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Objective: The Management of Myelomeningocele Study (MOMS) trial demonstrated the safety and efficacy of open fetal surgery for spina bifida aperta (SBA). Recently developed alternative techniques may reduce maternal risks without compromising the fetal neuroprotective effects. The aim of this systematic review was to assess the learning curve (LC) of different fetal SBA closure techniques., Methods: MEDLINE, Web of Science, EMBASE, Scopus and Cochrane databases and the gray literature were searched to identify relevant articles on fetal surgery for SBA, without language restriction, published between January 1980 and October 2018. Identified studies were reviewed systematically and those reporting all consecutive procedures and with postnatal follow-up ≥ 12 months were selected. Studies were included only if they reported outcome variables necessary to measure the LC, as defined by fetal safety and efficacy. Two authors independently retrieved data, assessed the quality of the studies and categorized observations into blocks of 30 patients. For meta-analysis, data were pooled using a random-effects model when heterogeneous. To measure the LC, we used two complementary methods. In the group-splitting method, competency was defined when the procedure provided results comparable to those in the MOMS trial for 12 outcome variables representing the immediate surgical outcome, short-term neonatal neuroprotection and long-term neuroprotection at ≥ 12 months of age. Then, when raw patient data were available, we performed cumulative sum analysis based on a composite binary outcome defining successful surgery. The composite outcome combined four clinically relevant variables for safety (absence of extreme preterm delivery < 30 weeks, absence of fetal death ≤ 7 days after surgery) and efficacy (reversal of hindbrain herniation and absence of any neonatal treatment of dehiscence or cerebrospinal fluid leakage at the closure site)., Results: Of 6024 search results, 17 (0.3%) studies were included, all of which had low, moderate or unclear risk of bias. Fetal SBA closure was performed using standard hysterotomy (11 studies), mini-hysterotomy (one study) or fetoscopy by either exteriorized-uterus single-layer closure (one study), percutaneous single-layer closure (three studies) or percutaneous two-layer closure (one study). Only outcomes for standard hysterotomy could be meta-analyzed. Overall, outcomes improved significantly with experience. Competency was reached after 35 consecutive cases for standard hysterotomy and was predicted to be achieved after ≥ 57 cases for mini-hysterotomy and ≥ 56 for percutaneous two-layer fetoscopy. For percutaneous and exteriorized-uterus single-layer fetoscopy, competency was not reached in the 81 and 28 cases available for analysis, respectively, and LC prediction analysis could not be performed., Conclusions: The number of cases operated is correlated with the outcome of fetal SBA closure, and the number of operated cases required to reach competency ranges from 35 for standard hysterotomy to ≥ 56-57 for minimally invasive modifications. Our observations provide important information for institutions looking to establish a new fetal center, develop a new fetal surgery technique or train their team, and inform referring clinicians, potential patients and third parties. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: Fetoscopic laser surgery for twin-twin transfusion syndrome is a procedure for which no objective tools exist to assess technical skills. To ensure that future fetal surgeons reach competence prior to performing the procedure unsupervised, we developed a performance assessment tool. The aim of this study was to validate this assessment tool for reliability and construct validity., Methods: We made use of a procedure-specific evaluation instrument containing all essential steps of the fetoscopic laser procedure, which was previously created using Delphi methodology. Eleven experts and 13 novices from three fetal medicine centers performed the procedure on the same simulator. Two independent observers assessed each surgery using the instrument (maximum score: 52). Interobserver reliability was assessed using Spearman correlation. We compared the performance of novices and experts to assess construct validity., Results: The interobserver reliability was high (Rs  = 0.974, P < 0.001). Checklist scores for experts and novices were significantly different; the median score for novices was 28/52 (54%), whereas that for experts was 47.5/52 (91%) (P < 0.001). The procedure time and fetoscopy time were significantly shorter (P < 0.001) for experts. Residual anastomoses were found in 1/11 (9%) procedures performed by experts and in 9/13 (69%) procedures performed by novices (P = 0.005). Multivariable analysis showed that the checklist score, independent of age and gender, predicted competence., Conclusions: The procedure-specific assessment tool for fetoscopic laser surgery shows good interobserver reliability and discriminates experts from novices. This instrument may therefore be a useful tool in the training curriculum for fetal surgeons. Further intervention studies with reassessment before and after training may increase the construct validity of the tool. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the effect of a newly developed training curriculum on the performance of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS) using an advanced high-fidelity simulator model., Methods: Ten novices were randomized to receive verbal instructions and either skills training using the simulator (study group; n = 5) or no training (control group; n = 5). Both groups were evaluated with a pre-training and post-training test on the simulator. Performance was assessed by two independent observers and comprised a 52-item checklist for surgical performance (SP) score, measurement of procedure time and number of anastomoses missed. Eleven experts set the benchmark level of performance. Face validity and educational value of the simulator were assessed using a questionnaire., Results: Both groups showed an improvement in SP score at the post-training test compared with the pre-training test. The simulator-trained group significantly outperformed the control group, with a median SP score of 28 (54%) in the pre-test and 46 (88%) in the post-test vs 25 (48%) and 36 (69%), respectively (P = 0.008). Procedure time decreased by 11 min (from 44 to 33 min) in the study group vs 1 min (from 39 to 38 min) in the control group (P = 0.69). There was no significant difference in the number of missed anastomoses at the post-training test between the two groups (1 vs 0). Subsequent feedback provided by the participants indicated that training on the simulator was perceived as a useful educational activity., Conclusions: Proficiency-based simulator training improves performance, indicated by SP score, for fetoscopic laser therapy. Despite the small sample size of this study, practice on a simulator is recommended before trainees carry out laser therapy for TTTS in pregnant women., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To determine, by expert consensus, the essential substeps of fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) that could be used to create an authority-based curriculum for training in this procedure among fetal medicine specialists., Methods: A Delphi survey was conducted among an international panel of experts (n = 98) in FLS. Experts rated the substeps of FLS on a five-point Likert-type scale to indicate whether they considered them to be essential, and were able to comment on each substep, using a dedicated online platform accessed by the invited tertiary care facilities that specialize in fetal therapy. Responses were returned to the panel until consensus was reached (Cronbach's α ≥ 0.80). All substeps that were rated  ≥ 4 by 80% of the experts were included in the evaluation instrument., Results: After the first iteration of the Delphi procedure, a response rate of 74% (73/98) was reached, and in the second and third iterations response rates of 90% (66/73) and 81% (59/73) were reached, respectively. Among a total of 81 substeps rated in the first round, 21 substeps had to be re-rated in the second round. Finally, from the initial list of substeps, 55 were agreed by experts to be essential. In the third round, the 18 categorized substeps were ranked in order of importance, with 'coagulation of all anastomoses that cross the equator' and 'determination of fetoscope insertion site' as the most important., Conclusions: A total of 55 substeps of FLS for TTTS were defined by a panel of experts to be essential in the procedure. This list is the first authority-based evidence to be used in the development of a final training model for future fetal surgeons., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To investigate the efficacy of collagen plugs at reducing the risk of preterm premature rupture of membranes (PPROM) after fetoscopic surgery for congenital diaphragmatic hernia (CDH)., Methods: This was a single-center cohort study on all consecutive cases undergoing fetoscopic endoluminal tracheal occlusion (FETO) for severe or moderate CDH, between April 2002 and May 2011 (n = 141). Cases either received a collagen plug for sealing the fetal membrane defect after FETO or did not, depending on the operating surgeon. The principal outcome measure was the time from fetal surgery to PPROM, further referred to as 'latency'. A multivariable Cox regression model was used to investigate the association between collagen plug and latency while adjusting for risk factors for PPROM., Results: Of the 141 cases, 54 (38%) received a collagen plug and 87 (62%) did not. Sixty cases experienced PPROM, 26 among cases with and 34 among cases without a plug (48 vs 39%). The hazard ratio of plug use was 1.29 (95% CI, 0.76-2.19), which does not exclude a potentially increased risk for PPROM when a collagen plug is used. For cases with a plug, 24% had PPROM before balloon removal and 24% had PPROM after elective balloon removal. For cases without a plug, these rates were 30 and 9%, respectively. Perinatal outcomes were similar in both groups., Conclusions: No evidence was found that collagen plugs reduce the risk of PPROM after FETO for CDH., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: Fetuses with congenital diaphragmatic hernia (CDH) and for whom additional ultrasound findings are abnormal typically are considered to have a dismal prognosis. Our aim was to assess the outcome of fetuses with CDH and associated intrafetal fluid effusions., Methods: This was a retrospective bicentric cohort study on the perinatal management of fetuses with CDH and intrafetal fluid effusions., Results: The incidence of effusions was 5.2% (n = 14) in 269 consecutive cases of left-sided CDH and 29.2% (n = 14) in 48 cases of right-sided CDH. Hydrothorax (n = 19 (68%)) and ascites (n = 16 (57%)) were the most common effusions. A combination of both was present in 11 (39%) fetuses. Of 20 ongoing pregnancies with CDH and fluid effusions, without other anomalies, five with moderate or mild pulmonary hypoplasia were managed without fetoscopic endoluminal tracheal occlusion (FETO). The 15 other cases underwent FETO because of severe pulmonary hypoplasia. Neonatal survival rate was similar in both groups (n = 2/5 and n = 6/15, respectively (P = 1.0)). Survival among those who underwent FETO was similar to previously published results concerning isolated cases undergoing FETO., Conclusions: Our observations do not support the view that intrafetal effusions are an adverse prognostic factor in fetuses with CDH. In CDH fetuses with effusions and severe pulmonary hypoplasia treated with FETO, neonatal survival is similar to that in isolated cases undergoing the intervention. Whether pleural effusions should be addressed by thoracic drainage procedures remains unproven., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: To predict neonatal survival and pulmonary hypertension by measurement of fetal pulmonary artery reactivity to maternal hyperoxygenation in fetuses with severe congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion (FETO)., Methods: Thirty-eight fetuses underwent FETO at around 28 weeks' gestation and the balloon was removed at 34 weeks in most cases. We performed a hyperoxygenation test and measured the lung-to-head ratio of each fetus before and after each procedure. Outcome measures were neonatal survival, occurrence of pulmonary hypertension and its response to inhaled nitric oxide (iNO)., Results: Fetuses that survived had a larger increase in lung size and decrease of resistance in the first branch of the main pulmonary artery than did those that died. Both measures were also predictive of pulmonary hypertension unresponsive to iNO. The hyperoxygenation test and lung-to-head ratio were both best predictive for neonatal survival when measured following removal of the balloon (P < 0.002). Discriminant analysis confirmed that these two parameters are independent predictors of outcome., Conclusions: In fetuses undergoing FETO, pulmonary vascular reactivity in relation to oxygen and lung size are independent predictors of neonatal survival and pulmonary hypertension. The hyperoxygenation test merits further study in expectantly managed cases., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Congenital diaphragmatic hernia (CDH) affects one in 2500 to 5000 births and can be detected in utero by means of ultrasound screening Associated structural problems aggravate the prognosis. The survival rate is 70% or more for cases managed in tertiary care centers. The commonest causes of neonatal death in this setting are pulmonary hypoplasia and pulmonary hypertension. Prenatal imaging findings can now accurately predict postnatal outcome, based mainly on ultrasound determination of the lung-to-head ratio and liver position. This information can be used to counsel patients. In severe cases, prenatal intervention can reverse pulmonary hypoplasia. We review current data on prenatal prediction of neonatal survival. We also discuss experimental and clinical data on the benefits of fetal tracheal occlusion. The TOTAL trial (Tracheal Occlusion To Accelerate Lung growth) is currently ongoing in Europe.

Objective: To evaluate the impact of fetoscopic laser coagulation of placental anastomoses in severe twin-twin transfusion syndrome on fetal Doppler indices and umbilical vein blood flow volume as calculated with Doppler and two-dimensional ultrasound., Methods: Thirty-two cases of second-trimester severe twin-twin transfusion undergoing laser therapy were examined with serial ultrasound before and 1, 3 and 5 days after therapy. Pulsatility indices in the umbilical artery and ductus venosus were measured. Blood volume flow at the level of the intra-abdominal umbilical vein was calculated by means of Doppler and two-dimensional ultrasound. The development of hydropic signs in donors was recorded. Perinatal outcome in terms of neonatal survival was recorded for all cases., Results: In recipients, ductus venosus pulsatility index decreased progressively after therapy and, by day 5, median pulsatility index was significantly lower than that before therapy (0.97 vs. 0.82, P < 0.0001). Umbilical vein blood flow volume in recipient twins showed no significant variations before and after laser. In donors, umbilical artery pulsatility index decreased significantly by the first day following therapy (2.1 vs. 1.6, P < 0.0001). Previously absent or reverse umbilical end-diastolic flow reappeared after therapy in 46% (7/15) of donors. Ductus venosus pulsatility index in donors increased significantly by day 1 after therapy (0.99 vs. 1.35, P < 0.0001) but, over days 3 and 5, it returned towards preoperative values. Umbilical vein flow volume measurements (mL/min/kg) in the donor increased by approximately 50% the day after treatment (151 vs. 232, P < 0.0001) and remained elevated. Umbilical vein flow volume before laser therapy was significantly lower in donors compared to recipients (151 vs. 260, P < 0.0001), but the difference was non-significant after treatment (240 vs. 267). One or more hydropic signs developed in eight (25%) donors during the 5 days' observation after therapy., Conclusions: Laser therapy induced important changes in fetal hemodynamic parameters, resulting in a reversion of the disturbances associated with severe twin-twin transfusion syndrome. The recipient twin showed a progressive improvement of previous signs of right cardiac overload. The donor experienced a substantial increase in umbilical vein blood volume flow accompanied by a transitory state of relative right overload, which may explain the development of transient hydropic signs in a proportion of donors.

Objective: To evaluate the incidence, characteristics, and impact on perinatal outcome of the development of hydropic signs in the donor fetus after laser coagulation for severe twin-twin transfusion syndrome in the second trimester., Methods: Forty cases of second-trimester severe twin-twin transfusion underwent fetoscopic laser coagulation of placental anastomoses and were followed up with serial ultrasound up to 14 days after therapy. Ultrasound scans were performed just before, and on days 1, 3, 5 and 14 after therapy, and fetuses were monitored for the presence of hydropic signs (skin edema, pleural effusion, ascites and pericardial effusion). Response to therapy and perinatal outcome in terms of neonatal survival were recorded for all cases., Results: Four recipients (10%) and three donors (7.5%) died over the first 72 h after therapy. During the study period, two recipients (5.5%) developed frank hydrops fetalis, and eventually died in utero. Ten donors (27.0%) developed one or more hydropic signs. In nine (90%), signs were mild or moderate and transient (mean, 3.2 days), while in one case hydrops worsened and the fetus eventually died. No donors with transient hydrops died in utero, and two died postnatally due to extreme prematurity. Gestational age at procedure and deepest amniotic fluid vertical pocket were similar between hydropic and non-hydropic donors. Discrepancy in estimated fetal weight at procedure was significantly lower in donors developing hydrops (9.6 (SD, 6.4) vs. 17.8 (14.4)%,P = 0.018). In pregnancies with hydropic donors, gestational age at delivery (33.1 (3.4) vs. 29.7 (3.5) weeks,P = 0.015) and birth weight for recipient (2392 (423) vs. 1631 (576) g, P < 0.001) and donor (1908 (774) vs. 1281 (583) g,P = 0.021) were significantly higher. The development of transient hydrops had no influence on neonatal survival at 28 days nor on the rate of clinical resolution of intertwin transfusion., Conclusions: Transient hydropic signs may develop in a proportion of donor fetuses after laser coagulation for severe twin-twin transfusion syndrome. This phenomenon is normally not associated with a poor prognosis, and possibly indicates an hemodynamic adaptation response following interruption of the transfusion process.

The cellular mechanisms underlying fetal membrane repair are poorly understood. Matrix metalloproteinases (MMP) and the endogenous tissue inhibitors of metalloproteinases (TIMP) play a key role in the control of turnover of extracellular matrix in fetal membranes at normal parturition and preterm prelabour rupture of the fetal membranes (PPROM). The time course of secretion of MMP-2 (72 kDa, gelatinase A) and MMP-9 (92 kDa, gelatinase B) and TIMP into extra-embryonic coelomic, allantoic and amniotic fluids in a rabbit model was examined. Furthermore, to evaluate their role in fetal membrane repair, the changes induced by fetoscopy at mid-gestation (23 days; gestation length is 32 days) were investigated. Zymography showed predominantly secretion of latent MMP-2 at 18, 23 and 30 days of gestation in all gestational compartments. Reverse zymography detected a broad range of TIMP activity with molecular weights of 27-30 kDa (TIMP-1, glycosylated TIMP-3 and TIMP-4), 24 kDa (unglycosylated TIMP-3) and 21 kDa (TIMP-2). Following fetoscopy, both MMP-2 and TIMP increased significantly in amniotic fluid and extra-embryonic coelomic fluid, but not in allantoic fluid, as demonstrated by densitometric analyses. These findings indicate a modulating role for MMP and TIMP in the repair processes following a surgically induced fetal membrane defect.

ABSTRACTObjectiveTo establish by Doppler ultrasound the effects of acute blockage of umbilical cord vessels on the fetal central circulation. DesignExperimental study in anesthetized pregnant sheep. MethodsIn 11 anesthetized pregnant sheep (0.66 of gestation), Doppler velocity profiles and/or venous flow rates were recorded in the ductus venosus, the fetal aorta, the umbilical arteries and the umbilical vein. This involved three phases. In Phase 1, the abdominal wall was closed (n = 9); Phase 2 was during fetoscopy after laparotomy (n = 8); Phase 3 was after coagulation of one of the umbilical arteries (n = 10). As an additional intervention in six fetuses, the umbilical cord was clamped for 5–15 s while blood flow velocity changes in the ductus venosus were observed. ResultsThere were no significant differences between Doppler recordings in Phases 1 and 2. During Phase 3, the pulsatiltiy index of the aorta and of the coagulated umbilical artery increased significantly. The umbilical vein blood flow rate was significantly reduced from a median of 408 (range, 243–575) mL/min/kg in Phase 1 to a median of 173 (range, 107–426) mL/min/kg in Phase 3, but the blood flow rate in the ductus venosus (median, 94; range, 56–148 mL/min/kg vs. median, 92; range, 33–237 mL/min/kg) remained unchanged. The ductus venosus/umbilical vein ratio increased from a median of 0.22 (range, 0.13–0.41) to 0.56 (range, 0.17–0.97) (P < 0.05). Compression of the cord (5–15 s) immediately reduced the time averaged maximum velocity in the ductus venosus from a mean of 51 (standard deviation, 11) cm/s to 20 (standard deviation, 6) cm/s (P < 0.001) without significant changes of the velocity profile. However, the pulsatiltiy index increased from a mean of 0.55 (standard deviation, 0.19) to 1.89 (standard deviation, 0.73) (P < 0.001). ConclusionCentral venous flows in anesthetized fetal sheep are unaffected by laparotomy and hysterotomy. Obliteration of one umbilical artery increases the ductus venosus/umbilical vein volume flow (mL/min/kg) ratio. Compression of the umbilical cord shifts down blood flow velocity profiles in the ductus venosus, and the pulsatiltiy index thus increases. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Rate of amniorrhexis is not affected by fetoscopic access cannula diameter" by S. Petersen and colleagues is presented.

An abstract of the conference paper "Outcomes of different anesthetic techniques in fetoscopic laser treatment for TTTS," by F. Debuck and colleagues is presented.