Fetal Surgery For Spina Bifida Research Articles

Fetal surgery for spina bifida – An upcoming standard of care

Open spina bifida or myelomeningocele (MMC) is one of the most common serious congenital malformations that have been historically treated with a repair after birth. However, this “repair” does not avert neurological injury, reverse hindbrain herniation, or prevent hydrocephalus. With the intention to reduce numerous medical procedures, lifelong morbidities, and medical complications, fetal surgery was proposed about a quarter century ago. Fetal surgery has become the standard of care for MMC, especially after the advent of the Management of Myelomeningocele Study (MOMS) trial. Dr. Michael Harrison from the University of California was the first to birth this idea in the 1980s. While earlier research was carried out on ovine models, it was deduced that intrauterine repair reduces the secondary damage to exposed neural tissue and improves post-natal neurological outcomes. After the promising results in animal models and some clinical series, it paved the way for a prospective multicenter randomized controlled trial that compared prenatal versus postnatal MMC repair, with the aim to prove its efficacy and safety with Level-1 evidence- the MOMS. However, it was stopped early due to the improved prenatal repair outcomes, thus establishing open fetal MMC repair as the standard of care. We aim to discuss the origin story of this remarkable procedure, its rationales and advantages for the unborn child and mother and its short-term and long-term superiority and limitations. The operative procedure and the criteria with other essential aids in its diagnosis have also been discussed briefly. We also intend to eliminate the apprehension faced toward this procedure by the supporting team of obstetricians, anesthetists, neonatologists, and radiologists essential to making this procedure a success.

Patient empowerment improves follow-up data collection after fetal surgery for spina bifida: institutional audit.

To define and grade fetal and maternal adverse events following fetal surgery for spina bifida and to report on the impact of engaging patients in collecting follow-up data. This prospective single-center audit included 100 consecutive patients undergoing fetal surgery for spina bifida between January 2012 and December 2021. In our setting, patients return to their referring unit for further pregnancy care and delivery. On discharge, referring hospitals were requested to return outcome data. For this audit, we prompted patients and referring hospitals to provide data in cases of missing outcomes. Outcomes were categorized as missing, returned spontaneously or returned following additional request, by the patient and/or referring center. Postoperative maternal and fetal complications until delivery were defined and graded according to Maternal and Fetal Adverse Event Terminology (MFAET) and the Clavien-Dindo classification. There were no maternal deaths, but severe maternal complications occurred in seven women (anemia in pregnancy, postpartum hemorrhage, pulmonary edema, lung atelectasis, urinary tract obstruction and placental abruption). No cases of uterine rupture were reported. Perinatal death occurred in 3% of fetuses and other severe fetal complications in 15% (perioperative fetal bradycardia/cardiac dysfunction, fistula-related oligohydramnios, chorioamnionitis and preterm prelabor rupture of membranes (PPROM) before 32 weeks). PPROM occurred in 42% of patients and, overall, delivery took place at a median gestational age of 35.3 weeks (interquartile range, 34.0-36.6 weeks). Information provided following additional request, from both centers and patients but mainly from the latter, reduced missing data by 21% for gestational age at delivery, 56% for uterine-scar status at birth and 67% for shunt insertion at 12 months. Compared with the generic Clavien-Dindo classification, the MFAET system ranked complications in a more clinically relevant way. The nature and rate of severe complications following fetal surgery for spina bifida were similar to those reported in other large series. Spontaneous return of outcome data by referring centers was low, yet patient empowerment improved data collection. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Administration of prosaposin-derived neurotrophic factor to neural tube defects facilitates regeneration and restores neurological functions.

Neural tube defects (NTDs) cause fetal and pediatric deaths or lifelong neurological disabilities. No effective treatment is currently available for NTDs. We attempted to elucidate the pathogenesis of NTDs and propose a therapeutic strategy. Intra-amniotic treatment with prosaposin-derived 18-mer peptide (PS18) protected the spinal cord from secondary damage and rescued neurological function in an established chicken model of spina bifida aperta (SBA), the severe type of NTDs. PS18 promoted the formation of a neuroectodermal covering over the defective neural tube within 24-h after treatment, enhanced the regeneration/restoration process, and decreased apoptotic activity in the developing spinal cord. PS18 reduced the SBA wound and almost completely formed the spinal cord. SBA chicks that received PS18 exhibited relatively normal walking and sensorimotor responses, and reduced pain-associated behavior in postnatal life. In conclusion, PS18 is a promising therapeutic agent for NTDs and may be useful for treating other types of spinal cord injuries.

Preterm rupture of membranes following alternative hysterotomy for spina bifida open fetal surgery: systematic review

The objective of this study was to establish whether different types of hysterotomy technique for spina bifida open fetal surgery impact in preterm prelabor rupture of membranes (PPROM) rates. Before data extraction, the project was registered in the PROSPERO International Register of Systematic Reviews (registration number: CRD42021249622). A systematic search was performed to identify relevant studies, using PubMed, Embase, Web of Science and Cochrane Library databases. Alternative hysterotomy technique was defined as opening with sutures and size ≥ 4cm (as opposed to mini-hysterotomy or fetal microneurosurgery). The comparison was made with studies reporting standard technique (with staplers and size from 6-8 cm) published post-MOMs trial (after 2011). The incidence of the main outcome (PPROM before 37 weeks’ gestation) and other relevant variables were compared using Mann-Whitney test, with significance level as a two-sided p-value < 0.05. From 3636 assessed studies, 217 were selected by title and abstract. Fifty-nine were excluded due to duplicated records. One hundred fifty-eight full-text articles were reviewed and 27 were selected as relevant. From those, 14 were excluded due to duplication of data and one due to lack of data in the main outcome. Therefore, 12 studies were retained for analysis, 2 of them addressing alternative hysterotomy and 10 reporting standard technique follow up. The results showed no differences in maternal characteristics such as age, BMI or gestational age at surgery. Median PPROM rates were not significantly different between groups [27.9% (standard) vs. 20.8% (alternative)], p=0.39. Other perinatal parameters such as placental abruption, chorioamniotic separation, fetal death, preterm delivery, gestational age at birth, and birth weight were not significantly different. Women undergoing open fetal surgery for spina bifida with alternative hysterotomy technique had similar PPROM rates as those undergoing standard technique.

Fetal surgery for spina bifida: a great success story in surgical innovation.

This commentary is on the original articles by Worley et al. on pages 1294–1301 and Hepp et al. on pages 1302–1307 of this issue.

Validation of a high-fidelity training model for fetoscopic spina bifida surgery

Open fetal surgery for spina bifida (SB) is safe and effective yet invasive. The growing interest in fetoscopic SB repair (fSB-repair) prompts the need for appropriate training. We aimed to develop and validate a high-fidelity training model for fSB-repair. fSB-repair was simulated in the abdominal cavity and on the stomach of adult rabbits. Laparoscopic fetal surgeons served either as novices (n = 2) or experts (n = 3) based on their experience. Technical performance was evaluated using competency Cumulative Sum (CUSUM) analysis and the group splitting method. Main outcome measure for CUSUM competency was a composite binary outcome for surgical success, i.e. watertight repair, operation time ≤ 180 min and Objective-Structured-Assessment-of-Technical-Skills (OSATS) score ≥ 18/25. Construct validity was first confirmed since competency levels of novices and experts during their six first cases using both methods were significantly different. Criterion validity was also established as 33 consecutive procedures were needed for novices to reach competency using learning curve CUSUM, which is a number comparable to that of clinical fSB-repair. Finally, we surveyed expert fetal surgeons worldwide to assess face and content validity. Respondents (26/49; 53%) confirmed it with ≥ 71% of scores for overall realism ≥ 4/7 and usefulness ≥ 3/5. We propose to use our high-fidelity model to determine and shorten the learning curve of laparoscopic fetal surgeons and retain operative skills.

Association of uterine activity and maternal volatile anesthetic exposure during open fetal surgery for spina bifida: a retrospective analysis

BackgroundRecent warnings postulate a possible damaging effect of volatile anesthetics on the fetus. In our archive of fetal surgeries, we found wide variation in dosing of volatile anesthetics during spina bifida surgeries. We hypothesized that there was an association between volatile anesthetic exposure and uterine activity. MethodsSixty anesthesia records from spina bifida operations were assessed. We analyzed the course of the administered volatile anesthetic during surgery and calculated from each patient’s anesthesia record the volatile anesthetic exposure expressed in vol%h. We divided the records into two post hoc groups of the 20 lowest exposure (Group L) versus the 20 highest exposure (Group H), and compared them for uterine activity and fetal heart rate. ResultsThe number of contractions per hour was significantly greater in Group H (mean 1.3, SD ± 1.2) compared with Group L (mean 0.5, SD ± 0.6, P=0.049). There was no difference between the groups for the administration of the tocolytic drug atosiban (P=0.29). The course of the mean arterial pressure did not significantly differ but group H needed significantly more vasoactive medication (P <0.05). ConclusionsWe found that a lower intra-operative volatile anesthetic exposure than recommended in the MOMS-trial (i.e. <2.0 minimum alveolar concentration [MAC]) was not associated with an increase in intra-operative uterine activity. This is an indication that during spina bifida surgery, 2.0 MAC may not be necessary to avoid potentially harmful uterine activity.

Long-term Outcomes of Children After Fetal Surgery for Spina Bifida—Toward Sustainability

Long-term Outcomes of Children After Fetal Surgery for Spina Bifida—Toward Sustainability

Fetal surgery for spina bifida in Zurich: results from 150 cases.

Over the past 10years, over 150 fetal spina bifida surgeries were performed at the Zurich Center for Fetal Diagnosis and Therapy. This study looks at surrogates for success and failure of this approach. We focused on key outcome parameters including hydrocephalus shunt rate at one year, bladder control at 4, independent ambulation at 3years, and maternal, fetal, and neonatal complications. From the first 150 patients undergoing fetal surgery for spina bifida, 148 (98.7%) were included in the study. Maternal-fetal surgery was uneventful in 143/148 (97%) cases. Intraoperative problems included resuscitation in 4/148 fetuses (2.7%). 1/148 fetuses (0.7%) died on postoperative day 4. Maternal complications included chorioamniotic membrane separation in 22/148 (15%), lung embolism in 3/148 (2.1%), chorioamnionitis in 2/148 (1.4%), AV-block III and uterine rupture in 1/148 each (0.7%). 1/148 (0.7%) newborn death was recorded. Hindbrain herniation was identified preoperatively in 132/148 (90%) fetuses and resolved completely in 119/132 (90%). At one year, 39/106 (37%) children had required a CSF diversion. At 4years, 4/34 patients (12%) had normal bladder control. At 3years, 48/57 (84%) walked independently. A majority of patients benefitted from prenatal intervention, in that the shunt rate was lower and the rates of continent and walking patients were higher than reported with postnatal care.

VP21.03: A qualitative study of acceptability of fetal surgery for spina bifida to parents

VP21.03: A qualitative study of acceptability of fetal surgery for spina bifida to parents

Bioengineering of Fetal Skin: Differentiation of Amniotic Fluid Stem Cells into Keratinocytes

Purpose: Open fetal spina bifida repair has become a novel clinical standard of care. In very large spina bifida lesions, the skin defect cannot be covered primarily, asking for alternative solutions. We hypothesize that amniotic fluid stem cells (AFSC) could be differentiated into keratinocytes that could then be used to bioengineer autologous skin usable for in utero back coverage. Methods: To obtain human AFSC, amniotic fluid samples obtained from fetal surgeries were subjected to immunoselection for c-kit. C-kit-positive samples and controls were cultured with the additives morphogenetic protein 4 and vitamin C to induce differentiation towards keratinocytes. This process was monitored by measuring the expression of K8 and K14 via immunohistochemical staining, flow cytometry, and polymerase chain reaction. Results: After immunoselection and expansion, most cells were positive for K8, but none for K14. After completion of the differentiation protocol, cell colonies with keratinocyte-like appearance could be observed, but cells remained positive for K8 and negative for K14, indicating failed differentiation into keratinocytes. Conclusions: Culturing of keratinocyte-like cells from AFSC, harvested intraoperatively, was not feasible in this setting. The reasons for failure must be investigated and eliminated, as bioengineering of fetal skin for clinical use during fetal surgery for spina bifida remains an attractive goal.

Benchmarking against the MOMS Trial: Zurich Results of Open Fetal Surgery for Spina Bifida

Introduction: The Management of Myelomeningocele Study, a.k.a. the MOMS trial, was published in 2011 in the New England Journal of Medicine. This prospective randomized controlled trial proved to be a milestone publication that provided definitive evidence that fetal surgery is a novel standard of care for select fetuses with spina bifida aperta (SB). The goal of our study is to assess whether our center can match these benchmark results. Materials and Methods: Our study was conducted according to the MOMS protocol using the same inclusion and exclusion criteria and looked at the same outcome parameters that were used in the MOMS trial. Zurich and MOMS results were compared. Results: We enrolled 20 patients between December 2010 and May 2015 all of whom underwent fetal surgery for SB. Among 51 different outcome variables, there were only 3 favorable (multiplicity-adjusted) significant differences (gestational age at birth, hindbrain herniation, and psychomotor development). There were no statistically significant differences regarding any other parameters. Conclusion: Our findings confirm that rigorous apprenticeship, training, and comprehensive prospective data collection enable centers like the Zurich Center for Fetal Diagnosis and Therapy to achieve benchmark results for open fetal surgery for myelomeningocele and myeloschisis. These results justify the existence and continuation of our program. Outcome documentation is an essential element of quality management. It is medically and ethically fundamental for fetal medicine and surgery centers offering high-end innovative medical care.

Current controversies in prenatal diagnosis 1: in utero therapy for spina bifida is ready for endoscopic repair.

What's already known about this topic? There is level 1 (RCT) evidence for improved neurological outcomes after open fetal surgery for spina bifida versus postnatal surgery. There is a lack of standardization of techniques and comparative outcome data in clinical trials for endoscopic fetal surgery for spina bifida. What does this study add? Different techniques, their strengths, limitations and clinical implications of endoscopic versus open fetal surgery for spina bifida are discussed. Open fetal surgery anticipates postnatal surgery, whereas novel and less invasive endoscopic approaches aim to simplify the technique. More data on long‐term follow‐up of intrauterine closure of spina bifida are needed, and open surgery is one step ahead of fetoscopic approaches.

Intrauterine Treatment of Spina Bifida

ABSTRACT Prenatal repair for open spina bifida (OSB) represents nowadays a valid therapeutic option that must be considered whenever a fetus is diagnosed with this severe congenital malformation. However, a judicious weighing of the benefits obtained by fetal surgery against the risks is necessary for every individual case. This article provides the background information that is needed to accomplish that. It describes the evolution of fetal surgery for spina bifida, its benefits and risks, and the different techniques used today. How to cite this article Mazzone L, Meuli M. Intrauterine Treatment of Spina Bifida. Donald School J Ultrasound Obstet Gynecol 2017;11(4):347-354.

Neural stem cell delivery to the spinal cord in an ovine model of fetal surgery for spina bifida

We introduce the notion of prenatal neural stem cell (NSC) delivery to the spinal cord as an adjuvant to fetal repair of spina bifida. Fetal lambs with experimental myelomeningocele (MMC; n = 25) were divided in 3 groups: group I, no repair; group II, standard surgical MMC coverage; and group III, MMC coverage plus delivery of a murine NSCs clone into the spinal cord defect. Donor cells constitutively expressed lacZ encoding for Escherichia coli beta-galactosidase, yet they were further labeled by exposure to either BrdU and/or to the fluorescent membrane dye PKH-26. Blinded initial clinical evaluations and multiple spinal cord analyses were undertaken soon after birth. Both survival and the incidence of major paraparesis were significantly worse in group I compared with groups II and III. In group III, NSC density was highest within the most damaged areas of the spinal cord, with selective engraftment within those regions. Donor NSCs retained an undifferentiated state in vivo, producing neurotrophic factors within the defect. No animals in group III had a worsened condition following this intervention. Neural stem cells retain an undifferentiated state and produce neurotrophic factors in the short term after delivery to the fetal spinal cord, in the setting of experimental MMC. Further scrutiny of NSC delivery to the spinal cord as a therapeutic strategy against spina bifida is warranted.

Gender, head size and disease: A hypothesis related to posterior fossa growth

This hypothesis proposes that the difference in head size between the genders has a bearing on disease incidence. Smaller head size predisposes to spina bifida and larger head size predisposes to autism. In the fetus, the posterior fossa has a regulatory influence on maximum intracerebral cerebrospinal fluid (CSF) pressure. CSF pressure pulsations are generated by movements in the chest and abdomen and transmitted to the intracranial CSF spaces via the posterior fossa. The efficiency of transmission of pressure to the head is influenced by the size of posterior fossa CSF spaces. The larger posterior fossa in the male fetus allows higher peaks of pressure in the lateral ventricles than the female, resulting in larger head size. Restriction of posterior fossa growth has a greater influence on females than males. This leads to a greater incidence of spina bifida in females, where reduced head size is characteristic in the fetal stages. Fetal surgery for spina bifida expands posterior fossa CSF spaces and improves transmission of pressure waves generated in the fetal abdomen and thorax into the head. This results in an increase in head circumference following surgery. Males are susceptible to autism where head growth is accelerated in early childhood. This is because they have a larger average head size.

Ethics of maternal–fetal surgery

The transition from innovation to standard of care for maternal-fetal surgery should be guided by ethical as well as scientific considerations. This chapter provides an ethical framework that identifies criteria for the investigation of maternal-fetal surgery. Using this framework, physicians should address the initiation and assessment of clinical trials to determine whether they establish a standard of care, use an appropriately informed consent process to recruit and enroll subjects, consider whether selection criteria should include the abortion preferences of the pregnant woman, and consider whether physicians have an obligation to offer referral to such investigation. This ethical framework, in a clinically comprehensive fashion, takes account of the physician's obligations to the fetal patient, the pregnant woman, and future fetal and pregnant patients. The ethical framework is illustrated by the example of fetal surgery for spina bifida.

A comprehensive ethical framework for fetal research and its application to fetal surgery for spina bifida

The transition from innovation to standard of care for fetal surgery should be guided by ethical considerations. We provide an ethical framework that identifies criteria for the investigation of fetal surgery. This framework addresses the initiation and assessment of clinical trials to determine whether they establish a standard of care, describes an appropriate informed consent process, considers whether selection criteria should include the abortion preferences of the pregnant woman, and considers whether physicians have an obligation to offer referral to such investigation. This ethical framework, in a clinically comprehensive fashion, takes account of the physician's obligations to the fetal patient, the pregnant woman, and future fetal and pregnant patients. We apply this framework to clinical investigations of fetal surgery for spina bifida. (Am J Obstet Gynecol 2002;187:10-4.)