Prenatal MMC Repair Research Articles

Maternal and obstetric complications in fetal surgery for prenatal myelomeningocele repair: a systematic review.

Comparing prenatal and postnatal surgical repair techniques for myelomeningocele (MMC), in utero fetal surgery has increasingly gained acceptance and is considered by many specialized centers the first choice of treatment. Despite its benefits, as demonstrated in the Management of Myelomeningocele Study (MOMS), including reduced need for CSF shunting in neonates and improved motor outcomes at 30 months, there is still an ongoing debate on fetal and maternal risks associated with the procedure. Prenatal open hysterotomy, fetoscopic MMC repair techniques, and subsequent delivery by cesarean section are associated with maternal complications. The aim of this systematic review is to assess the available literature on maternal and obstetric complication rates and perinatal maternal outcomes related to fetal MMC repair. The authors identified references for inclusion in this review by searching PubMed and MEDLINE, with restrictions to English language, case series, case reports, clinical trials, controlled clinical trials, meta-analyses, randomized controlled trials, reviews, and systematic reviews. The rate of maternal and obstetric complications was analyzed based on studies focusing on this issue and presenting clear results on the matter. Of 1264 articles screened, 36 were included in this systemic review, whereof 11 were eligible for data analysis and comparison. The average overall rate of maternal and obstetric complications corresponds to 78.6%. The majority of the described events are obstetric complications, varying from chorioamniotic membrane separation in 65.6% of cases, oligohydramnios in 13.0% of cases, placental abruption in 5.0% of cases, spontaneous or preterm premature membrane rupture in 42.0% of cases, and early preterm delivery in 11.3% of cases due to uterine dehiscence, occurring in 0.9% of cases. The most common medical complications are development of pulmonary edema occurring in 2.8%, gestational diabetes in 3.7%, gestational hypertension/preeclampsia in 3.7%, and need for blood transfusions in 3.2% of cases. Limitations of the review arise from the lack of data in the current literature, with maternal and obstetric complications being underreported. Although the efforts of further advancement of intrauterine prenatal MMC repair aim to increase neonatal outcomes, maternal health hazard will continue to be an issue of crucial importance and further studies are required.

Pediatric neurosurgeons' views regarding prenatal surgery for myelomeningocele and the management of hydrocephalus: a national survey.

The Management of Myelomeningocele Study (MOMS) compared prenatal with postnatal surgery for myelomeningocele (MMC). The present study sought to determine how MOMS influenced the clinical recommendations of pediatric neurosurgeons, how surgeons' risk tolerance affected their views, how their views compare to those of their colleagues in other specialties, and how their management of hydrocephalus compares to the guidelines used in the MOMS trial. A cross-sectional survey was sent to all 154 pediatric neurosurgeons in the American Society of Pediatric Neurosurgeons. The effect of surgeons' risk tolerance on opinions and counseling of prenatal closure was determined by using ordered logistic regression. Compared to postnatal closure, 71% of responding pediatric neurosurgeons viewed prenatal closure as either "very favorable" or "somewhat favorable," and 51% reported being more likely to recommend prenatal surgery in light of MOMS. Compared to pediatric surgeons, neonatologists, and maternal-fetal medicine specialists, pediatric neurosurgeons viewed prenatal MMC repair less favorably (p < 0.001). Responders who believed the surgical risks were high were less likely to view prenatal surgery favorably and were also less likely to recommend prenatal surgery (p < 0.001). The management of hydrocephalus was variable, with 60% of responders using endoscopic third ventriculostomy in addition to ventriculoperitoneal shunts. The majority of pediatric neurosurgeons have a favorable view of prenatal surgery for MMC following MOMS, although less so than in other specialties. The reported acceptability of surgical risks was strongly predictive of prenatal counseling. Variation in the management of hydrocephalus may impact outcomes following prenatal closure.

Abnormal anisotropic diffusion properties in pediatric myelomeningocele patients treated with fetal surgery: an initial DTI study.

To investigate white matter microstructural abnormality based on diffusion tensor imaging (DTI) in pediatric patients with fetal repair for myelomeningocele (MMC). This was a retrospective analysis of DTI data from 8 pediatric patients with prenatal MMC repair (age range 1.64-33.70months; sex 3F/5M) and 8 age-matched controls (age 2.24-31.20months; sex 5F/2M). All participants were scanned on 1.5T GE Signa MR scanner (GE Healthcare, Milwaukee, WI) with the same sequence specifications. Two DTI measures, including fractional anisotropy (FA) and mean diffusivity (MD), were calculated from the genu of corpus callosum (gCC) and the posterior limb of internal capsule (PLIC). DTI values and fronto-occipital horn ratio (FOHR) were tested for group difference based on two-tailed paired t test. The ventricle size based on FOHR in patients with prenatal MMC repair was significantly larger than that in the age-matched control group (p < 0.001). Statistically significant group difference in DTI (lower FA and higher MD in patient group) was found in gCC (p = 0.007 and 0.003, respectively). A trend level increase in MD was also found (p = 0.065) in PLIC in patients when compared with the age-matched controls. Our data showed white matter abnormality based on DTI in pediatric patient with fetal repair for MMC. The sensitivity of DTI in detecting white matter abnormality, as shown in the present study, may help to serve as an imaging biomarker for assessing hydrocephalus and improve and optimize decision making for the treatment of hydrocephalus in this patient population.

211: Chorioamniotic separation after prenatal myelomeningocele repair

To assess the risks associated with development of CAS after prenatal MMC repair We conducted a retrospective cohort study of patients who underwent open or fetoscopic prenatal MMC repair from December 2011-May 2018. Open repair technique was performed as reported in the MOMS Trial. Fetoscopic repair was performed using uterine CO2 insufflation, two or three ports, and an exteriorized uterus. Perinatal outcomes of patients who developed CAS after prenatal MMC repair were compared with those of patients who did not develop CAS. Degree of CAS was classified as mild if CAS occupied <25% of uterine surface area, moderate if 25-50%, or severe if >50%. Comparisons between cases with and without CAS were performed using Student's t-test, Chi-square, or Fisher’s exact test. Logistic regression analysis was used to determine risk of developing CAS, PPROM, or preterm delivery. Of 73 patients who underwent prenatal MMC repair, 24 (32.9%) developed CAS. CAS was detected at median of 28.9 (25.4 – 37.6) weeks gestation and 4 (0.4 – 12.6) weeks post-surgery. 70.8% of CAS cases were identified after fetoscopic repairs and 29.2% after open repairs (p=0.05). Development of CAS after fetoscopic repairs was independent of number of ports (3 ports: 35.3% vs. 2 ports: 64.7%; p=0.7) or maximal uterine pressure used (CAS: 11.9±1.7 mmHg vs. no CAS: 11.8±1.9 mmHg; p=0.7). Four variables were assessed for increased risk of developing CAS. Anterior placenta was the only variable with significant predictive value (p=0.03; OR: 3.23, 95% CI: 1.1-18.2). Fetoscopic repair, duration of surgery >3 hours, and use of three ports did not significantly increase risk of developing CAS. Cases with CAS developed PPROM 5.2 times more frequently than cases without CAS (95% CI:1.5-18.3; p<0.01). Cases of PPROM preceded by CAS occurred at later gestational age than those not preceded by CAS. A trend was noted for an association between CAS and placental abruption. When cases of moderate or severe CAS (n=11) were compared with mild CAS cases (n=12; severity of 1 case could not be assessed) at time of diagnosis, a trend for longer interval between CAS and delivery was observed in mild cases [7.8 (1.3-12.28) weeks vs. 2 (0.1-13.2 weeks); p=0.02]. Development of CAS increases the risk of adverse perinatal events. Efforts should be taken to reduce its incidence after prenatal MMC repair.

An Injectable Reverse Thermal Gel for Minimally Invasive Coverage of Mouse Myelomeningocele

BackgroundMyelomeningocele (MMC) results in lifelong neurologic and functional deficits. Currently, prenatal repair of MMC closes the defect, resulting in a 50% reduction in postnatal ventriculoperitoneal shunting. However, this invasive fetal surgery is associated with significant morbidities to mother and baby. We have pioneered a novel reverse thermal gel (RTG) to cover MMC defects in a minimally invasive manner. Here, we test in-vitro RTG long-term stability in amniotic fluid and in vivo application in the Grainy head-like 3 (Grhl3) mouse MMC model. Materials and methodsRTG stability in amniotic fluid (in-vitro) was monitored for 6 mo and measured using gel permeation chromatography and solution–gel transition temperature (lower critical solution temperature). E16.5 Grhl3 mouse fetuses were injected with the RTG or saline and harvested on E19.5. Tissue was assessed for RTG coverage of the gross defect and inflammatory response by immunohistochemistry for macrophages. ResultsPolymer backbone molecular weight and lower critical solution temperature remain stable in amniotic fluid after 6 mo. Needle injection over the MMC of Grhl3 fetuses successfully forms a stable gel that covers the entire defect. On harvest, some animals demonstrate >50% RTG coverage. RTG injection is not associated with inflammation. ConclusionsOur results demonstrate that the RTG is a promising candidate for a minimally invasive approach to patch MMC. We are now poised to test our RTG patch in the large preclinical ovine model used to evaluate prenatal repair of MMC.

New directions in fetal surgery for myelomeningocele.

The treatment of children with myelomeningocele (MMC) has improved over time, from supportive management to early postnatal closure to prenatal repair of the defect. The Management of Myelomeningocele Study (MOMS) showed that prenatal repair of MMC resulted in improved neurological outcomes compared to postnatal closure. Follow-up studies showed that prenatal repair was, as with any other fetal intervention, associated with higher rates of obstetrical complications. There was no significant difference in urological outcomes. Long-term follow-up of ambulatory status, executive functioning, and urological outcomes is needed to determine the durable effects of fetal MMC repair on mobility, functional independence, and the prevalence of renal insufficiency in patients with MMC who survive to adulthood. The future of fetal MMC repair consists of developing strategies to reduce maternal morbidity and improve infant outcomes. Fetoscopic MMC repair has been suggested as an alternative to open repair that may reduce obstetrical complications and the need for cesarean delivery in subsequent pregnancies. Translational research using mesenchymal stromal cells to augment fetal repair of ovine MMC has shown improvement in motor function.

First 60 fetal in-utero myelomeningocele repairs at Saint Louis Fetal Care Institute in the post-MOMS trial era: hydrocephalus treatment outcomes (endoscopic third ventriculostomy versus ventriculo-peritoneal shunt).

The published results of the Management of Myelomeningocele Study (MOMS) trial in 2011 showed improved outcomes (reduced need for shunting, decreased incidence of Chiari II malformation, and improved scores of mental development and motor function) in the fetal prenatal repair group compared to the postnatal group. Historically, endoscopic third ventriculostomy (ETV) remains as a controversial hydrocephalus treatment option with high failure rates in pediatric patients with a history of myelomeningocele (MMC). We report hydrocephalus treatment outcomes in the fetal in-utero myelomeningocele repair patients who underwent repair at our Saint Louis Fetal Care Institute following the MOMS trial. We looked carefully at ETV outcomes in this patient population and we identified risk factors for failure. At our Saint Louis Fetal Care Institute, we followed the maternal and fetal inclusion and exclusion criteria used by the MOMS trial. The records of our first 60 fetal MMC repairs performed at our institute between 2011 and 2017 were examined. We retrospectively reviewed the charts, prenatal fetal magnetic resonance imaging (MRI) and ultrasound (US) imaging findings, postnatal brain MRI, and Bayley neurodevelopment testing results for infants and children who underwent surgical treatment of symptomatic hydrocephalus (VP shunt versus ETV). Multiple variables possibly related to ETV failure were considered for identifying risk factors for ETV failure. Between May 2011 and March 2017, 60 pregnant female patients underwent the prenatal MMC repair for their fetuses between 20 and 26weeks' gestational age (GA) utilizing the standard hysterotomy for exposure of the fetus, and microsurgical repair of the MMC defect. All MMC defects underwent successful in-utero repair, with subsequent progression of the pregnancy. At the time of this study, 58 babies have been born, 56 are alive since there were 2 mortalities in the neonatal period due to prematurity. One patient was excluded given lack of consent for research purposes. From the remaining 55 patient included in this study, a total of 30 infants and toddlers underwent treatment of hydrocephalus (ETV and VPS groups). Twenty-five patients underwent ETV (24 primary ETV and 1 after shunt failure). Nineteen patients underwent shunt placements (6 primary/13 after ETV failure). Mean GA at time of MMC repair for the ETV group was 24+6/7weeks (range 22+4/7 to 25+6/7). Mean follow up for patients who had a successful ETV was 17.25months (range 4-57months). Bayley neurodevelopmental testing results were examined pre- and post-ETV. Overall ETV success rate was 11/24 (45.8%) at the time of this study. The total number of patients who underwent shunt placement was 19/55 (34.5%), while shunting rate was 40% in the MOMS trial. Using a simple logistic regression analysis to identify predictors of ETV failure, ETV age ≤6months and gestational age ≥23weeks at repair of myelomeningocele were significant predictors for ETV failure while in-utero ventricular stability ≤4mm and in-utero ventricular size post-repair ≤15.5mm were significant predictors for ETV success. None of the listed variables independently predicted classification into ETV success versus ETV failure groups when entered into multiple logistic regression analysis. ETV, as an alternative to initial shunting, may continue to show promising results for treating fetal MMC repair patient population who present with symptomatic hydrocephalus during infancy and early childhood. Although our overall CSF diversion rate (ETV and VPS groups) in our fetal MMC group is higher than the MOMS trial, our shunting rate is lower given our higher incidence of patients with successful ETV. To our knowledge, this is the largest reported ETV series in patients who underwent fetal MMC repair. ETV deserves a closer look in the setting of improved hindbrain herniation in fetal in-utero MMC repair patients. In our series, young age (less than 6months) and late GA at time of fetal MMC repair (after 23weeks GA) were predictors for ETV failure, while in-utero stability of ventricular size (less than 4mm) and in-utero ventricular size post-repair ≤15.5mm were predictors for ETV success. Larger series and potential prospective randomized studies are required for further evaluation of risk factors for ETV failure in the fetal MMC patient population.

Prenatal myelomeningocele repair: Do bladders better?

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.

Prenatal surgery for myelomeningocele.

This review summarizes outcomes of fetal surgery for myelomeningocele (MMC) as they compare to postnatal MMC repair and provides insights into areas of investigation to improve fetal MMC repair. Recent studies confirm the findings of the Management of Myelomeningocele Study and support the decreased need for postnatal ventricular shunts, improved hindbrain herniation, and improved neurofunctional outcome following open fetal repair compared to postnatal repair at the risk of increased maternal complications and preterm birth. Larger studies of minimally invasive fetal repair demonstrate that, although technically feasible, this approach is associated with longer operative times, increased membrane complications, an earlier gestational age at birth, persistent cerebrospinal fluid leakage, and incidences of persistent postnatal hindbrain herniation resulting in death or requiring surgical decompression. Open prenatal MMC repair is a new standard of care option with improved postnatal outcomes in a highly specific patient population when performed at select multidisciplinary fetal surgery centers. More investigations are required to optimize minimally invasive approaches prior to reliable clinical application.

Limits of the surgically induced model of myelomeningocele in the fetal sheep.

The prevention of Chiari type II malformation (CM) is commonly used as a primary outcome for the evaluation of techniques of fetal myelomeningocele (MMC) surgery in the fetal lamb. The aim of our study was to investigate the frequency of the associated CM in the MMC fetal sheep model and to investigate the contribution of prenatal ultrasound evaluation of CM at the time of prenatal repair. A MMC-like lesion was surgically created at 75 days of gestation in 21 fetuses performing a L1-L5 laminectomy followed by an excision of the exposed dura and a midline myelotomy. At a 90-day gestation, among the 19 alived fetuses, a conventional repair of the MMC-like lesion was performed in seven, four of whom underwent cerebral ultrasound (US) examination before the repair. Twelve fetuses remained untreated (control group). All fetuses underwent post-mortem examination (PM) at 138 days. At a 90-day gestation, CM was demonstrated by US examination in all four evaluated fetuses. At birth, CM was found in 3/6 control whether CM was absent in all alived fetuses in the prenatal repair group (n = 4). Creation of a MMC-like lesion with an additional myelotomy does not always lead to hindbrain herniation. Our study suggests that CM should be assessed by ultrasound examination at the time of the prenatal repair to demonstrate the effectiveness of new techniques for the prenatal repair of MMC.

Prenatal repair of myelomeningocele with aligned nanofibrous scaffolds—a pilot study in sheep

Background/Purpose Spinal cord damage in myelomeningocele (MMC) results from abnormal cord development and subsequent local trauma. Prenatal surgery prevents additional neural injury. However, existing damage is not reversed. Biodegradable nanofibrous scaffolds (NSs) promote regeneration of neural tissues. They mimic the microtopography of the extracellular matrix and guide tissue formation and organization. The purpose of this pilot study was to evaluate the practicality and safety of using biodegradable NS as a regenerative device in prenatal MMC repair. Methods Two fetal lambs underwent a surgically induced MMC defect followed by open fetal repair using aligned biodegradable NS. Lambs were killed at day 138. Spinal cords were examined for inflammation or fibrosis and stained for spinal cord architecture, myelin, and neuron cell bodies. Results Prenatal repair with NS demonstrated technical feasibility. There was no evidence of a surrounding inflammatory response or foreign-body reaction to the scaffold. Conclusion Biodegradable NS can be used surgically for the prenatal repair of MMC in a large animal model and does not appear to elicit an inflammatory or fibrotic reaction in fetal tissue. Further studies will determine their potential for neural cell infiltration, delivery of growth factors, drugs or stem cells, and functional recovery greater than standard repair.

Myelomeningocele: prenatal diagnosis, pathophysiology and management

Myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. Early fetal intervention may improve neurologic outcome and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.

Foetal surgery for spina bifida

In utero repair of open spina bifida or myelomeningocele (MMC) is now performed in selected patients and presents an additional alternative to obstetricians and neonatologists counselling expectant mothers carrying a foetus with MMC. Early foetal intervention may improve neurologic outcomes and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation in open spina bifida. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.