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IntroductionFetal myelomeningocele (MMC) repair improves lower extremity motor function. We have previously demonstrated that augmentation of fetal MMC repair with placental mesenchymal stromal cells (PMSCs) seeded on extracellular matrix (PMSC-ECM) further improves motor function in the ovine model. However, little progress has been made in improving bowel and bladder function, with many patients suffering from neurogenic bowel and bladder. We hypothesized that fetal MMC repair with PMSC-ECM would also improve bowel and bladder function.MethodsMMC defects were surgically created in twelve ovine fetuses at median gestational age (GA) 73 days, followed by defect repair at GA101 with PMSC-ECM. Fetuses were delivered at GA141. Primary bladder function outcomes were voiding posture and void volumes. Primary bowel function outcome was anorectal manometry findings including resting anal pressure and presence of rectoanal inhibitory reflex (RAIR). Secondary outcomes were anorectal and bladder detrusor muscle thickness. PMSC-ECM lambs were compared to normal lambs (n = 3).ResultsEighty percent of PMSC-ECM lambs displayed normal voiding posture compared to 100% of normal lambs (p = 1). Void volumes were similar (PMSC-ECM 6.1 ml/kg vs. normal 8.8 ml/kg, p = 0.4). Resting mean anal pressures were similar between cohorts (27.0 mmHg PMSC-ECM vs. normal 23.5 mmHg, p = 0.57). RAIR was present in 3/5 PMSC-ECM lambs that underwent anorectal manometry and all normal lambs (p = 0.46). Thicknesses of anal sphincter complex, rectal wall muscles, and bladder detrusor muscles were similar between cohorts.ConclusionOvine fetal MMC repair augmented with PMSC-ECM results in near-normal bowel and bladder function. Further work is needed to evaluate these outcomes in human patients.

IntroductionThe Management of Myelomeningocele Study demonstrated that in utero repair of myelomeningocele improved motor outcomes compared with postnatal repair. However, even after in utero repair, many children were still unable to walk. We have previously demonstrated that augmentation of in utero repair with early-gestation placental mesenchymal stromal cells (PMSCs) improves motor outcomes in lambs compared with standard in utero repair. The neuroprotective potential of PMSCs of all gestational ages has not been evaluated previously.MethodsPMSCs were isolated from discarded first trimester (n = 3), second trimester (n = 3), and term (n = 3) placentas by explant culture. Cytokine array analysis was performed. Secretion of two neurotrophic factors, brain-derived neurotrophic factor and hepatocyte growth factor, was evaluated by enzyme-linked immunosorbent assay. An in vitro neuroprotective assay demonstrated to be associated with in vivo function was performed.ResultsAll cell lines secreted immunomodulatory and neuroprotective cytokines and secreted the neurotrophic factors evaluated. Increased neuroprotective capabilities relative to no PMSCs were demonstrated in two of the three first trimester cell lines (5.61, 4.96-6.85, P

BackgroundWhile fetal repair of myelomeningocele (MMC) revolutionized management, many children are still unable to walk independently. Preclinical studies demonstrated that research-grade placental mesenchymal stromal cells (PMSCs) prevent paralysis in fetal ovine MMC, however this had not been replicated with clinical-grade cells that could be used in an upcoming human clinical trial. We tested clinical-grade PMSCs seeded on an extracellular matrix (PMSC-ECM) in the gold standard fetal ovine model of MMC.MethodsThirty-five ovine fetuses underwent MMC defect creation at a median of 76 days gestational age, and defect repair at 101 days gestational age with application of clinical-grade PMSC-ECM (3 × 105 cells/cm2, n = 12 fetuses), research-grade PMSC-ECM (3 × 105 cells/cm2, three cell lines with n = 6 (Group 1), n = 6 (Group 2), and n = 3 (Group 3) fetuses, respectively) or ECM without PMSCs (n = 8 fetuses). Three normal lambs underwent no surgical interventions. The primary outcome was motor function measured by the Sheep Locomotor Rating scale (SLR, range 0: complete paralysis to 15: normal ambulation) at 24 h of life. Correlation of lumbar spine large neuron density with SLR was evaluated.ResultsClinical-grade PMSC-ECM lambs had significantly better motor function than ECM-only lambs (SLR 14.5 vs. 6.5, p = 0.04) and were similar to normal lambs (14.5 vs. 15, p = 0.2) and research-grade PMSC-ECM lambs (Group 1: 14.5 vs. 15, p = 0.63; Group 2: 14.5 vs. 14.5, p = 0.86; Group 3: 14.5 vs. 15, p = 0.50). Lumbar spine large neuron density was strongly correlated with motor function (r = 0.753, p

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Myelomeningocele, characterized by extrusion of the spinal cord through a spinal canal defect, is the most common form of spina bifida, often resulting in lifelong disability and significant orthopaedic issues. A randomized controlled trial (RCT) has shown the efficacy of prenatal repair in decreasing the need for shunting and improving motor outcomes. However, no studies have evaluated the effects of prenatal repair on orthopaedic outcomes. The purpose of this study was to determine the rates of orthopaedic conditions in patients with prenatal and postnatal repair of myelomeningocele and compare the rates of treatment required. This study analyzes the relevant outcomes from a prospective RCT (Management of Myelomeningocele Study). Eligible women were randomized to prenatal or postnatal repair, and patients were evaluated prospectively. Outcomes of interest included rates of scoliosis, kyphosis, hip abnormality, clubfoot, tibial torsion, and leg length discrepancy (LLD) at 12 and 30 months. The need for orthopaedic intervention at the same time points was also evaluated. Statistical analyses included descriptive statistics and univariate analyses. Data for the full cohort of 183 patients were analyzed (91 prenatal, 92 postnatal). There were no differences in rates of scoliosis, kyphosis, hip abnormality, clubfoot or tibial torsion between patients treated with prenatal or postnatal repair. The rate of LLD was lower in the prenatal repair group at 12 and 30 months (7 vs. 16% at 30 months, P = 0.047). The rates of patients requiring casting or bracing were significantly lower in patients treated with prenatal repair at 12 and 30 months (78 vs. 90% at 30 months, P = 0.036). Patients treated with prenatal myelomeningocele repair may develop milder forms of orthopaedic conditions and may not require extensive orthopaedic management.

Spina bifida is the most common congenital defect of the central nervous system which can portend lifelong disability to those afflicted. While the complete underpinnings of this disease are yet to be fully understood, there have been great advances in the genetic and molecular underpinnings of this disease. Moreover, the treatment for spina bifida has made great advancements, from surgical closure of the defect after birth to the now state-of-the-art intrauterine repair. This review will touch upon the genetics, embryology, and pathophysiology and conclude with a discussion on current therapy, as well as the first FDA-approved clinical trial utilizing stem cells as treatment for spina bifida.

PurposeAugmentation of in utero myelomeningocele repair with human placental mesenchymal stromal cells seeded onto extracellular matrix (PMSC-ECM) improves motor outcomes in an ovine myelomeningocele model. This study evaluated the safety of PMSC-ECM application directly onto the fetal spinal cord in preparation for a clinical trial.MethodsLaminectomy of L5-L6 with PMSC-ECM placement directly onto the spinal cord was performed in five fetal lambs at gestational age (GA) 100-106 days. Lambs and ewes were monitored for three months following delivery. Lambs underwent magnetic resonance imaging (MRI) of the brain and spine at birth and at three months. All organs from lambs and uteri from ewes underwent histologic evaluation. Lamb spinal cords and brains and ewe placentas were evaluated for persistence of PMSCs by polymerase chain reaction for presence of human DNA.ResultsMRIs demonstrated no evidence of abnormal tissue growth or spinal cord tethering. Histological analysis demonstrated no evidence of abnormal tissue growth or treatment related adverse effects. No human DNA was identified in evaluated tissues.ConclusionThere was no evidence of abnormal tissue growth or PMSC persistence at three months following in utero application of PMSC-ECM to the spinal cord. This supports proceeding with clinical trials of PMSC-ECM for in utero myelomeningocele repair.Level of evidenceN/A TYPE OF STUDY: Basic science.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

The history of fetal surgery is one of constant evolution. Over the last 50 years, fetal surgery has progressed from a mere idea to an internationally respected innovative field of surgery. This article aims to provide a historical review of how the enterprise of maternal-fetal surgery came to be its modern version. This review is less focused on the history of specific therapies for a relatively small number of conditions, and more on how the whole field of maternal-fetal surgery evolved. The various internal and external influences that steered the field's evolution are discussed in chronologic order. Since the start of modern fetal surgery in the 1980s, large paradigm shifts have characterized the growth of the field as a whole. Innovative interventions are now based on physiologic manipulation as opposed to simple anatomic repair, fetoscopy has become the more frequently preferred surgical approach, and rigorous scientific evaluation with randomized controlled trials is now the standard expected by the community. In a very similar fashion to when the field first began in the early 1980s, recently community's leaders have risen to protect the integrity of maternal-fetal surgery by publishing ethical guidelines for innovation and clinical practice. This incredible history of innovation, rigorous science and ethical contemplation is the foundation on which modern maternal-fetal surgery rests.

Fetal surgery is a relatively new field of medicine. The purpose of this narrative review is to present the history of how fetal surgery became the standard of care for myelomeningocele (MMC), the current controversies of this treatment, and active areas of research that may change how MMC is treated. Fetal surgery for MMC emerged out of the University of California, San Francisco in the 1980s in the laboratory of Dr. Michael Harrison. Initial research focused on testing the hypothesis that the in utero repair of MMC could improve outcomes in the ovine model. Evidence from this model suggested that in utero repair decreases the secondary damage to the exposed neural tissue and improves post-natal neurologic outcomes, opening the door for human intervention. This was followed by the Management of Myelomeningocele Study (MOMS), which was a multicenter randomized controlled trial comparing the prenatal versus postnatal MMC repair. The MOMS trial was stopped early due to the improved outcomes of the prenatal repair, establishing the open fetal MMC repair as the standard of care. Since the MOMS trial, two primary areas of controversy have arisen: the operative approach and criteria for the repair. The three operative approaches include open, endoscopic and a hybrid approach combining open and endoscopic. Several of the inclusion and exclusion criteria from the MOMS trial have been challenged, to include body mass index, gestational diabetes, other fetal abnormalities, maternal infections and Rh alloimmunization. New areas of research have also emerged, exploring cell based therapies to improve fetal outcomes, alternatives to fetal surgery and alternatives to primary skin closure of the fetus.

BackgroundThe inherent morbidity associated with fetal ovine models of myelomeningocele (MMC) has created challenges for long-term survival of lambs. We aimed to develop a fetal ovine surgical spinal exposure model which could be used to evaluate long-term safety after direct spinal cord application of novel therapeutics for augmentation of in utero MMC repair.MethodsAt gestational age (GA) 100-106, fetal lambs underwent surgical intervention. Laminectomy of L5-L6 was performed, dura was removed, and an experimental product was directly applied to the spinal cord. Paraspinal muscles and skin were closed and the fetus was returned to the uterus. Lambs were delivered via cesarean section at GA 140-142. Lambs were survived for 3 months with regular evaluation of motor function by the sheep locomotor rating scale. Spinal angulation was evaluated by magnetic resonance imaging at 2 weeks and 3 months.ResultsFive fetal surgical intervention lambs and 6 control lambs who did not undergo surgical intervention were included. All lambs survived to the study endpoint of 3 months. No lambs had motor function abnormalities or increased spinal angulation.ConclusionThis model allows for long-term survival after fetal spinal cord exposure with product application directly onto the spinal cord.

IntroductionOpen fetal surgery requires a hemostatic hysterotomy that minimizes membrane separation. For over 30 years, the standard of care for hysterotomy in the gravid uterus has been the AutoSuture Premium Poly CS*-57 stapler.ObjectiveIn this study, we sought to test the feasibility of hysterotomy in a rhesus monkey model with the Harmonic ACE®+7 Shears.MethodsA gravid rhesus monkey underwent midgestation hysterotomy at approximately 90 days of gestation (2nd trimester; term = 165 ± 10 days) using the Harmonic ACE®+7 Shears. A two-layer uterine closure was completed and the dam was monitored by ultrasound intermittently throughout the pregnancy. At 58 days after hysterotomy (near term), a final surgery was performed to evaluate the uterus and hysterotomy site.ResultsA 3.5-cm hysterotomy was completed in 2 min 7 s. The opening was hemostatic and the membranes were sealed. Immediately after closure and throughout the pregnancy, ultrasound revealed intact membranes without separation and normal amniotic fluid levels. At term, the scar was well healed without signs of thinning or dehiscence.ConclusionsThe Harmonic ACE®+7 Shears produced a hemostatic midgestation hysterotomy with membrane sealing in the rhesus monkey model. Importantly, healing was acceptable.

BackgroundWe determined whether in vitro potency assays inform which placental mesenchymal stromal cell (PMSC) lines produce high rates of ambulation following in utero treatment of myelomeningocele in an ovine model.MethodsPMSC lines were created following explant culture of three early-gestation human placentas. In vitro neuroprotection was assessed with a neuronal apoptosis model. In vivo, myelomeningocele defects were created in 28 fetuses and repaired with PMSCs at 3 × 105 cells/cm2 of scaffold from Line A (n = 6), Line B (n = 7) and Line C (n = 5) and compared to no PMSCs (n = 10). Ambulation was scored as ≥13 on the Sheep Locomotor Rating Scale.ResultsIn vitro, Line A and B had higher neuroprotective capability than no PMSCs (1.7 and 1.8 respectively vs 1, p = 0.02, ANOVA). In vivo, Line A and B had higher large neuron densities than no PMSCs (25.2 and 27.9 respectively vs 4.8, p = 0.03, ANOVA). Line C did not have higher neuroprotection or larger neuron density than no PMSCs. In vivo, Line A and B had ambulation rates of 83% and 71%, respectively, compared to 60% with Line C and 20% with no PMSCs.ConclusionThe in vitro neuroprotection assay will facilitate selection of optimal PMSC lines for clinical use.Level of evidencen/a.Type of studyBasic science.

IntroductionThe ovine model is the gold standard large animal model of myelomeningocele (MMC); however, it has a high rate of fetal loss. We reviewed our experience with the model to determine risk factors for fetal loss.MethodsWe performed a retrospective review from 2009 to 2018 to identify operative factors associated with fetal loss (early fetal demise, abortion, or stillbirth). Operative risk factors included gestational age at operation, operative time, reduction of multiple gestations, amount of replaced amniotic fluid, ambient temperature, and method of delivery.ResultsMMC defects were created in 232 lambs with an overall survival rate of 43%. Of the 128 fetuses that died, 53 (42%) had demise prior to repair, 61 (48%) aborted, and 14 (11%) were stillborn. Selective reduction of multiple gestations in the same uterine horn was associated with increased fetal demise (OR 3.03 [95% CI 1.29-7.05], p = 0.01). Later gestational age at MMC repair and Cesarean delivery were associated with decreased abortion/stillbirth (OR 0.90 [95% CI 0.83-0.90], p = 0.03, and OR 0.37 [95% CI 0.16-0.31], p = 0.02), respectively.ConclusionAvoiding selective reduction, repairing MMC later in gestation, and performing Cesarean delivery decreases the rate of fetal loss in the ovine MMC model.

BackgroundFetal repair of myelomeningocele (MMC) with placental mesenchymal stromal cells (PMSCs) rescues ambulation in the ovine model up to 48 h postnatally. Outcomes past 48 h are unknown as MMC lambs have not been survived past this timepoint.ObjectiveWe aimed to survive lambs for 6 months following the fetal repair of MMC with PMSCs.MethodsFetal MMC lambs were repaired with PMSCs. Lambs received either no additional treatment or postnatal bracing and physical therapy (B/PT). Motor function was assessed with the sheep locomotor rating (SLR). Lambs with an SLR of 15 at birth were survived for 6 months or until a decline in SLR less than 15, whichever came first. All lambs underwent a perimortem MRI.ResultsThe lambs with no postnatal treatment (n = 2) had SLR declines to 7 and 13 at 29 and 65 days, respectively, and were euthanized. These lambs had a spinal angulation of 57° and 47°, respectively. The B/PT lamb (n = 1) survived for 6 months with a sustained SLR of 15 and a lumbar angulation of 42°.ConclusionPostnatal physical therapy and bracing counteracted the inherent morbidity of the absent paraspinal muscles in the ovine MMC model allowing for survival and maintenance of rescued motor function of the prenatally treated lamb up to 6 months.

IntroductionOpen fetal repair of myelomeningocele (MMC) is an option for prenatally diagnosed spina bifida. Historically, high-dose volatile anesthetic was used for uterine relaxation but is associated with fetal cardiovascular depression. We examined the impact of administering a supplemental remifentanil infusion on the concentration of inhaled anesthetic required for intraoperative uterine relaxation.MethodsWe retrospectively analyzed 22 consecutive patients who underwent open fetal MMC repair with desflurane anesthesia from 2014 to 2018. The anesthetic protocol was modified to include high-dose opioid with remifentanil in 2016. We examined intraoperative end-tidal desflurane concentrations, vasopressor use, incidence of umbilical artery Doppler abnormalities, and incidence of preterm labor and delivery.ResultsPatients (n = 11) who received desflurane and remifentanil (Des/Remi) were compared to patients (n = 11) who received desflurane (Des) alone. Intraoperatively, the maximum end-tidal desflurane required to maintain uterine relaxation was lower in the Des/Remi group (7.9 ± 2.2% vs. 13.1 ± 1.2%, p < 0.001). The mean phenylephrine infusion rate was also lower in the Des/Remi group (36 ± 14 vs. 53 ± 10 mcg/min, p = 0.004).DiscussionUse of opioid with supplemental remifentanil was associated with lower volatile anesthetic dosing and decreased vasopressor use; fetal outcomes were not different. Remifentanil may allow for less volatile anesthetic use while maintaining adequate uterine relaxation.

The COVID-19 pandemic has stressed patients and healthcare givers alike and challenged our practice of antenatal care, including fetal diagnosis and therapy. This document aims to review relevant recent information to allow us to optimize prenatal care delivery. We discuss potential modifications to obstetric management and fetal procedures in SARS-CoV2-negative and SARS-CoV2-positive patients with fetal anomalies or disorders. Most fetal therapies are time sensitive and cannot be delayed. If personnel and resources are available, we should continue to offer procedures of proven benefit, acknowledging any fetal and maternal risks, including those to health care workers. There is, to date, minimal, unconfirmed evidence of spontaneous vertical transmission, though it may theoretically be increased with some procedures. Knowing a mother's preoperative SARS-CoV-2 status would enable us to avoid or defer certain procedures while she is contagious and to protect health care workers appropriately. Some fetal conditions may alternatively be managed neonatally. Counseling regarding fetal interventions which have a possibility of additional intra- or postoperative morbidity must be performed in the context of local resource availability. Procedures of unproven benefit should not be offered. We encourage participation in registries and trials that may help us to understand the impact of COVID-19 on pregnant women, their fetuses, and neonates.

BACKGROUND:Open maternal-fetal surgery for fetal myelomeningocele results in reduction in neonatal morbidity related to spina bifida but may be associated with fetal, neonatal, and maternal complications in subsequent pregnancies. OBJECTIVE:The objective of this study was to ascertain obstetric risk in subsequent pregnancies after open maternal-fetal surgery for fetal myelomeningocele closure. STUDY DESIGN:An international multicenter prospective observational registry created to track and report maternal, obstetric, fetal/neonatal, and subsequent pregnancy outcomes following open maternal-fetal surgery for fetal myelomeningocele was evaluated for subsequent pregnancy outcome variables. Institutional Review Board approval was obtained for the registry. RESULTS:From 693 cases of open maternal-fetal surgery for fetal myelomeningocele closure entered into the registry, 77 subsequent pregnancies in 60 women were identified. The overall live birth rate was 96.2%, with 52 pregnancies delivering beyond 20 weeks gestational age and median gestational age at delivery of 37 (36.3-37.1) weeks. The uterine rupture rate was 9.6% (n = 5), resulting in 2 fetal deaths. Maternal transfusion was required in 4 patients (7.7%). CONCLUSION:The risk of uterine rupture or dehiscence in subsequent pregnancies with associated fetal morbidity after open maternal-fetal surgery is significant, but is similar to that reported for subsequent pregnancies after classical cesarean deliveries. Future pregnancy considerations should be included in initial counseling for women contemplating open maternal-fetal surgery.

PurposeThe purpose of this study was to determine whether seeding density of placental mesenchymal stromal cells (PMSCs) on extracellular matrix (ECM) during in utero repair of myelomeningocele (MMC) affects motor function and neuronal preservation in the ovine model.MethodsMMC defects were surgically created in 33 fetuses and repaired following randomization into four treatment groups: ECM only (n = 10), PMSC-ECM (42 K cells/cm2) (n = 8), PMSC-ECM (167 K cells/cm2) (n = 7), or PMSC-ECM (250-300 K cells/cm2) (n = 8). Motor function was evaluated using the Sheep Locomotor Rating Scale (SLR). Serial sections of the lumbar spinal cord were analyzed by measuring their cross-sectional areas which were then normalized to normal lambs. Large neurons (LN, diameter 30-70 μm) were counted manually and density calculated per mm2 gray matter.ResultsLambs treated with PMSCs at any density had a higher median SLR score (15 [IQR 13.5-15]) than ECM alone (6.5 [IQR 4-12.75], p = 0.036). Cross-sectional areas of spinal cord and gray matter were highest in the PMSC-ECM (167 K/cm2) group (p = 0.002 and 0.006, respectively). LN density was highest in the greatest density PMSC-ECM (250-300 K/cm2) group (p = 0.045) which positively correlated with SLR score (r = 0.807, p

IntroductionThe surgically induced fetal lamb model is the most commonly used large animal model of myelomeningocele (MMC) but is subject to variation due to surgical technique during defect creation.Material and methodsThirty-one fetal lambs underwent creation of the MMC defect, followed by defect repair with either an extracellular matrix (ECM) patch (n = 10) or ECM seeded with placental mesenchymal stromal cells (n = 21). Postnatal hindlimb function was assessed using the Sheep Locomotor Rating (SLR) scale. Postmortem magnetic resonance imaging of the lumbar spine was used to measure the level and degree of spinal angulation, as well as cross-sectional area of remaining vertebral bone.ResultsMedian level of angulation was between the 2nd and 3rd lumbar vertebrae, with a median angle of 24.3 degrees (interquartile range 16.2-35.3). There was a negative correlation between angulation degree and SLR (r = -0.44, p = 0.013). Degree of angulation also negatively correlated with the normalized cross-sectional area of remaining vertebral bone (r = -0.75, p < 0.0001).DiscussionSurgical creation of fetal MMC leads to varying severity of spinal angulation in the ovine model, which affects postnatal functional outcomes. Postnatal assessment of spinal angulation aids in standardization of the surgical model of fetal MMC repair.

BackgroundPrevious reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously.ObjectiveThe purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study.Study designEligible women were randomly assigned to undergo standard postnatal repair or prenatal repair

Fetal surgery corrects severe congenital anomalies in utero to prevent their severe consequences on fetal development. The significant risk of open fetal operations to the pregnant mother has driven innovation toward minimally invasive procedures that decrease the risks inherent to hysterotomy. In this article, we discuss the basic principles of minimally invasive fetal surgery, the general history of its development, specific conditions and procedures used to treat them, and the future of the field.

The current standard for fetal repair of myelomeningocele is an open exposure of the gravid uterus with control of the amniotic membranes, and then a multi-layer closure of the fetal defect. The nature of the surgical repair has evolved and requires a series of steps that take into account the delicate nature of the fetal tissues. The individual surgical steps are described including potential pitfalls.

IntroductionFetal amniotic membranes (FM) have been shown to preserve spinal cord histology in the fetal sheep model of myelomeningocele (MMC). This study compares the effectiveness of placenta-derived mesenchymal stromal cells (PMSCs) from early-gestation versus term-gestation placenta to augment FM repair to improve distal motor function in a sheep model.MethodsFetal lambs (n = 4) underwent surgical MMC creation followed by repair with FM patch with term-gestation PMSCs (n = 1), FM with early-gestation PMSCs (n = 1), FM only (n = 1), and skin closure only (n = 1). Histopathology and motor assessment was performed.ResultsHistopathologic analysis demonstrated increased preservation of spinal cord architecture and large neurons in the lamb repaired with early-gestation cells compared to all others. Lambs repaired with skin closure only, FM alone, and term-gestation PMSCs exhibited extremely limited distal motor function; the lamb repaired with early-gestation PMSCs was capable of normal ambulation.DiscussionThis pilot study is the first in vivo comparison of different gestational-age placenta-derived stromal cells for repair in the fetal sheep MMC model. The preservation of large neurons and markedly improved motor function in the lamb repaired with early-gestation cells suggest that early-gestation placental stromal cells may exhibit unique properties that augment in utero MMC repair to improve paralysis.

ObjectThe Management of Myelomeningocele Study (MOMS) was a multicenter randomized trial comparing the safety and efficacy of prenatal and postnatal closure of myelomeningocele. The trial was stopped early because of the demonstrated efficacy of prenatal surgery, and outcomes on 158 of 183 pregnancies were reported. Here, the authors update the 1-year outcomes for the complete trial, analyze the primary and related outcomes, and evaluate whether specific prerandomization risk factors are associated with prenatal surgery benefit.MethodsThe primary outcome was a composite of fetal loss or any of the following: infant death, CSF shunt placement, or meeting the prespecified criteria for shunt placement. Primary outcome, actual shunt placement, and shunt revision rates for prenatal versus postnatal repair were compared. The shunt criteria were reassessed to determine which were most concordant with practice, and a new composite outcome was created from the primary outcome by replacing the original criteria for CSF shunt placement with the revised criteria. The authors used logistic regression to estimate whether there were interactions between the type of surgery and known prenatal risk factors (lesion level, gestational age, degree of hindbrain herniation, and ventricle size) for shunt placement, and to determine which factors were associated with shunting among those infants who underwent prenatal surgery.ResultsNinety-one women were randomized to prenatal surgery and 92 to postnatal repair. The primary outcome occurred in 73% of infants in the prenatal surgery group and in 98% in the postnatal group (p < 0.0001). Actual rates of shunt placement were only 44% and 84% in the 2 groups, respectively (p < 0.0001). The authors revised the most commonly met criterion to require overt clinical signs of increased intracranial pressure, defined as split sutures, bulging fontanelle, or sunsetting eyes, in addition to increasing head circumference or hydrocephalus. Using these modified criteria, only 3 patients in each group met criteria but did not receive a shunt. For the revised composite outcome, there was a difference between the prenatal and postnatal surgery groups: 49.5% versus 87.0% (p < 0.0001). There was also a significant reduction in the number of children who had a shunt placed and then required a revision by 1 year of age in the prenatal group (15.4% vs 40.2%, relative risk 0.38 [95% CI 0.22-0.66]). In the prenatal surgery group, 20% of those with ventricle size < 10 mm at initial screening, 45.2% with ventricle size of 10 up to 15 mm, and 79.0% with ventricle size ≥ 15 mm received a shunt, whereas in the postnatal group, 79.4%, 86.0%, and 87.5%, respectively, received a shunt (p = 0.02). Lesion level and degree of hindbrain herniation appeared to have no effect on the eventual need for shunting (p = 0.19 and p = 0.13, respectively). Similar results were obtained for the revised outcome.ConclusionsLarger ventricles at initial screening are associated with an increased need for shunting among those undergoing fetal surgery for myelomeningocele. During prenatal counseling, care should be exercised in recommending prenatal surgery when the ventricles are 15 mm or larger because prenatal surgery does not appear to improve outcome in this group. The revised criteria may be useful as guidelines for treating hydrocephalus in this group.

AimTo investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering.MethodsPMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis.ResultsWe determined that an average of 2.09 × 10(6) (SD ± 8.59 × 10(5)) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 10(3). Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation.ConclusionOur findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.

Purpose of reviewMaternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between mother and fetus during pregnancy. This results in the presence of fetal cells in the maternal circulation, known as fetal microchimerism, and maternal cells in the fetal circulation, known as maternal microchimerism. The biologic role of this transplacental cellular trafficking during pregnancy is not known, although it has been implicated in development of the fetal immune system, tolerance mechanisms during pregnancy, tissue repair in autoimmune disease and cancer, and immune surveillance.Recent findingsClinical utility of MFCT has been identified in prenatal testing for aneuploidies and prediction of pregnancy complications. Additionally, this transplacental passage of cells has been implicated in the delicate balance between immunologic priming and tolerance, which can influence the occurrence of autoimmune disease and transplantation outcomes. Ongoing studies are evaluating the utility of microchimerism in predicting the risk of graft rejection in transplantation.SummaryIn this review, we will discuss the clinical implications of MFCT in pregnancy, fetal surgery, autoimmune disease, transplantation, and cancer.

BackgroundDespite advances in prenatal repair, myelomeningocele (MMC) still produces devastating neurologic deficits. The amniotic membranes (AM) are a biologically active tissue that has been used anecdotally for human fetal MMC repair. This study evaluated the use of autologous AM compared to skin closure in an established fetal MMC model.MethodsSeven fetal lambs underwent surgical creation of MMC at gestational age of 75days followed by in utero repair at gestational age of 100days. Lambs were repaired with an autologous AM patch followed by skin closure (n=4) or skin closure alone (n=3). Gross necropsy and histopathology of the spinal cords were performed at term to assess neuronal preservation at the lesion.ResultsAn increase in preserved motor neurons and a larger area of spinal cord tissue were seen in AM-repaired lambs, as was decreased wound healing of the overlying skin. Loss of nearly all spinal cord tissue with limited motor neuron preservation was seen in skin only-repaired lambs.ConclusionsAM-repaired lambs showed increased protection of spinal cord tissue compared to skin only-repaired lambs, but the overlying skin failed to close in AM-repaired lambs. These results suggest a potential role for AM in fetal MMC repair that warrants further study.

BackgroundSmall left heart structures are observed in fetuses with left-sided congenital diaphragmatic hernia (CDH). Fetoscopic tracheal occlusion (FETO) in mid-gestation promotes lung growth in fetuses with CDH, however cardiac effects of FETO are poorly described. We studied the effects of FETO on cardiac structure size at birth, hypothesizing that left heart structures would be larger in neonates who had undergone fetal intervention.Methods/resultsWe performed retrospective measurements of atrioventricular and semilunar valve and pulmonary artery diameters, ventricular lengths, left ventricular end-diastolic volume indexed (LVEDVi) to body surface area. 35 patients were studied (9 FETO, 26 controls). All fetuses had liver herniation and a lung-to-head ratio

Congenital pulmonary hypoplasia is a devastating condition affecting fetal and newborn pulmonary physiology, resulting in great morbidity and mortality. The fetal lung develops in a fluid-filled environment. In this work, we describe a novel, implantable pressure sensing and recording device which we use to study the pressures present in the fetal pulmonary tree throughout gestation. The system achieves 0.18 cm H2O resolution and can record for twenty one days continuously at 256 Hz. Sample tracings of in vivo fetal lamb recordings are shown.

Background/purposeBidirectional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking.MethodsCellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n = 5), patients with MMC who had routine postnatal repair (n = 6), and healthy control healthy patients (n = 9). As an additional control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment procedure (n = 6). Microchimerism in maternal and cord blood was determined using quantitative real-time polymerase chain reaction for nonshared alleles.ResultsMaternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared with healthy controls, patients who underwent postnatal MMC repair, and patients who underwent ex utero intrapartum treatment. There were no differences in fetal-to-maternal cell trafficking among groups.ConclusionPatients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor.