Effect of cannula insertion site during fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia on preterm prelabor rupture of membranes.

OBJECTIVE: To assess whether the cannula insertion site on the maternal abdomen during fetal endoscopic tracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) was associated with preterm prelabor rupture of membranes (PPROM) before balloon removal. METHODS: This was a multicenter retrospective study of consecutive pregnancies with isolated left- or right-sided CDH that underwent FETO in four centers between January 2009 and January 2021. The site for balloon insertion was categorized as above or below the umbilicus. One propensity score was analyzed in both groups to calculate an average treatment effect (ATE) by inverse probability of treatment weighting. Logistic regression and Cox proportional hazard regression including the ATE weights were performed to examine the effect size of entry point on the frequency and timing of PPROM before balloon removal. RESULTS: A total of 294 patients were included. The mean ± SD gestational age at PPROM was 33.45 ± 2.01 weeks and the mean rate of PPROM before balloon removal was 25.9% (76/294). Gestational age at FETO was later in the below-umbilicus group (mean ± SD, 29.47 ± 1.29 weeks vs 29.00 ± 1.25 weeks; P = 0.002) and the duration of FETO was longer in the above-umbilicus group (median, 14.49 min (interquartile range (IQR), 8.00-21.00 min) vs 11.00 min (IQR, 7.00-14.49 min); P = 0.002). After balancing for possible confounding factors, trocar entry point below the umbilicus did not increase the risk of PPROM before balloon removal (adjusted odds ratio, 1.56 (95% CI, 0.89-2.74); P = 0.120) and had no effect on the timing of PPROM before balloon removal (adjusted hazard ratio, 1.56 (95% CI, 0.95-2.55); P = 0.080). CONCLUSION: There was no evidence that uterine entry site for FETO was correlated with the risk of PPROM before balloon removal. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Complex gastroschisis: a new indication for fetal surgery?

Gastroschisis (GS) is a congenital abdominal wall defect, in which the bowel eviscerates from the abdominal cavity. It is a non-lethal isolated anomaly and its pathogenesis is hypothesized to occur as a result of two hits: primary rupture of the 'physiological' umbilical hernia (congenital anomaly) followed by progressive damage of the eviscerated bowel (secondary injury). The second hit is thought to be caused by a combination of mesenteric ischemia from constriction in the abdominal wall defect and prolonged amniotic fluid exposure with resultant inflammatory damage, which eventually leads to bowel dysfunction and complications. GS can be classified as either simple or complex, with the latter being complicated by a combination of intestinal atresia, stenosis, perforation, volvulus and/or necrosis. Complex GS requires multiple neonatal surgeries and is associated with significantly greater postnatal morbidity and mortality than is simple GS. The intrauterine reduction of the eviscerated bowel before irreversible damage occurs and subsequent defect closure may diminish or potentially prevent the bowel damage and other fetal and neonatal complications associated with this condition. Serial prenatal amnioexchange has been studied in cases with GS as a potential intervention but never adopted because of its unproven benefit in terms of survival and bowel and lung function. We believe that recent advances in prenatal diagnosis and fetoscopic surgery justify reconsideration of the antenatal management of complex GS under the rubric of the criteria for fetal surgery established by the International Fetal Medicine and Surgery Society (IFMSS). Herein, we discuss how conditions for fetoscopic repair of complex GS might be favorable according to the IFMSS criteria, including an established natural history, an accurate prenatal diagnosis, absence of fully effective perinatal treatment due to prolonged need for neonatal intensive care, experimental evidence for fetoscopic repair and maternal and fetal safety of fetoscopy in expert fetal centers. Finally, we propose a research agenda that will help overcome barriers to progress and provide a pathway toward clinical implementation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Intrapulmonary artery Doppler to predict mortality and morbidity in fetuses with mild or moderate left-sided congenital diaphragmatic hernia.

OBJECTIVES: In fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH), prenatal detection of severe pulmonary hypoplasia is important, as fetal therapy can improve survival. Cases with mild or moderate lung hypoplasia still carry a considerable risk of mortality and morbidity, but there has been less interest in the accurate prediction of outcome in these cases. In this study of fetuses with mild or moderate isolated LCDH, we aimed to investigate: (1) the association between intrapulmonary artery (IPA) Doppler findings and mortality at discharge; (2) whether adding IPA Doppler findings improves the prediction of mortality based on lung size and liver herniation; and (3) the association between IPA Doppler findings and early neonatal morbidity. METHODS: This was a retrospective study of all consecutive fetuses assessed at the BCNatal and UZ Leuven hospitals between 2008 and 2020 with a prenatal diagnosis of isolated, non-severe LCDH, defined as observed-to-expected lung-to-head ratio (o/e-LHR) > 25%, that were managed expectantly during pregnancy followed by standardized neonatal management. An additional inclusion criterion was the availability of IPA Doppler measurements. The primary outcome was the association between IPA Doppler findings and mortality at discharge. Other predictors included o/e-LHR, liver herniation and gestational age at birth. Secondary outcomes were the association between IPA Doppler findings and the presence of pulmonary hypertension (PHT), need for supplemental oxygen at discharge and need for extracorporeal membrane oxygenation. IPA pulsatility index (PI) values were converted into Z-scores. Logistic regression analysis was performed to investigate the associations between predictor variables and outcome, and the best model was chosen based on the Nagelkerke R2 . RESULTS: Observations for 70 non-severe LCDH cases were available. Fifty-four (77%) fetuses survived until discharge. On logistic regression analysis, higher IPA-PI was associated with an increased risk of mortality (odds ratio (OR), 3.96 (95% CI, 1.62-9.70)), independently of o/e-LHR (OR, 0.87 (95% CI, 0.79-0.97)). An IPA-PI Z-score cut-off of 1.8 predicted mortality with a detection rate of 69% and specificity of 93%. Adding IPA-PI to o/e-LHR improved significantly the model's performance (Nagelkerke R2 , 46% for o/e-LHR + IPA-PI vs 28% for o/e-LHR (P < 0.002)), with a detection rate of 81% at a 10% false-positive rate. IPA-PI was associated with PHT (OR, 2.20 (95% CI, 1.01-4.59)) and need for oxygen supplementation at discharge (OR, 1.90 (95% CI, 1.10-3.40)), independently of lung size. CONCLUSIONS: In fetuses with mild or moderate LCDH, IPA-PI was associated with mortality and morbidity, independently of lung size. A model combining o/e-LHR with IPA-PI identified up to four in five cases that eventually died, despite being considered to have non-severe pulmonary hypoplasia. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal endoscopic tracheal occlusion reverses the natural history of right-sided congenital diaphragmatic hernia: European multicenter experience.

OBJECTIVE: To evaluate the neonatal outcome of fetuses with isolated right-sided congenital diaphragmatic hernia (iRCDH) based on prenatal severity indicators and antenatal management. METHODS: This was a retrospective review of prospectively collected data on consecutive cases diagnosed with iRCDH before 30 weeks' gestation in four fetal therapy centers, between January 2008 and December 2018. Data on prenatal severity assessment, antenatal management and perinatal outcome were retrieved. Univariate and multivariate logistic regression analysis were used to identify predictors of survival at discharge and early neonatal morbidity. RESULTS: Of 265 patients assessed during the study period, we excluded 40 (15%) who underwent termination of pregnancy, two cases of unexplained fetal death, two that were lost to follow-up, one for which antenatal assessment of lung hypoplasia was not available and six cases which were found to have major associated anomalies or syndromes after birth. Of the 214 fetuses with iRCDH included in the neonatal outcome analysis, 86 were managed expectantly during pregnancy and 128 underwent fetal endoscopic tracheal occlusion (FETO) with a balloon. In the expectant-management group, lung size measured by ultrasound or by magnetic resonance imaging was the only independent predictor of survival (observed-to-expected lung-to-head ratio (o/e-LHR) odds ratio (OR), 1.06 (95% CI, 1.02-1.11); P = 0.003). Until now, stratification for severe lung hypoplasia has been based on an o/e-LHR cut-off of 45%. In cases managed expectantly, the survival rate was 15% (4/27) in those with o/e-LHR ≤ 45% and 61% (36/59) for o/e-LHR > 45% (P = 0.001). However, the best o/e-LHR cut-off for the prediction of survival at discharge was 50%, with a sensitivity of 78% and specificity of 72%. In the expectantly managed group, survivors with severe pulmonary hypoplasia stayed longer in the neonatal intensive care unit than did those with mildly hypoplastic lungs. In fetuses with an o/e-LHR ≤ 45% treated with FETO, survival rate was higher than in those with similar lung size managed expectantly (49/120 (41%) vs 4/27 (15%); P = 0.014), despite higher prematurity rates (gestational age at birth: 34.4 ± 2.7 weeks vs 36.8 ± 3.0 weeks; P < 0.0001). In fetuses treated with FETO, gestational age at birth was the only predictor of survival (OR, 1.25 (95% CI, 1.04-1.50); P = 0.02). CONCLUSIONS: Antenatal measurement of lung size can predict survival in iRCDH. In fetuses with severe lung hypoplasia, FETO was associated with a significant increase in survival without an associated increase in neonatal morbidity. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Safety and efficacy of smart tracheal occlusion device in diaphragmatic hernia lamb model.

OBJECTIVE: To investigate the efficacy and safety of the 'smart' tracheal occlusion (Smart-TO) device in fetal lambs with diaphragmatic hernia (DH). METHODS: DH was created in fetal lambs on gestational day 70 (term, 145 days). Fetuses were allocated to either pregnancy continuation until term (DH group) or fetoscopic endoluminal tracheal occlusion (TO), performed using the Smart-TO balloon on gestational day 97 (DH + TO group). On gestational day 116, the presence of the balloon was confirmed on ultrasound, then the ewe was walked around a 3.0-Tesla magnetic resonance scanner for balloon deflation, which was confirmed by ultrasound immediately afterwards. At term, euthanasia was performed and the fetus retrieved. Efficacy of occlusion was assessed by the lung-to-body-weight ratio (LBWR) and lung morphometry. Safety parameters included tracheal side effects assessed by morphometry and balloon location after deflation. The unoccluded DH lambs served as a comparator. RESULTS: Six fetuses were included in the DH group and seven in the DH + TO group. All balloons deflated successfully and were expelled spontaneously from the airways. In the DH + TO group, in comparison to controls, the LBWR at birth was significantly higher (1.90 (interquartile range (IQR), 1.43-2.55) vs 1.07 (IQR, 0.93-1.46); P = 0.005), while on lung morphometry, the alveolar size was significantly increased (mean linear intercept, 47.5 (IQR, 45.6-48.1) vs 41.9 (IQR, 38.8-46.1) µm; P = 0.03); whereas airway complexity was lower (mean terminal bronchiolar density, 1.56 (IQR, 1.0-1.81) vs 2.23 (IQR, 2.14-2.40) br/mm2 ; P = 0.005). Tracheal changes on histology were minimal in both groups, but more noticeable in fetal lambs that underwent TO than in unoccluded lambs (tracheal score, 2 (IQR, 1-3) vs 0 (0-1); P = 0.03). CONCLUSIONS: In fetal lambs with DH, TO using the Smart-TO balloon is effective and safe. Occlusion can be reversed non-invasively and the deflated intact balloon expelled spontaneously from the fetal upper airways. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

New device permitting non-invasive reversal of fetal endoscopic tracheal occlusion: ex-vivo and in-vivo study.

OBJECTIVE: One of the drawbacks of fetal endoscopic tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to re-establish airway patency. The 'Smart-TO' device is a new balloon for FETO that deflates spontaneously when placed in a strong magnetic field, therefore overcoming the need for a second procedure. The safety and efficacy of this device have not yet been demonstrated. The aim of this study was to investigate the reversibility, local side effects and occlusiveness of the Smart-TO balloon, both in a simulated in-utero environment and in the fetal lamb model. METHODS: First, the reversibility of tracheal occlusion by the Smart-TO balloon was tested in a high-fidelity simulator. Following videoscopic tracheoscopic balloon insertion, the fetal mannequin was placed within a 1-L water-filled balloon to mimic the amniotic cavity. This was held by an operator in front of their abdomen, and different fetal and maternal positions were simulated to mimic the most common clinical scenarios. Following exposure to the magnetic field generated by a 1.5-T magnetic resonance (MR) machine, deflation of the Smart-TO balloon was assessed by tracheoscopy. In cases of failed deflation, the mannequin was reinserted into a water-filled balloon for additional MR exposure, up to a maximum of three times. Secondly, reversibility, occlusiveness and local effects of the Smart-TO balloon were tested in vivo in fetal lambs. Tracheal occlusion was performed in fetal lambs on gestational day 95 (term, 145 days), either using the balloon currently used in clinical practice (Goldbal2) (n = 5) or the Smart-TO balloon (n = 5). On gestational day 116, the presence of the balloon was assessed by tracheoscopy. Deflation was performed by puncture (Goldbal2) or MR exposure (Smart-TO). Six unoccluded fetal lambs served as controls. Following euthanasia, the lung-to-body-weight ratio (LBWR), lung morphometry and tracheal circumference were assessed. Local tracheal changes were measured using a hierarchical histologic scoring system. RESULTS: Ex vivo, Smart-TO balloon deflation occurred after a single MR exposure in 100% of cases in a maternal standing position with the mannequin at a height of 95 cm (n = 32), 55 cm (n = 8) or 125 cm (n = 8), as well as when the maternal position was 'lying on a stretcher' (n = 8). Three out of eight (37.5%) balloons failed to deflate at first exposure when the maternal position was 'sitting in a wheelchair'. Of these, two balloons deflated after a second MR exposure, but one balloon remained inflated after a third exposure. In vivo, all Smart-TO balloons deflated successfully. The LBWR in fetal lambs with tracheal occlusion by a Smart-TO balloon was significantly higher than that in unoccluded controls, and was comparable with that in the Goldbal2 group. There were no differences in lung morphometry and tracheal circumference between the two balloon types. Tracheal histology showed minimal changes for both balloons. CONCLUSIONS: In a simulated in-utero environment, the Smart-TO balloon was effectively deflated by exposure of the fetus in different positions to the magnetic field of a 1.5-T MR system. There was only one failure, which occurred when the mother was sitting in a wheelchair. In healthy fetal lambs, the Smart-TO balloon is as occlusive as the clinical standard Goldbal2 system and has only limited local side effects. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Synergistic mode of action of catechin, vanillic and protocatechuic acids to inhibit the adhesion of uropathogenic Escherichia coli on silicone surfaces.

AIMS: To study the individual and combined contribution of catechin, protocatechuic and vanillic acids to inhibit the adhesion of uropathogenic Escherichia coli (UPEC) on the surface of silicone catheters. METHODS AND RESULTS: The adhesion of UPEC to silicone catheters during the exposure to nonlethal concentrations of phenolic compounds was measured, as well as changes in motility, presence of fimbriae, extra-cellular polymeric substances, surface charge, hydrophobicity and membrane fluidity. The phenolic combination reduced 26-51% of motility, 1 log CFU per cm2 of adhered bacteria and 20-40% the carbohydrate and protein content in the biofilm matrix. Curli fimbriae, surface charge and cell hydrophobicity were affected to a greater extent by the phenolic combination. In the mixture, vanillic acid was the most effective for reducing bacterial adhesion, extra-polymeric substance production, motility, curli fimbriae and biofilm structure. Notwithstanding, protocatechuic acid caused major changes in the bacterial cell surface properties, whereas catechin affected the cell membrane functionality. CONCLUSION: Catechin, protocatechuic and vanillic acids have different bacterial cell targets, explaining the synergistic effect of their combination against uropathogenic E. coli. SIGNIFICANCE AND IMPACT OF STUDY: This study shows the contribution of catechin, protocatechuic and vanillic acids in producing a synergistic mixture against the adhesion of uropathogenic E. coli on silicone catheters. The action of catechin, vanillic and protocatechuic acids included specific contributions of each compound against the E. coli membrane's integrity, motility, surface properties and production of extracellular polymeric substances. Therefore, the studied mixture of phenolic compounds could be used as an antibiotic alternative to reduce urinary tract infections associated with silicone catheters.