-4 days.
| Case | Placental location | Operating time, min | Gestational age at time of surgery, wk | Gestational age at time of PROM, wk | Surgery-PROM interval, wk | Placental abruption | Gestational age at delivery, wk | Birthweight, g | Neonatal demise | PROM delivery latency, d | Surgery completed |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Anterior | 450 | 25 | 25 | 0 | No | 32.1 | 1500 | No | 46 | Yes |
| 2 | Anterior | 240 | 27 | 33 | 6 | No | 33.7 | 1990 | No | 5 | Yes |
| 3 | Anterior | 145 | 25 | 31 | 6 | No | 31.4 | 1625 | No | 2 | No |
| 4 | Anterior | 310 | 27 | 31 | 4 | No | 33.9 | 2380 | No | 17 | Yes |
| 5 | Posterior | 270 | 27 | 27 | 0 | No | 28.0 | 560 | Stillbirth | 5 | No |
| 6 | Posterior | 240 | 27 | 28 | 1 | No | 29.6 | 1250 | Yes | 11 | Yes |
| 7 | Posterior | 180 | 27 | 33 | 6 | No | 35.1 | 2545 | No | 16 | Yes |
| 8 | Anterior | 240 | 28 | 30 | 2 | Yes | 31.0 | 1465 | No | 10 | Yes |
| 9 | Anterior | 160 | 26 | 30 | 4 | No | 34.7 | 2270 | No | 30 | Yes |
| 10 | Anterior | 190 | 27 | 32 | 5 | No | 32.6 | 1580 | No | 3 | Yes |
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