MRI in Sheep Model for Myelomeningocele Repair Using a Novel Polymer and Other Dural Patches.

Short-term results demonstrate that prenatal repair of a myelomeningocele is associated with a reduction in hydrocephalus and an increased likelihood of the reversal of Chiari II malformations compared with postnatal repair. The purpose of this study was to identify the long-term imaging findings at school age among subjects who underwent pre- versus postnatal repair of a myelomeningocele. A subset of subjects enrolled in the Management of Myelomeningocele Study who underwent either prenatal (n = 66) or postnatal (n = 63) repair of a lumbosacral myelomeningocele and had follow-up brain MR imaging at school age were included. The prevalence of posterior fossa features of Chiari II malformation and supratentorial abnormalities and the change in these findings from fetal to school-age MR imaging were compared between the 2 groups. Prenatal repair of a myelomeningocele was associated with higher rates of normal location of fourth ventricle and lower rates of hindbrain herniation, cerebellar herniation, tectal beaking, brainstem distortion, and kinking at school age compared with postnatal repair (all P < .01). Supratentorial abnormalities, including corpus callosal abnormalities, gyral abnormalities, heterotopia, and hemorrhage, were not significantly different between the 2 groups (all P > .05). The rates of resolution of brainstem kinking, tectal beaking, cerebellar and hindbrain herniation, and normalization of fourth ventricle size from fetal to school age MR imaging were higher among the prenatal compared with postnatal surgery group (all, P < .02). Prenatal repair of a myelomeningocele is associated with persistent improvement in posterior fossa imaging findings of Chiari II malformation at school age compared with postnatal repair.

Open prenatal myelomeningocele (MMC) repair is typically associated with reversal of in utero hindbrain herniation (HBH) and has been posited to be associated with a reduction in both postoperative prenatal and immediate postnatal hydrocephalus (HCP) risks. However, the long-term postnatal risk of HCP following HBH reversal in these cases has not been well defined. The authors describe the results of a long-term HCP surveillance in a cohort of patients who underwent prenatal MMC repair at their institution. A retrospective review of all prenatal MMC repair operations performed at the Mayo Clinic between 2012 and 2017 was conducted. Pertinent data regarding the clinical courses of these patients before and after MMC repair were summarized. Outcomes of interest were occurrences of HBH and HCP and the need for intervention. A total of 9 prenatal MMC repair cases were identified. There were 7 cases in which MRI clearly demonstrated prenatal HBH, and of these 86% (6/7) had evidence of HBH reversal after repair and prior to delivery. After a mean postnatal follow-up of 20 months, there were 3 cases of postnatal HCP requiring intervention. One case that failed to show complete HBH reversal after MMC repair required early ventriculoperitoneal shunting. The other 2 cases were of progressive, gradual-onset HCP despite complete prenatal HBH reversal, requiring endoscopic third ventriculostomy with choroid plexus cauterization at ages 5 and 7 months. Although prenatal MMC repair can achieve HBH reversal in a majority of well-selected cases, the prevention of postnatal HCP requiring intervention appears not to be predicated on this outcome alone. In fact, it appears that in a subset of cases in which HBH reversal is achieved, patients can experience a progressive, gradual-onset HCP within the 1st year of life. These findings support continued rigorous postnatal surveillance of all prenatal MMC repair patients, irrespective of postoperative HBH outcome.

Prenatal myelomeningocele (MMC) repair has been proven to significantly reduce the need for hydrocephalus shunting and improve lower-extremity motor outcomes. The aim of this study was to evaluate the effect of prenatal MMC repair on the urological outcome. All patients who underwent fetal MMC repair at our institution are followed prospectively. Assessments include medical history, renal and bladder ultrasound, voiding cystourethrogram and urodynamic study, need for clean intermittent catheterization (CIC) and anticholinergics, and the occurrence of urinary tract infections (UTI). Of the 30 patients who underwent prenatal MMC closure from December 2010 to December 2015, eight patients with a postnatal follow-up of at least 2 years were included in this study and compared with eight patients after postnatal MMC repair. The level of the bony spinal defect was similar in both groups. Urological evaluation at 2 years revealed normal bladder function in 50% after prenatal repair. Neurogenic bladder dysfunction requiring CIC and anticholinergic therapy was seen in 50% in the prenatal and in 100% in the postnatal group. Significant bladder wall thickening was found in 37.5% and 87.5%, respectively. Febrile UTIs occurred in 37.5% in the prenatal and 62.5% in the postnatal group during the observation period. Our data suggest a positive effect of prenatal MMC closure on lower urinary tract function. The long-term significance of these results remains unclear. Therefore, continued close monitoring of renal and bladder function are mandatory.

Correction of hindbrain herniation and anatomy of the vermis after in utero repair of myelomeningocele in sheep

Myelomeningocele (MMC) is associated with hindbrain herniation (HBH) and brainstem compression as part of Chiari II. Prenatal MMC repair can reverse HBH, but its effect on brainstem microstructure remains unclear. This study aims to evaluate fetal brainstem and cerebellar diffusion characteristics before and after prenatal MMC repair using Diffusion-weighted imaging (DWI), and to compare these changes according to HBH reversal. Retrospective study of fetuses who underwent a prenatal MMC repair at a single institution. Fetal brain MRI at referral and 6 weeks postoperatively was performed using a 1.5 T scanner including axial DWI. HBH was graded (0-3) based on cerebellar tonsil position relative to the foramen magnum. Regions of interest were placed in the pons, cerebellar vermis, and hemispheres to obtain apparent diffusion coefficient (ADC) values (×10-3 mm2/s). ADC values were compared by HBH grade and by HBH reversal status using Mann-Whitney U and Kruskal-Wallis tests. Fifty-nine fetuses were included (50 fetoscopic, 9 open repair). Before surgery, all had HBH (grade 2 = 17%; grade 3 = 83%) with no ADC difference between grades. At 6 weeks, HBH resolved in 78% of fetuses, partially reversed in 12%, and persisted in 10%. ADC values were significantly higher in the pons, vermis, and cerebellar hemispheres of fetuses with persistent severe HBH compared with those with partial or complete reversal (p ≤ 0.04). Fetuses without HBH reversal showed the highest ADC values, consistent with greater microstructural disruption. Persistent HBH after prenatal MMC repair is associated with increased ADC in the brainstem and cerebellum, suggesting ongoing microstructural alteration likely related to chronic compression. DWI may provide a candidate imaging marker associated with the degree of hindbrain herniation reversal after fetal surgery and may help refine postoperative imaging assessment.

Hindbrain herniation develops in surgically created myelomeningocele but is absent after repair in fetal lambs

The Management of Myelomeningocele Study (MOMS), a randomized clinical trial of prenatal vs standard postnatal repair for myelomeningocele, found that prenatal repair reduced hydrocephalus and hindbrain herniation and improved motor function in children aged 12 to 30 months. The Management of Myelomeningocele Study Follow-up (MOMS2) was conducted in children at ages 5 to 10 years. The primary (neurocognitive) outcome has already been reported. To determine whether MOMS2 participants who had prenatal repair have better physical functioning than those with postnatal repair. Participants from MOMS were recruited for participation in the follow-up study, MOMS2, conducted from April 9, 2012, to April 15, 2017. For this secondary analysis of the randomized clinical trial, trained examiners without knowledge of the treatment group evaluated the physical characteristics, self-care skills, neurologic function, and mobility of the children. Physical functioning outcomes were compared between the prenatal and postnatal repair groups. MOMS2 was conducted at the same 3 clinical sites as MOMS. Home visits were conducted for families who were unable to travel to one of the clinical sites. Of the 161 children with myelomeningocele aged 5 to 10 years old enrolled in MOMS2, 154 had a physical examination and were included in the analyses. Prenatal repair of myelomeningocele. Prespecified secondary trial outcomes of self-care skills, functional mobility, walking skills, and motor level. This analysis included 78 children with postnatal repair (mean [SD] age, 7.4 [2.1] years; 50 girls [64.1%]; 69 White children [88.5%]) and 76 with prenatal repair (mean [SD] age, 7.5 [1.2] years; 43 boys [56.6%]; 70 White children [92.1%]). Children in the prenatal repair group were more competent with self-care skills (mean [SD] percentage of maximum FRESNO Scale score, 90.8% [9.6%] vs 85.5% [17.6%]) and were commonly community ambulators per the Modified Hoffer Classification (51.3% prenatal vs 23.1% postnatal; adjusted relative risk [aRR] for sex, 1.70; 95% CI, 1.23-2.34). Children with prenatal repair also performed the 10-m walk test 1 second faster (difference in medians, 1.0; 95% CI, 0.3-1.7), had better gait quality (adjusted mean difference for home distances of 5 m, 1.71; 95% CI, 1.14-2.54), and could perform higher-level mobility skills (adjusted mean difference for motor total, 5.70; 95% CI, 1.97-11.18). Children in the prenatal repair group were less likely to have a motor function level worse than their anatomic lesion level (aRR, 0.44; 95% CI, 0.25-0.77). This secondary analysis of a randomized clinical trial found that the physical functioning benefits of prenatal repair for myelomeningocele reported at age 30 months persisted into school age. These findings indicate the benefit of prenatal repair of myelomeningocele for school-aged children. ClinicalTrials.gov Identifier: NCT00060606.

To review current evidence on neurosurgical and obstetric outcomes following prenatal versus postnatal repair of myelomeningocele (MMC) after the landmark Management of Myelomeningocele Study (MOMS) trial, emphasizing evolving surgical techniques and long-term implications. A systematic review was performed according to PRISMA guidelines. PubMed/MEDLINE was searched from 2011 (MOMS publication) to the present for studies on fetal MMC repair. Eligible studies included randomized trials, cohort comparisons, technical series, and evidence-based guidelines. Primary outcomes were cerebrospinal fluid (CSF) shunt placement, reversal of hindbrain herniation, and motor/ambulation function; secondary outcomes included maternal morbidity, urological, and orthopedic endpoints. Forty-three studies met the inclusion criteria. Prenatal repair reduced ventriculoperitoneal shunt requirements by approximately 50% (about 40% vs. 80%) and doubled the rate of independent walking (about 45% vs. 24%) compared with postnatal repair, consistent with MOMS findings. Hindbrain herniation reversal occurred in up to 75% of prenatal cases. However, prenatal surgery increased risks of preterm delivery (around 34weeks), premature membrane rupture, and uterine dehiscence. Refinements such as mini-hysterotomy and fetoscopy achieved similar fetal benefits with improved maternal safety profiles, depending on surgical expertise and institutional experience. Prenatal MMC repair is one of the most significant advances in fetal neurosurgery, providing durable neurological and functional benefits such as reduced reliance on ventriculoperitoneal shunts and improved motor functions. Continued improvements in surgical techniques, maternal-obstetric safety, and equitable access to experienced fetal centers are essential to establishing prenatal surgical repair as a key advancement in modern pediatric neurosurgery and fetal therapy.

Prenatal repair of myelomeningocele, the most common form of spina bifida, may result in better neurologic function than repair deferred until after delivery. We compared outcomes of in utero repair with standard postnatal repair. We randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function. The trial was stopped for efficacy of prenatal surgery after the recruitment of 183 of a planned 200 patients. This report is based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68% of the infants in the prenatal-surgery group and in 98% of those in the postnatal-surgery group (relative risk, 0.70; 97.7% confidence interval [CI], 0.58 to 0.84; P<0.001). Actual rates of shunt placement were 40% in the prenatal-surgery group and 82% in the postnatal-surgery group (relative risk, 0.48; 97.7% CI, 0.36 to 0.64; P<0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (P=0.007) and in improvement in several secondary outcomes, including hindbrain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery. Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00060606.).

Little is known about the impact of spinal cord microstructural alterations after prenatal myelomeningocele (MMC) repair and their associations with neurological clinical assessments. To assess spinal cord diffusivity using diffusion-weighted imaging (DWI) obtained between 10 months and 30 months of age in children who underwent prenatal MMC repair, and to explore associations with neurological clinical assessments. This retrospective cohort study included children who underwent prenatal MMC repair from November 2011 to May 2023. All children met the Management Of Myelomeningocele Study (MOMS) inclusion criteria. DWI (b=0 s/mm2 and 800 s/mm2) was performed between 10 months and 30 months of age, and apparent diffusion coefficient (ADC) values were obtained at the level of the spinal lesion. Neurological clinical assessments included intact S1 motor and sensory level, need for anticholinergic therapy or clean intermittent catheterization at the evaluation closest to 12 months, and ambulatory status at the evaluation closest to 30 months. Associations between ADC values (expressed as median [interquartile range]) and neurological clinical assessments were evaluated using the Mann-Whitney U test. A P-value <0.05 was considered significant. Thirty-six children were included (23 fetoscopic, 13 open-hysterotomy repairs). ADC values were significantly higher in children with intact S1 motor function (1.25 [1.00-1.89] vs 1.19 [1.00-1.30]×10-3 mm2/s, P=0.01), intact S1 sensory level (1.36 [1.12-1.74] vs 1.21 [1.04-1.38]×10-3 mm2/s, P=0.02), no anticholinergic therapy (1.31 [1.13-1.70] vs 1.22 [1.04-1.40]×10-3 mm2/s, P=0.04), no catheterization (1.33 [1.04-1.74] vs 1.21 [1.12-1.32]×10-3 mm2/s, P=0.04), and independent ambulation (1.36 [1.04-1.89] vs 1.19 [1.00-1.46]×10-3 mm2/s, P=0.02). Lower ADC values at the lesion level were associated with worse neurological and urological clinical assessments in children after prenatal MMC repair, suggesting that DWI may provide imaging biomarkers of spinal cord integrity.

The aim of this study was to evaluate the incidence of spinal inclusion cyst (sIC) formation after open fetal myelomeningocele (fMMC) repair and the effect of dural patch closure. The authors conducted a retrospective review of patients who underwent open fMMC repair at their institution between March 2011 and June 2020. All patients met the criteria for intervention defined by the Management of Myelomeningocele Study (MOMS). The primary outcomes investigated were development of sIC and need for surgical intervention. Secondary outcomes included need for CSF diversion, extent of reversal of hindbrain herniation, and ambulatory status. Of 56 patients who underwent open fMMC repair, 52 had adequate spinal imaging for review. Twelve of these patients (23%) developed sIC (95% CI 0.11-0.35). Six patients experienced symptoms and required surgical detethering with sIC resection. Six additional patients had evidence of sIC on surveillance MRI but remained asymptomatic. The authors found a statistically significant relationship between the use of a dural allograft patch and sIC formation (p = 0.05). In terms of sIC development, there was no statistically significant difference between patients who underwent primary closure and those who received an allograft at the level of the fascia (p = 0.34) or skin (p = 0.26). The rate of hydrocephalus requiring CSF diversion was 52%. Interestingly, 98% of patients had improvement in extent of hindbrain herniation. Dural patch closure did not have any effect on the rate of progressive hydrocephalus (p = 0.33) or degree of reversal of hindbrain herniation (p > 0.99). This study suggested that children with prenatally repaired MMC are at higher risk for development of sIC and associated symptoms than those who undergo postnatal repair. The presentation of symptoms was also earlier in these patients than previously reported after postnatal repair. The use of a dural allograft patch appears to have a positive correlation with sIC formation. Future investigations evaluating the incidence of sIC after fetoscopic MMC repair, in which primary dural closure typically cannot be achieved and a dural patch is most often utilized, will be helpful in facilitating prenatal counseling for patients considering fetal intervention.

Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study.

Prenatal myelomeningocele (MMC) repair has been shown to provide significant benefits to the infant, decreasing the postnatal need for ventriculoperitoneal shunt and improving motor outcome. Chorioamniotic membrane separation (CAS) is a potential complication following prenatal MMC repair and may increase the risk of preterm prelabor rupture of membranes (PPROM) and preterm birth. The objectives of this study were: (1) to evaluate the incidence of CAS after prenatal MMC repair; (2) to determine risk factors associated with its occurrence; and (3) to assess its association with adverse perinatal outcomes. This was a retrospective cohort study of patients who underwent fetal MMC repair between November2011 and December 2018. Surgery was performed using either a fetoscopic (laparotomy or exteriorized uterus) approach or an open-hysterotomy approach. Eligibility criteria were those reported in the Management of Myelomeningocele Study. If CAS was detected on ultrasound (US), its severity was graded as 'mild' if amnion detachment involved < 25% of the uterine cavity, 'moderate' if it involved 25-50% and 'severe' if it involved > 50%. Evolution of CAS was classified as stable, increasing or decreasing based on the difference in severity grading between the time at first diagnosis and the last US scan before delivery. Logistic regression analysis was performed to identify pre- or perisurgical factors associated with the development of CAS and to determine the risk of adverse perinatal outcome associated with CAS. In total, 91 cases were included. Fetoscopic or open-hysterotomy repair of MMC was performed in 52/91 (57.1%) and 39/91 (42.9%) cases, at a median gestational age (GA) of 25.0 weeks (range, 22.9-26.0 weeks) and 25.0 weeks (range, 21.3-25.9 weeks), respectively. CAS was diagnosed in 31/91 (34.1%) patients, at a median GA of 28.1 weeks (range, 24.4-37.6 weeks). Anterior placenta was identified as a risk factor for the postoperative development of CAS (odds ratio (OR), 3.72 (95% CI, 1.46-9.5); P < 0.01). This risk was dependent on the repair technique. An anterior placenta significantly increased the risk of CAS after fetoscopic repair (OR, 3.94 (95% CI, 1.14-13.6); P = 0.03) but not after open repair (OR, 2.8 (95% CI, 0.6-12.5); P = 0.16). There was no significant difference in the rate of CAS after fetoscopic repair (21/52 (40.4%)) vs open-hysterotomy repair (10/39 (25.6%)) (P = 0.14), nor were there any differences in GA at diagnosis of CAS, interval between surgery and diagnosis, distribution of CAS severity or progression of CAS between the two groups. CAS increased the risk of PPROM (50% in those with vs 12% in those without CAS) (OR, 7.6 (95% CI, 2.5-21.9); P < 0.01) and preterm delivery (70% vs 38%) (OR, 3.2 (95% CI, 1.3-8.1); P < 0.01). Fetoscopically repaired cases with CAS had a higher rate of PPROM (12/20 (60.0%) vs 2/31 (6.5%); P < 0.01) and preterm delivery (13/20 (65.0%) vs 5/31 (16.1%); P < 0.01) than those that did not develop CAS, while the differences were not significant in cases with open-hysterotomy repair. Early detection of CAS (before 30 weeks' gestation) was a risk factor for preterm delivery (90% before 30 weeks vs 36% at or after 30 weeks) (OR, 15.7 (95% CI, 2.3-106.3); P < 0.01). There was no association between PPROM or preterm delivery and the severity or progression of CAS. The presence of an anterior placenta was the only factor that increased the risk for CAS after fetoscopic MMC repair. Detection of CAS after fetoscopic MMC repair significantly increases the risk for PPROM and preterm delivery. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

ObjectiveInfants with myelomeningocele (MMC) are at risk of brainstem dysfunction secondary to symptomatic Chiari II malformation with hindbrain herniation (HH), which can manifest as feeding difficulties including aspiration and dysphagia. This study aims to investigate whether prenatal repair of MMC is associated with improved feeding outcomes compared to postnatal repair.Study designRetrospective observational study of 208 infants with MMC, 105 repaired prenatally and 103 repaired postnatally, from January 2011 to July 2022. Primary outcome was feeding tube at discharge and longitudinally through 12 months corrected gestational age (CGA).Results9.5% of infants repaired prenatally and 13.6% repaired postnatally required feeding tube at discharge (p = 0.3585). By 53 weeks CGA, the prenatal repair group had decreased odds of requiring feeding tube (0.325 [95% CI 0.121, 0.872]).ConclusionPrenatal MMC repair was associated with decreased need for long-term feeding support, suggesting a potential functional benefit of prenatal repair related to reversal of HH.

The Management of Myelomeningocele Study (MOMS) showed that prenatal repair of myelomeningocele (MMC) resulted in better neurological outcomes than postnatal closure but was, by necessity, associated with higher rates of obstetrical complications. Fetoscopic MMC repair has been explored as an alternative to reduce complications of the open approach used in MOMS. This review summarizes the trends in fetoscopic and open fetal repair of MMC. We searched PubMed and Embase® for studies on fetal repair of MMC published since the completion of the MOMS trial. Fetoscopic MMC repair was temporarily halted in the United States (US) prior to the initiation of the MOMS trial. The German Center for Fetal Surgery has reported the largest series of fetoscopic MMC repair. The other largest series is the Brazilian Cirurgia Endoscopica para Correcao Antenatal da Meningomielocele (CECAM) trial. Both groups demonstrate the feasibility of minimally invasive fetal MMC repair, but also report high rates of premature rupture of membranes, preterm births, and persistent cerebrospinal fluid (CSF) leakage that requires postnatal revision of the MMC repair. In addition, these groups have yet to report long term cognitive, behavioral, and functional outcomes of fetoscopic MMC repair. The fetoscopic approach to fetal MMC repair is a promising alternative to the open approach if preterm birth and persistent CSF leakage can be overcome.