Accepted Article Article Type: Main Research Article Perinatal outcomes after open fetal surgery for myelomeningocele repair: a retrospective cohort study. Antonio Fernandes Moron1,3, Mauricio Mendes Barbosa1,3, Herbene José Figuinha Milani1,3, Stephanno Gomes Sarmento1,3, Eduardo Felix Martins Santana1,3, Italo Capraro Suriano 2,3, Patrícia Alessandra Dastoli2,3, Sergio Cavalheiro2,3 1 Department of Obstetrics, Escola Paulista de Medicina - Federal University of São Paulo-UNIFESP, São Paulo, Brazil; 2Department of Neurosurgery, Hospital São Paulo - Escola Paulista de Medicina Federal University of São Paulo-UNIFESP, São Paulo, Brazil; 3Hospital e Maternidade Santa Joana, São Paulo, Brazil. Correspondence: Dr. Antonio Fernandes Moron, Department of Obstetrics, Federal University of São Paulo-UNIFESP, Rua Leandro Dupret, 334 apto 81, CEP 04025-011, São Paulo – SP, Brazil Telephone: +55-11-999907564 - email antonio_moron@uol.com.br Running title: Open fetal surgery for myelomeningocele repair. Abstract Objective Describe outcomes of open fetal surgery for myelomeningocele (MMC) repair in two Brazilian hospitals and the impact of surgical experience on outcome. Design Retrospective cohort study. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1471-0528.15312 This article is protected by copyright. All rights reserved. Accepted Article Setting Sao Paulo, Brazil. Population 237 pregnant women carrying a fetus with an open spinal defect. Methods Surgical details and maternal and fetal outcomes collected from all patients. Main Outcome Measures Analysis of surgical and perinatal outcome parameters. Results Total surgical time was 119 +/- 7.6 min. Preterm labor occurred in 24.2%, premature rupture of membranes in 26.7%, placental abruption in 0.8%, need for a blood transfusion at delivery in 2.1% and dehiscence at the repair site in 2.5%. Reversal hindbrain herniation at birth was 71.4%. There were no maternal deaths or severe maternal morbidities. The failure rate with the patient anesthetized was 0.42% and perinatal mortality was 2.1% (3 intrauterine demises and 2 neonatal deaths). Comparing results from our study in the first 3 years vs. the last 3 years demonstrated improvement in the total surgical time (121.2 ± 6.4 min vs. 118.5±8.2 min, p= 0.005) and increased in reversal hindbrain herniation at birth (64.0% vs. 77.1%, p= 0.042). Conclusion Our open fetal surgical approach for MMC was effective and results were comparable to past studies. Improvements in surgical performance and perinatal outcome increased as the surgical team became more familiar with the procedure. Funding. The study was funded solely by institutional funds Keywords Myelomeningocele, spina bifida, open fetal surgery, perinatal outcome. Tweetable abstract Brazilian experience of in utero open surgery for myelomeningocele repair. Introduction Myelomeningocele (MMC) is a life-altering birth defect resulting from incomplete closure of the neural tube determined by a complex interaction between genetic and environmental factors during the early stages of fetal development. Each year in the USA, approximately 1,500 babies are born This article is protected by copyright. All rights reserved. Accepted Article with spina bifida1, a defect associated with morbidities during the life span of affected individuals, such as cognitive and respiratory deficiencies, varying degrees of motor deficiencies, skeletal deformities, bladder and fecal incontinence and hydrocephalus secondary to brainstem herniation by the foramen magnum resulting from obstruction of cerebrospinal fluid flow.2 Despite medical and surgical interventions performed after birth, Chiari II malformation is associated with high personal, family and social costs and remains the main cause of death in the first five years of life in patients with MMC.3,4 The justification for performing an intrauterine MMC correction was based on the possibility of preventing or minimizing the effects of brain stem herniation and nerve root lesions due to prolonged exposure to amniotic fluid. Indeed, initial nonrandomized studies suggested a significant benefit from prenatal repair of MMC.5-7 A multicenter, prospective, randomized clinical trial, the Management of Myelomeningocele Study (MOMS) compared fetal surgery to standard neonatal repair and demonstrated that fetal repair led to a decreased rate of shunting at 12 months of age, reversal of hindbrain herniation and improved outcomes, including the ability to walk at 30 months of age.8 Based upon the results of this randomized clinical trial, the American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine recommended that women with pregnancies complicated by fetal MMC who meet established criteria for intrauterine repair should be counselled in a nondirective fashion regarding all management options, including the possibility of open maternal–fetal surgery.9 The establishment of an open fetal surgery program for MMC in Brazil has become a necessity considering the high number of births and the legal limitation against termination of pregnancy. Based on our initial experience we initiated a fetal MMC repair program soon after publication of the MOMS study.13 However, due to Brazilian administrative limitations against use of the surgical This article is protected by copyright. All rights reserved. Accepted Article stapler recommended by the MOMS trial we developed a surgical technique that did not use surgical stapler.14 The present study analyzes the results of intrauterine MMC repair on a large cohort performed in two Brazilian hospitals and, in addition, analyzes the influence by surgical team experience on patients’ outcome. Material and methods In this retrospective cohort study, we review the outcomes of 237 patients selected for open fetal surgery for MMC repair in two hospitals in the city of São Paulo (Hospital e Maternidade Santa Joana and Hospital São Paulo-EPM/UNIFESP) during a 6-year period, between 2011 and 2017, performed by the same surgical team using a modified surgical approach, described previously.14,15 All patients gave written informed consent for the procedure and consented to their clinical data being used for research purposes. The study was approved by the institutional review board of Hospital São Paulo and Hospital e Maternidade Santa Joana (April 27, 2016, Reference: CEP 0598). There was no patient or public involvement in this retrospective study and no specific funding was sought for this study. The inclusion criteria were: singleton pregnancy; maternal age ≥ 18 years; gestational age at surgery between 24 and 27 weeks; MMC with the upper boundary located between T1 and S1; evidence of hindbrain herniation; normal karyotype and absence of other fetal malformations; body mass index (BMI) < 40 kg/m2, The exclusion criteria were: fetal kyphosis >30o, high risk for preterm deliveries (cervix length measurement by transvaginal ultrasound < 25 mm and/or history of prematurity in a previous pregnancy); placenta previa; uterine anomaly (fibroids and Müllerian abnormality); maternal conditions that would place additional risk to maternal health (poorly controlled diabetes and hypertension, HIV, hepatitis B or C positivity); maternal-fetal Rh/Kell alloimmunization, or history of fetal neonatal alloimmune thrombocytopenia and maternal psychosocial limitations. This article is protected by copyright. All rights reserved. Accepted Article Pregnant women were admitted to both hospitals one day before surgery to undergo preanesthetic evaluation, oral hydration and prescribed 10 mg diazepam as pre-operative medication. After a fasting period of 8 hours the patients were conducted to a high complexity surgical ward. Prior to anesthesia 2 g of intravenous cephazolin were administered prophylactically. The patients were anesthetized with a combination of general and intradural anesthesia followed by magnesium sulfate 2 g/hour for tocolysis. The gravid uterus was exposed through an 18 cm Joel-Cohen laparotomy and exteriorized under continuous fetal well-being evaluation. The fetal position, placenta and umbilical cord were then scanned using a sterile ultrasonography transducer. If the fetus was in the breech position, cephalic version was required. The site of the longitudinal hysterotomy was chosen according to the placental insertion being performed in the corporal region of the uterus with extension of 4 to 6 cm. After the location of the hysterotomy was chosen, two full-thickness stay sutures 1 cm apart of Vycril 0 were placed to keep the amniotic membrane attached to the myometrium and serving as a support point for uterine opening using electrocautery. Then, 4 Allis forceps were placed on the cut edges of the myometrium until the amniotic membrane was exposed. The amniotic membrane was then opened under direct visualization and two De Bakey vascular forceps were placed and the myometrium and fetal membrane were open with scalpel and scissor. A repair stitch was positioned at the end of the opening and a full-thickness running suture of Vicryl 0 suture was placed around the forceps encircling the entire incision. A continuous suture with monocryl 4-0 was performed around the uterine opening involving the inner portion of the myometrium and the amniotic membrane to prevent membrane separation and rupture premature of membrane. Indeed, it was observed that the reparative activity at the suture site of the fetal membrane was characterized by a significant increase in collagen fibers. The findings suggest collagen synthesis, tissue remodeling and repair of suture site, a mechanism likely to prevent the amniotic fluid leakage.17 This article is protected by copyright. All rights reserved. Accepted Article The fetus was visualized and positioned by extrauterine manipulation through the uterine wall until the MMC sac was in the center of the hysterotomy and an additional fetal analgesia by subcutaneous injection of fentanyl (20 mg/kg of fetal estimated weight) was given. Fetal heart rate (FHR) was monitored during all procedures and we identified a reduction in fetal heart rate mainly during the neurosurgical stage.16 Subsequently, we decided to avoid intramuscular fentanyl for fetal anesthesia and we no longer observed fetal bradycardia during our surgeries. The fetal temperature was monitored during the entire procedure with a digital infrared laser thermometer as well as the temperature in the operating room. To prevent the uterine temperature from decreasing below 30°C the uterine surface was irrigated with a heated saline solution and the uterus was wrapped using a sterile plastic cover (Figure 1), leaving only the region of the hysterotomy exposed. In cases of maternal hypotension, ephedrine or metaraminol were used for preservation of utero-placental flow. Additionally, in cases of fetal bradycardia, atropine (0.02 mg/kg) and adrenaline (1 mcg/kg) were administered to the pregnant women. The MMC was closed in a fashion similar to postnatal closure with the assistance of a Zeiss surgical microscope and/or Zeiss magnifying glass. The most important steps were the release of the cord and the treatment of the tethered spinal cord. Often, we found a fibrotic band fixing the top part of the placode to the dura mater. This ligament was found in more than 90% of cases of MMC and we have advocated that the release of the cord as one of the most important steps in the procedure. After reconstruction of the placode to its original form, the dura mater was hermetically closed with polyglactin 910 (Vicryl) 5.0. In most cases, the dura mater was firmly adhered to the aponeurosis and closed the two membranes together. The skin was closed placing a continuous suture with poliglecaprone 25 (monocryl) 5.0. If the primary closure was not achieved a suture of a two skin flaps This article is protected by copyright. All rights reserved. Accepted Article transposition (zetaplasty) was placed. In all cases, the skin could be closed, and the healing process was efficient without the use of exogenous material. 15 The uterine closure was performed in two steps. The first step involves continuous suture of the myometrium with Vicryl 2–0 followed by interrupted suture of the myometrium with Vicryl 0. Before the complete closure of the uterine wall, a silicone urinary catheter number 10 was inserted into the uterine cavity and the uterus was filled with saline solution at a temperature of 37 °C. Then, the uterus was put back into the abdominal cavity and the laparotomy was closed in standard fashion. The patient was transferred to an intensive care unit for the first 24 hours of postoperative care due to general anesthesia and magnesium sulfate effects. The perioperative management involved the use of tocolytics including magnesium sulfate, terbutaline and nifedipine. The patients were discharged from the hospital when they were ambulating well, eating a regular diet, and had achieved appropriate pain control. In addition to regular prenatal clinical follow-up, patients were monitored weekly with transabdominal ultrasonography for assessment of amniotic fluid index, uterine scar conditions, cerebral ventricular dimension, position of the cerebellum in the posterior fossa, and fetal well-being. Each patient was scheduled for elective cesarean delivery at 37 weeks of gestation or earlier in case of obstetric indications such as preterm labor, premature rupture of membranes, chorioamnionitis, placental abruption, fetal distress or in cases of a suspected uterine dehiscence or rupture by ultrasound examination with uterine scar thickness below 2 mm. During postoperative follow-up, patients were advised to remain at home for up to 30 weeks with access to specialists in maternal-fetal medicine. Corticosteroids were prescribed for pulmonary maturity and patients were allowed, if they wished, to return to their homes for prenatal care and This article is protected by copyright. All rights reserved. Accepted Article delivery. When the delivery was necessary before 32 weeks, the patients were enrolled in a neuroprotection protocol with magnesium sulfate given at least four hours before the cesarean section. On the day of delivery, laboratory tests of the institutional postpartum hemorrhage protocol were requested. The patients were submitted to intradural anesthesia and the cesarean section was performed through the same skin surgical scar of the fetal surgery. In all procedures, the obstetric team was supplemented with a pediatric neurosurgeon to analyze clinical conditions of the newborn as well as assess the surgical scar in the lumbar region. During the cesarean section, due care was taken during fetal extraction to prevent lumbar scar damage. After removal of the placenta, a detailed evaluation of the conditions of the uterine scar was performed and sutures were performed with separate stitches of Vicryl 0 and the closure of the cesarean section was performed in a habitual manner. The criteria for providing a blood transfusion at the time of delivery followed the institutional protocol considering the volume of blood loss, maternal hemodynamic conditions and the weight of the surgical sponges. The data on maternal and fetal characteristics, fetal surgery and delivery conditions and perinatal outcome were collected prospectively and transferred to an Excel spread sheet (Microsoft Corp., Redmond, WA, USA) and analyzed using PASW program (version 18.0, SPSS Inc., Chicago, IL, USA). Continuous variables were reported as mean ± SD and categorical variables as n (%). Maternal and fetal characteristics data as parity, fetal gender, predominant placental location, lesion level, type of lesion was presented as percentage, while maternal age and schooling (years) were presented as mean ± standard deviation (SD). The surgical and perinatal characteristics as gestational age at surgery, total operative time, interval between surgery and delivery, gestational age at delivery and birthweight were presented as mean ± SD. While maternal pulmonary edema in the perioperative This article is protected by copyright. All rights reserved. Accepted Article period, preterm labor, premature rupture of membrane (PPROM), chorioamniotic membrane separation, chorioamnionitis, oligohydramnios, abruptio placentae, uterine scar dehiscence, blood transfusion at delivery, perinatal death, reversal hindbrain herniation at birth, blood transfusion at delivery, dehiscence of repair site, reversal hindbrain herniation at birth and perinatal mortality were presented as percentage. To compare our perinatal results from the first 3 years (Group 1) with those from the last 3 years (Group 2), we used Mann-Whitney and chi-square (χ2) tests. We used a level of significance (p) <0.05. Results During the study period 319 pregnant women with a sonographic diagnosis of MMC were screened for the possibility of fetal surgery. After a multidisciplinary evaluation using a similar protocol to the MOMS trial with minor modifications and performed parental counselling 82 (25.7%) were not included in this study due to one the following reasons: gestational age > 27 weeks (23), fetal surgery was not authorized by health managers for different reasons (17), maternal diseases such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus, positive serology for acquired immunodeficiency virus, BMI ≥ 40 kg/m2 (16), increased risk of preterm delivery or hemorrhage (12), fetal kyphosis or other associated malformation (10) and psychosocial issues (4). Two hundred and thirty-seven consecutive fetal surgeries were performed, and no maternal death or severe maternal morbidity was observed among these women. The perinatal loss rate was 2.1% (three were intrauterine demises - one in the immediate postoperative period because of abruptio placentae; another on postoperative day 29 because of umbilical cord constrictions after chorioamniotic membrane separation and another on postoperative day 58 after premature rupture of membrane and severe oligohydramnios). One fetal surgery could not be performed due to abruptio placentae as soon as the uterus was displaced out of the abdominal cavity. In this case a longitudinal cesarean section was performed, a liveborn 830-gram baby was delivered and was sent This article is protected by copyright. All rights reserved. Accepted Article to the neonatal intensive care unit. The baby underwent postnatal MMC repair three days later after their vital conditions had been stabilized. Thus, the rate of failure to perform the procedure with the patient anesthetized in the surgical room was 0.42% (1 in 237 surgeries). Table 1 details the relevant maternal and fetal characteristics of our cohort. The mean ± SD maternal age was 30.9 +/- 4.5 years and years education were 14.4 ± 1.7. The percentage of nulliparas (57.2%) was higher than multiparas (42.8%), and 54.2% of the fetuses were male. Placenta location was more frequently in the anterior uterine wall (56.4%). The types of spinal defect were MMC (74.6%) and myeloschisis (25.4%). The spinal dysraphism located at L3 / L4 (69.5%) was most frequent followed by L5 / S1 (24.6%) and L1 / L2 (5.5%). In one patient the upper level of the lesion was located at T11 / T12 representing only 0.4% of our cohort. Table 2 presents the surgical and perinatal outcomes of our cohort. The mean ± SD gestational age at surgery was 25.2 +/- 0.4 weeks, gestational age at birth was 33.6 +/- 2.4 weeks, skin-to-skin surgery time was 119.7 +/- 7.6 minutes, time between fetal surgery and delivery was 52.1 +/- 16.7 days and neonatal birthweight was 2186 +/- 506 grams. Delivery at < 30 weeks occurred in 6.8% of subjects and 47.9% delivered at > 35 weeks. Chorioamniotic membrane separation was detected by postoperative ultrasonography in 20.8% of cases. Premature rupture of membranes occurred in 26.7% and was related to seven cases of chorioamnionitis (3%). Oligohydramnios was present in 23.3%. and abruptio placentae was diagnosed in two women during fetal surgery and was responsible for one fetal demise and one case of failure to perform fetal surgery. Preterm labor occurred in 24.2% and was associated with all cases of uterine scar dehiscence. Five women required blood transfusion at delivery and was associated with uterine atony (3) and uterine rupture (2). Superficial dehiscence of the fetal repair was diagnosed in 2.5% of neonates and required dressing changes during the neonatal period. Hindbrain herniation was reversed in 71.1%. according to This article is protected by copyright. All rights reserved. Accepted Article prenatal ultrasound follow-up and confirmed by neonatal ultrasound and /or magnetic resonance image. Table 3 presents the comparative surgical and perinatal outcomes between Group 1 (first 3 years, 104 patients) and Group 2 (last 3 years, 132 patients) of this study. There was a significant decrease in the total surgical time (121.2 ± 6.4 min vs 118.5 ± 8.2 min, p= 0.005), incidence of oligohydramnios (31.7% vs 16.7%, p=0.010) and increased reversal hindbrain herniation at birth (64.0% vs 77.1%, p= 0.042) in the second group. Other variables showing an improvement in perinatal outcome but that did not reach statistical significance were pulmonary edema (3.8% vs 1.5%), gestational age at birth (33.4 ± 2.6 weeks vs 33.7 ± 2.2 weeks) gestational age at birth below 30 weeks (8.7% vs 5.3%), interval between surgery and delivery (51.6 ±17.9 days vs 52.5 ± 16.5 days), birthweight (2,173 ± 533 g vs 2,195 ± 486 g), preterm labor (27.9% vs 21.2%), PROM (32.7% vs 22.0%), chorioamniotic membrane separation (26.0% vs 16.7%), chorioamnionitis (5,8% vs 0.8%,), abruptio placentae (1.0% vs 0.8%), uterine scar dehiscence (4.8% vs 3.0%), dehiscence at repair site (2.9% vs 2.3%), perinatal mortality (3.8% vs 0.8%). There was no need for hysterectomy after delivery in the two groups analyzed. Discussion Main Findings Our study comprising the largest number of subjects undergoing open fetal surgery for MMC repair validated prior reports on the value of this surgical approach compared to post-delivery intervention. 8, 11, 12 There was more than 70% reversal of hindbrain herniation while surgical failure and perinatal mortality rates were extremely low and there were no maternal deaths or severe maternal morbidities. Also, in agreement with earlier investigations, open fetal surgery was followed by preterm premature rupture of membranes in almost 27% of our subjects and 24% This article is protected by copyright. All rights reserved. Accepted Article experienced preterm labor. The prevalence of placental abruption was only 0.8%. As our surgical team became more experienced in the protocol outcome parameters improved over time. Strengths and Limitations This study summarizes findings of the largest case series of women who underwent open fetal surgery for MMC. The surgery was performed by an integrated multidisciplinary team (including anesthesiologist, obstetrician, specialist in fetal medicine, pediatric neurosurgeon, intensivist and neonatologist) in two specialized hospital centers.10 All surgeries were performed by the same team, followed the same protocol, with postoperative follow-up and delivery performed by professionals directly involved in fetal surgery program. Surgical outcomes and associated clinical variables were similar to prior results on smaller studies. This validates the reliability and reproducibility of the reported parameters and can serve as predictors of what can be expected in subsequent investigations. It also validates that an alternative protocol to the use of stapler for wound closure does not reduce outcome parameters. A limitation of open fetal surgery, as identified in the present and prior studies, is the subsequent high rate of preterm premature rupture of membranes and preterm labor. Further investigations are needed to pinpoint the variables associated with these events, identify which women are most susceptible to their occurrence and to develop more individualized protocols to reduce their prevalence. Interpretations The demographic data, surgical and perinatal outcomes of our study were similar to results reported in the MOMS study. The average maternal age, schooling, placental location, and fetal gender distribution were similar. The average gestational age at surgery in our cohort was higher than in the MOMS trial (25.2 vs 24.2 weeks). The decision to establish the period between 24 and 27 weeks to perform fetal surgery was due to prenatal care conditions in our country, where the diagnosis of fetal anomalies is usually performed between 20 and 24 weeks of gestation and the patients are referred late to the reference centers in maternal-fetal medicine. Average surgical time was This article is protected by copyright. All rights reserved. Accepted Article increased in our study compared to MOMS probably due to our inability to use staplers in our country and the need to perform the suture along the uterine incision to prevent hemorrhage and membrane displacement. However, the results were comparable in terms of pulmonary edema, gestational age at birth and perinatal mortality. The obstetrical postoperative management of the MOMS trial had more deliveries occurring later than 37 weeks (21.0% vs 13.1%) and higher mean birth weight (2,383 ± 688 g vs. 2,186 ± 506 g). However, the MOMS study had increased risk for preterm labor (38.0% vs. 24.2%), premature rupture of membrane (46.0% vs. 26.7%), abruptio placentae (6.0% vs. 0.8%), uterine scar dehiscence (10.5% vs. 3.8%), blood transfusion at delivery (9.0% vs. 2.1%) and dehiscence at repair site (13.0% vs. 2.5%). The reversal hindbrain herniation at birth was significantly higher in our study (71.4% vs 36.0%) probably because of the experience gained over the time that was clearly demonstrated comparing outcomes according to the first and last 3 years of the cohort. There was a significant improvement in the total surgical time and reversal hindbrain herniation at birth, showing the importance of the learning curve of the medical and hospital staff. Conclusion The surgical approach with minor modifications showed similar results compared to the MOMS trial. There were improvements in surgical performance and perinatal outcome as the multidisciplinary team became more familiar and confident with the procedure. However, women should be advised of the risks of this procedure, mainly risk of preterm premature rupture of membranes, preterm labor and future obstetrical limitations. Conflicts of interest None of the authors has any conflict of interest. Completed disclosure of interest forms are available to view online as supporting information. This article is protected by copyright. All rights reserved. Accepted Article Participation in the study AFM designed the study, analyzed the data and wrote the first draft and corrected the final version of the manuscript, MMB, HJFM, SGS, EFMS, ICS, PAD contributed to the analysis of the data and collaborated in the editing of the manuscript; SC contributed to the analysis of the data and corrected the final version of the manuscript of the study. All participants were members of the surgical team. Ethics approval The study was approved by the institutional review boards of Hospital São Paulo – Escola Paulista de Medicina/Federal University of São Paulo-UNIFESP and Hospital e Maternidade Santa Joana (April 27, 2016, Reference: CEP 0598) and all subjects signed written informed consent. Funding None Acknowledgements The authors thank Katia Regina de Carvalho and Nelma Bastos Bezerra Rego for updating and organizing the database. Marcos Maeda provided the statistical analysis. This article is protected by copyright. All rights reserved. Accepted Article References 1. Parker SE, Mai CT, Canfield MA, Rickard R, Wang Y, Meyer RE, et al. Updated national birth prevalence estimates for selected birth defects in the United States, 2004–2006. National Birth Defects Prevention Network. Birth Defects Res A Clin Mol Teratol 2010;88:1008–16. 2. Rintoul NE, Sutton LN, Hubbard AM, Cohen B, Melchionni J, Pasquariello PS, et al. A new look at myelomeningoceles: functional level, vertebral level, shunting, and the implications for fetal intervention. Pediatrics 2002;109:409-13. 3. Worley G, Schuster JM, Oakes WJ. Survival at 5 years of a cohort of newborn infants with myelomeningocele. Dev Med Child Neurol 1996;38:816e22. 4. Tennant PW, Pearce MS, Bythell M, Rankin J. 20-year survival of children born with congenital anomalies: a population-based study. Lancet 2010;375(9715):649-56. 5. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina bifida. Lancet 1998;352:1675–1676. 6. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF, Silva SR, et al. Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999; 282:1819–1825. 7. Farmer DL, von Koch CS, Peacock WJ, Danielpour M, Gupta N, Lee H, et al. In utero repair of myelomeningocele: experimental pathophysiology, initial clinical experience, and outcomes. Arch Surg 2003;138:872–878. 8. Adzick NS, Thom EA, Spong CY, Brock JW 3rd, Burrows PK, Johnson MP, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011 Mar 17; 364(11):993-1004. 9. Committee Opinion No. 720: Maternal-Fetal Surgery for Myelomeningocele. Committee on Obstetric Practice, Society for Maternal–Fetal Medicine. Obstet Gynecol 2017 Sep;130(3):e164-e167. 10. Cohen AR, Couto J, Cummings JJ, Johnson A, Joseph G, Kaufman BA, et al. MMC MaternalFetal Management Task Force: Position statement on fetal myelomeningocele repair. Am J Obstet Gynecol 2014; 210: 107–111. 11. Bennett KA, Carroll MA, Shannon CN, Braun SA, Dabrowiak MK, Crum AK, et al. Reducing perinatal complications and preterm delivery for patients undergoing in utero closure of fetal myelomeningocele: further modifications to the multidisciplinary surgical technique. J Neurosurg Pediatr 2014;14:108e14. This article is protected by copyright. All rights reserved. Accepted Article 12. Moldenhauer JS, Soni S, Rintoul NE, Spinner SS, Khalek N, Martinez-Poyer J, et al. Fetal myelomeningocele repair: the post-MOMS experience at the Children’s Hospital of Philadelphia. Fetal Diagn Ther 2015;37:235–40. 13. Hisaba WJ, Cavalheiro S, Almodim CG, Borges CP, de Faria TC, Araujo Júnior E, et al. Intrauterine myelomeningocele repair postnatal results and follow-up at 3.5 years of age-initial experience from a single reference service in Brazil. Childs Nerv Syst 2012 Mar; 28(3):461-7. 14. Moron AF, Barbosa M, Milani H, Hisaba W, Carvalho N, Cavalheiro S. 771: Short-term surgical and clinical outcomes with a novel method for open fetal surgery of myelomeningocele. Am J Obstet Gynecol 212: S374, 2015. 15. Cavalheiro S, da Costa MDS, Mendonça JN, Dastoli PA, Suriano IC, Barbosa MM, et al. Antenatal management of fetal neurosurgical diseases. Childs Nerv Syst 2017 Jul;33(7):11251141. 16. Santana EF, Moron AF, Barbosa MM, Milani HJ, Sarmento SG, Araújo E, et al. Fetal Heart rate monitoring during intrauterine open surgery for myelomeningocele repair. Fetal Diagn Ther.2016;39(3):172-8. 17. Carvalho NS, Moron AF, Menon R, Cavalheiro S, Barbosa MM, Milani HJ, et al. Histological evidence of reparative activity in chorioamniotic membrane following open fetal surgery for myelomeningocele. Exp Ther Med 2017 Oct;14(4):3732-3736. 18. Moldenhauer JS, Adzick NS. Fetal surgery for myelomeningocele: After the Management of Myelomeningocele Study (MOMS). Semin Fetal Neonatal Med 2017 Dec;22(6):360-366. Figure Legend Figure 1. The uterus was wrapped using a sterile plastic cover, leaving only the region of the hysterotomy exposed to perform the neurosurgery. This article is protected by copyright. All rights reserved. Accepted Article Table 1. Maternal and fetal characteristics of our cohort. Variable Maternal age, years 30.9 ± 4.5 Schooling, years 14.4 ± 1.7 Parity (%) Nulliparous 57.2 Multiparous 42.8 Fetal gender (%) Female 45.3 Male 54.7 Predominant placental location (%) Anterior 56.4 Posterior 43.6 Type of lesion (%) Myeloschisis 25.4 Myelomeningocele 74.6 Lesion level (%) T11/T12 0.4 L1/L2 5.5 L3/L4 69.5 L5/S1 24.6 This article is protected by copyright. All rights reserved. Accepted Article Table 2. Perinatal and surgical outcomes of our cohort. Variable Total operative time (min) 119.7 ± 7.6 Pulmonary edema (%) 2.5 Gestational age at birth (weeks) 33.6 ± 2.4 < 30 weeks (%) 6.8 30-34 weeks (%) 45.3 35-36 weeks (%) 34.7 ≥ 37 weeks (%) 13.1 Birthweight (grams) 2,186 ± 506 Preterm labor (%) 24.2 PPROM (%) 26.7 Chorioamniotic membrane separation (%) 20.8 Chorioamnionitis (%) 3.0 Oligohydramnios (%) 23.3 Abruptio placentae (%) 0.8 Uterine scar dehiscence (%) 3.8 Blood transfusion at delivery (%) 2.1 Dehiscence at repair site (%) 2.5 Reversal hindbrain herniation at birth (%) 71.4 Perinatal mortality (%) 2.1 Surgical outcomes on 236 subjects are reported. This article is protected by copyright. All rights reserved. Accepted Article Table 3. Comparative perinatal outcomes between Group 1 (first 3 years) and Group 2 (last 3 years) of this study. Group 1 Group 2 104 132 Total operative time (min) 121.2 ± 6.4 118.5±8.2 0.005* Pulmonary edema (%) 3.8 1.5 0.476 Gestational age at birth (weeks) 33.4 ± 2.6 33.7 ± 2,2 0.723 < 30 weeks (%) 8.7 5.3 0.321 30-34 weeks (%) 44.2 46.2 0.721 35-36 weeks (%) 34.6 34.8 0.970 ≥ 37 weeks (%) 12.5 13.6 0.797 Interval between surgery/delivery (days) 51.6 ± 17.9 52.5 ± 16.5 0.962 Birthweight (grams) 2,173 ± 533 2,195 ± 486 0.931 Preterm labor (%) 27.9 21.2 0.30 PPROM (%) 32.7 22.0 0.089 Chorioamniotic membrane separation (%) 26.0 16.7 0.113 Chorioamnionitis (%) 5.8 0.8 0.062 Oligohydramnios (%) 31.7 16.7 0.010* Abruptio placentae (%) 1.0 0.8 1.000 Uterine scar dehiscence (%) 4.8 3.0 0.715 Blood transfusion at delivery (%) 1.9 2.3 1.000 Dehiscence at repair site (%) 2.9 2.3 1.000 Reversal hindbrain herniation at birth (%) 64.0 77.1 0.042* Perinatal mortality (%) 3.8 0.8 0.238 This article is protected by copyright. All rights reserved. p Accepted Article This article is protected by copyright. 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